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  • Inhibition of the Receptor Tyrosine Kinase AXL Restores Paclitaxel Chemosensitivity in Uterine Serous Cancer
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Marguerite L. Palisoul, Jeanne M. Quinn, Emily Schepers, Ian S. Hagemann, Lei Guo, Kelsey Reger, Andrea R. Hagemann, Carolyn K. McCourt, Premal H. Thaker, Matthew A. Powell, David G. Mutch, Katherine C. Fuh

    Uterine serous cancer (USC) is aggressive, and the majority of recurrent cases are chemoresistant. Because the receptor tyrosine kinase AXL promotes invasion and metastasis of USC and is implicated in chemoresistance in other cancers, we assessed the role of AXL in paclitaxel resistance in USC, determined the mechanism of action, and sought to restore chemosensitivity by inhibiting AXL in vitro and in vivo . We used short hairpin RNAs and BGB324 to knock down and inhibit AXL. We assessed sensitivity of USC cell lines to paclitaxel and measured paclitaxel intracellular accumulation in vitro in the presence or absence of AXL. We also examined the role of the epithelial–mesenchymal transition (EMT) in AXL-mediated paclitaxel resistance. Finally, we treated USC xenografts with paclitaxel, BGB324, or paclitaxel plus BGB324 and monitored tumor burden. AXL expression was higher in chemoresistant USC patient tumors and cell lines than in chemosensitive tumors and cell lines. Knockdown or inhibition of AXL increased sensitivity of USC cell lines to paclitaxel in vitro and increased cellular accumulation of paclitaxel. AXL promoted chemoresistance even in cells that underwent the EMT in vitro . Finally, in vivo studies of combination treatment with BGB324 and paclitaxel showed a greater than 51% decrease in tumor volume after 2 weeks of treatment when compared with no treatment or single-agent treatments ( P < 0.001). Our results show that AXL expression mediates chemoresistance independent of EMT and prevents accumulation of paclitaxel. This study supports the continued investigation of AXL as a clinical target, particularly in chemoresistant USC. Mol Cancer Ther; 16(12); 1–11. ©2017 AACR.

    更新日期:2017-11-19
  • Theranostic radiolabeled anti-CD20 sdAb for targeted radionuclide therapy of Non-Hodgkin Lymphoma
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Ahmet Krasniqi, Matthias D'Huyvetter, Catarina Xavier, Kevin Van der Jeught, Serge Muyldermans, José Van Der Heyden, Tony Lahoutte, Jan Tavernier, Nick Devoogdt

    Anti-CD20 radioimmunotherapy is an effective approach for therapy of relapsed or refractory CD20pos lymphomas, but faces limitations due to poor tumor penetration and undesirable pharmacokinetics of full antibodies. Camelid single-domain Ab fragments (sdAb) might circumvent some of the limitations of radiolabeled full antibodies. In this study, a set of hCD20-targeting sdAbs was generated, and their capacity to bind hCD20 was evaluated in vitro and in vivo. A lead sdAb, sdAb 9079, was selected on the basis of its specific tumor targeting and significant lower kidney accumulation compared with other sdAbs. SdAb 9079 was then radiolabeled with 68Ga and 177Lu for PET imaging and targeted therapy. The therapeutic potential of 177Lu-DTPA-sdAb was compared with that of 177Lu-DTPA-rituximab and unlabeled rituximab in mice bearing hCD20pos tumors. Radiolabeled with 68Ga, sdAb 9079 showed specific tumor uptake, with very low accumulation in nontarget organs, except kidneys. The tumor uptake of 177Lu-DTPA-sdAb 9079 after 1.5 h was 3.4 ± 1.3% ID/g, with T/B and T/M ratios of 13.3 ± 4.6 and 32.9 ± 15.6. Peak tumor accumulation of 177Lu-DTPA-rituximab was about 9 times higher, but concomitantly with high accumulation in nontarget organs and very low T/B and T/M ratios (0.8 ± 0.1 and 7.1 ± 2.4). Treatment of mice with 177Lu-DTPA-sdAb 9079 significantly prolonged median survival compared with control groups and was as effective as treatment with rituximab or its 177Lu-labeled variant. Taken together, sdAb 9079 displays promising features as a theranostic drug to treat CD20pos lymphomas. Mol Cancer Ther; 16(12); 1–12. ©2017 AACR.

    更新日期:2017-11-19
  • Lycorine promotes autophagy and apoptosis via TCRP1/Akt/mTOR axis inactivation in human hepatocellular carcinoma
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Haiyang Yu, Yuling Qiu, Xu Pang, Jian Li, Song Wu, Shuangshuang Yin, Lifeng Han, Yi Zhang, Chengyun Jin, Xiumei Gao, Wenwei Hu, Tao Wang

    Lycorine is a multifunctional bioactive compound, and it possesses potential anticancer activities. However, little is known about the underlying mechanism. In this research, we have found that lycorine significantly induces the apoptotic and autophagic capacities of hepatocellular carcinoma (HCC) cells in vitro and in vivo . Treatment with specific autophagy inhibitor (3-methyladenine/Bafilomycin A1) or knockdown of LC-3B/Atg5 by siRNA drastically enhances the apoptotic cell death effect by facilitating the switch from autophagy to apoptosis. Molecular validation mechanistically demonstrates that lycorine-induced apoptosis and autophagy in HCC cells is associated with decreased protein levels of tongue cancer resistance–associated protein 1 (TCRP1), and we further find that inhibition of TCRP1 decreases phosphorylation level of Akt and represses Akt/mTOR signaling. Finally, lycorine-induced apoptosis and autophagy suppress the growth of xenograft hepatocellular tumors without remarkable toxicity. Our results elucidate a novel molecular mechanism whereby lycorine promotes apoptosis and autophagy through the TCRP1/Akt/mTOR pathway in HCC. Our results reveal that lycorine might be a potential therapeutic agent for the treatment of HCC. Mol Cancer Ther; 16(12); 1–13. ©2017 AACR.

    更新日期:2017-11-19
  • ABC294640, a novel sphingosine kinase 2 inhibitor induces oncogenic virus infected cell autophagic death and represses tumor growth
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Lu Dai, Aiping Bai, Charles D. Smith, Paulo C. Rodriguez, Fangyou Yu, Zhiqiang Qin

    Kaposi sarcoma–associated herpes virus (KSHV) is the etiologic agent of several malignancies, including Kaposi sarcoma and primary effusion lymphoma (PEL), which preferentially arise in HIV+ patients and lack effective treatment. Sphingosine kinase 2 (SphK2) is a key factor within sphingolipid metabolism, responsible for the conversion of proapoptotic ceramides to antiapoptotic sphingosine-1-phosphate (S1P). We have previously demonstrated that targeting SphK2 using a novel selective inhibitor, ABC294640, leads to the accumulation of intracellular ceramides and induces apoptosis in KSHV-infected primary endothelial cells and PEL tumor cells but not in uninfected cells. In this study, we found that ABC294640 induces autophagic death instead of apoptosis in a KSHV long-term–infected immortalized endothelial cell-line, TIVE-LTC, but not in uninfected TIVE cells, through the upregulation of LC3B protein. Transcriptomic analysis indicates that many genes related to cellular stress responses, cell cycle/proliferation, and cellular metabolic process are altered in TIVE-LTC exposed to ABC294640. One of the candidates, Egr-1 , was found to directly regulate LC3B expression and was required for the ABC294640-induced autophagic death. By using a Kaposi sarcoma–like nude mice model with TIVE-LTC, we found that ABC294640 treatment significantly suppressed KSHV-induced tumor growth in vivo , which indicates that targeting sphingolipid metabolism, especially SphK2, may represent a promising therapeutic strategy against KSHV-related malignancies. Mol Cancer Ther; 16(12); 1–11. ©2017 AACR.

    更新日期:2017-11-19
  • Basal-A Triple Negative Breast Cancer Cells Selectively Rely on RNA Splicing for Survival
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Stefanie Chan, Praveen Sridhar, Rory Kirchner, Ying Jie Lock, Zach Herbert, Silvia Buonamici, Peter Smith, Judy Lieberman, Fabio Petrocca

    Prognosis of triple-negative breast cancer (TNBC) remains poor. To identify shared and selective vulnerabilities of basal-like TNBC, the most common TNBC subtype, a directed siRNA lethality screen was performed in 7 human breast cancer cell lines, focusing on 154 previously identified dependency genes of 1 TNBC line. Thirty common dependency genes were identified, including multiple proteasome and RNA splicing genes, especially those associated with the U4/U6.U5 tri-snRNP complex (e.g., PRPF8, PRPF38A ). PRPF8 or PRPF38A knockdown or the splicing modulator E7107 led to widespread intronic retention and altered splicing of transcripts involved in multiple basal-like TNBC dependencies, including protein homeostasis, mitosis, and apoptosis. E7107 treatment suppressed the growth of basal-A TNBC cell line and patient-derived basal-like TNBC xenografts at a well-tolerated dose. The antitumor response was enhanced by adding the proteasome inhibitor bortezomib. Thus, inhibiting both splicing and the proteasome might be an effective approach for treating basal-like TNBC. Mol Cancer Ther; 16(12); 1–13. ©2017 AACR.

    更新日期:2017-11-19
  • Gamma secretase inhibition by BMS-906024 enhances efficacy of paclitaxel in lung adenocarcinoma
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Katherine M. Morgan, Bruce S. Fischer, Francis Y. Lee, Jamie J. Shah, Joseph R. Bertino, Jeffrey Rosenfeld, Amartya Singh, Hossein Khiabanian, Sharon R. Pine

    Notch signaling is aberrantly activated in approximately one third of non–small cell lung cancers (NSCLC). We characterized the interaction between BMS-906024, a clinically relevant Notch gamma secretase inhibitor, and front-line chemotherapy in preclinical models of NSCLC. Chemosensitivity assays were performed on 14 human NSCLC cell lines. There was significantly greater synergy between BMS-906024 and paclitaxel than BMS-906024 and cisplatin [mean combination index (CI) value, 0.54 and 0.85, respectively, P = 0.01]. On an extended panel of 31 NSCLC cell lines, 25 of which were adenocarcinoma, the synergy between BMS-906024 and paclitaxel was significantly greater in KRAS- and BRAF-wildtype than KRAS- or BRAF-mutant cells (mean CI, 0.43 vs. 0.90, respectively; P = 0.003). Paclitaxel-induced Notch1 activation was associated with synergy between BMS-906024 and paclitaxel in the KRAS- or BRAF-mutant group. Knockdown of mutant KRAS increased the synergy between BMS-906024 and paclitaxel in heterozygous KRAS-mutant cell lines. Among KRAS- or BRAF-mutant NSCLC, there was a significant correlation between synergy and mutant or null TP53 status, as well as between synergy and a low H2O2 pathway signature. Exogenous overexpression of activated Notch1 or Notch3 had no effect on the enhanced sensitivity of NSCLC to paclitaxel by BMS-906024. In vivo studies with cell line– and patient-derived lung adenocarcinoma xenografts confirmed enhanced antitumor activity for BMS-906024 plus paclitaxel versus either drug alone via decreased cell proliferation and increased apoptosis. These results show that BMS-906024 sensitizes NSCLC to paclitaxel and that wild-type KRAS and BRAF status may predict better patient response to the combination therapy. Mol Cancer Ther; 16(12); 1–11. ©2017 AACR.

    更新日期:2017-11-19
  • Simultaneous targeting of two distinct epitopes on MET effectively inhibits MET- and HGF-driven tumor growth by multiple mechanisms
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Michael M Grandal, Serhiy Havrylov, Thomas Tuxen Poulsen, Klaus Koefoed, Anna Dahlman, Gunther R Galler, Paolo Conrotto, Sara Collins, Karsten W Eriksen, Dafna Kaufman, George F Vande Woude, Helle J. Jacobsen, Ivan D. Horak, Michael Kragh, Johan Lantto, Thomas Bouquin, Morag Park, Mikkel Wandahl Pedersen

    Increased MET activity is linked with poor prognosis and outcome in several human cancers currently lacking targeted therapies. Here, we report on the characterization of Sym015, an antibody mixture composed of two humanized IgG1 antibodies against nonoverlapping epitopes of MET. Sym015 was selected by high-throughput screening searching for antibody mixtures with superior growth-inhibitory activity against MET-dependent cell lines. Synergistic inhibitory activity of the antibodies comprising Sym015 was observed in several cancer cell lines harboring amplified MET locus and was confirmed in vivo . Sym015 was found to exert its activity via multiple mechanisms. It disrupted interaction of MET with the HGF ligand and prompted activity-independent internalization and degradation of the receptor. In addition, Sym015 induced high levels of CDC and ADCC in vitro . The importance of these effector functions was confirmed in vivo using an Fc-effector function–attenuated version of Sym015. The enhanced effect of the two antibodies in Sym015 on both MET degradation and CDC and ADCC is predicted to render Sym015 superior to single antibodies targeting MET. Our results demonstrate strong potential for use of Sym015 as a therapeutic antibody mixture for treatment of MET-driven tumors. Sym015 is currently being tested in a phase I dose escalation clinical trial ([NCT02648724][1]). Mol Cancer Ther; 16(12); 1–12. ©2017 AACR. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02648724&atom=%2Fmolcanther%2Fearly%2F2017%2F11%2F17%2F1535-7163.MCT-17-0374.atom

    更新日期:2017-11-19
  • CCR5-dependent homing of T regulatory cells to the tumor microenvironment contributes to skin squamous cell carcinoma development
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Carine Ervolino de Oliveira, Thais Helena Gasparoto, Claudia Ramos Pinheiro, Nádia Ghinelli Amôr, Maria Renata Sales Nogueira, Ramon Kaneno, Gustavo Pompermaier Garlet, Vanessa Soares Lara, João Santana da Silva, Karen Angélica Cavassani, Ana Paula Campanelli

    Squamous cell carcinoma (SCC) is one of the most common human cancers worldwide. Recent studies show that regulatory T cells (Treg) have a critical role in the modulation of an antitumor immune response, and consequently the SCC development. Because the accumulation of Tregs at the tumor site is, in part, due to selective recruitment through CCR5- and CCR5-associated chemokines, we investigated the role of CCR5 in the SCC development. Our findings showed that CCR5-deficient mice (CCR5KO) were efficient in controlling papilloma's incidence when compared with wild-type mice. Analysis of tumor lesions in wild-type (WT) and CCR5KO mice revealed that lack of CCR5 lead to significant reduction in frequency of Tregs and increased of CD4 T cells into the tumors. Moreover, the adoptive transfer of naturally occurring Tregs CD4+CD25+CCR5+, CD4+CD25−CCR5+ or CD8+CCR5+ conventional T cells to CCR5KO mice resulted in an increased papilloma incidence. Interestingly, adoptive transfer of WT CD4+CD25+CCR5+ cells to CCR5KO mice induced more undifferentiated SCC lesions, characterized by higher infiltration of macrophages and dendritic cells. In this study, we also demonstrated that Treg migration to the tumor microenvironment is mediated by CCR5, and these cells are promoting tumor growth via inhibition of antitumor cells such as cytotoxic CD8+ T cells. Our findings reinforce the therapeutic potential of CCR5 inhibition for cancer treatment, and indicate an attractive approach for SCC treatment. Mol Cancer Ther; 16(12); 1–10. ©2017 AACR.

    更新日期:2017-11-19
  • Interleukin 4 receptor-targeted pro-apoptotic peptide blocks tumor growth and metastasis by enhancing anti-tumor immunity
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Sri Murugan Poongkavithai Vadevoo, Jung-Eun Kim, Gowri Rangaswamy Gunassekaran, Hyun-Kyung Jung, Lianhua Chi, Dong Eon Kim, Seung-Hyo Lee, Sin-Hyeog Im, Byungheon Lee

    Cellular cross-talk between tumors and M2-polarized tumor-associated macrophages (TAM) favors tumor progression. Upregulation of IL4 receptor (IL4R) is observed in diverse tumors and TAMs. We tested whether an IL4R-targeted proapoptotic peptide could inhibit tumor progression. The IL4R-binding peptide (IL4RPep-1) preferentially bound to IL4R-expressing tumor cells and M2-polarized macrophages both in vitro and in 4T1 breast tumors in vivo . To selectively kill IL4R-expressing cells, we designed an IL4R-targeted proapoptotic peptide, IL4RPep-1-K, by adding the proapoptotic peptide (KLAKLAK)2 to the end of IL4RPep-1. IL4RPep-1-K exerted selective cytotoxicity against diverse IL4R-expressing tumor cells and M2-polarized macrophages. Systemic administration of IL4RPep-1-K inhibited tumor growth and metastasis in 4T1 breast tumor-bearing mice. Interestingly, IL4RPep-1-K treatment increased the number of activated cytotoxic CD8+ T cells while reducing the numbers of immunosuppressive regulatory T cells and M2-polarized TAMs. No significant systemic side effects were observed. These results suggest that IL4R-targeted proapoptotic peptide has potential for treating diverse IL4R-expressing cancers. Mol Cancer Ther; 16(12); 1–14. ©2017 AACR.

    更新日期:2017-11-19
  • Discovery of a Highly Selective NAMPT Inhibitor That Demonstrates Robust Efficacy and Improved Retinal Toxicity with Nicotinic Acid Co-administration
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Genshi Zhao, Colin F Green, Yu-Hua Hui, Lourdes Prieto, Robert Shepard, Sucai Dong, Tao Wang, Bo Tan, Xueqian Gong, Lisa Kays, Robert L Johnson, Wenjuan Wu, Shobha Bhattachar, Miriam Del Prado, James R Gillig, Maria-Carmen Fernandez, Ken D Roth, Sean Buchanan, Ming-Shang Kuo, Sandaruwan Geeganage, Timothy P. Burkholder

    NAMPT, an enzyme essential for NAD+ biosynthesis, has been extensively studied as an anticancer target for developing potential novel therapeutics. Several NAMPT inhibitors have been discovered, some of which have been subjected to clinical investigations. Yet, the on-target hematological and retinal toxicities have hampered their clinical development. In this study, we report the discovery of a unique NAMPT inhibitor, LSN3154567. This molecule is highly selective and has a potent and broad spectrum of anticancer activity. Its inhibitory activity can be rescued with nicotinic acid (NA) against the cell lines proficient, but not those deficient in NAPRT1, essential for converting NA to NAD+. LSN3154567 also exhibits robust efficacy in multiple tumor models deficient in NAPRT1. Importantly, this molecule when coadministered with NA does not cause observable retinal and hematological toxicities in the rodents, yet still retains robust efficacy. Thus, LSN3154567 has the potential to be further developed clinically into a novel cancer therapeutic. Mol Cancer Ther; 16(12); 1–12. ©2017 AACR.

    更新日期:2017-11-19
  • HPMA-Copolymer Nanocarrier Targets Tumor-Associated Macrophages in Primary and Metastatic Breast Cancer
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Melissa N. Zimel, Chloe B. Horowitz, Vinagolu K. Rajasekhar, Alexander B. Christ, Xin Wei, Jianbo Wu, Paulina M. Wojnarowicz, Dong Wang, Steven R. Goldring, P. Edward Purdue, John H. Healey

    Polymeric nanocarriers such as N -(2-hydroxypropyl) methacrylamide (HPMA) copolymers deliver drugs to solid tumors and avoid the systemic toxicity of conventional chemotherapy. Because HPMA copolymers can target sites of inflammation and accumulate within innate immune cells, we hypothesized that HPMA copolymers could target tumor-associated macrophages (TAM) in both primary and metastatic tumor microenvironments. We verified this hypothesis, first in preliminary experiments with isolated bone marrow macrophage cultures in vitro and subsequently in a spontaneously metastatic murine breast cancer model generated from a well-established, cytogenetically characterized 4T1 breast cancer cell line. Using our standardized experimental conditions, we detected primary orthotopic tumor growth at 7 days and metastatic tumors at 28 days after orthotopic transplantation of 4T1 cells into the mammary fat pad. We investigated the uptake of HPMA copolymer conjugated with Alexa Fluor 647 and folic acid (P-Alexa647-FA) and HPMA copolymer conjugated with IRDye 800CW (P-IRDye), following their retroorbital injection into the primary and metastatic tumor-bearing mice. A significant uptake of P-IRDye was observed at all primary and metastatic tumor sites in these mice, and the P-Alexa647-FA signal was found specifically within CD11b+ TAMs costained with pan-macrophage marker CD68. These findings demonstrate, for the first time, a novel capacity of a P-Alexa647-FA conjugate to colocalize to CD11b+CD68+ TAMs in both primary and metastatic breast tumors. This underscores the potential of this HPMA nanocarrier to deliver functional therapeutics that specifically target tumor-promoting macrophage activation and/or polarization during tumor development. Mol Cancer Ther; 16(12); 1–10. ©2017 AACR.

    更新日期:2017-11-19
  • A ROLE FOR CXCR4 IN PERITONEAL AND HEMATOGENOUS OVARIAN CANCER DISSEMINATION
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Agnes Figueras, Elisenda Alsina-Sanchís, Alvaro Lahiguera, Manuel Abreu, Laura Muinelo-Romay, Gema Moreno-Bueno, Oriol Casanovas, Mariona Graupera, Xavier Matias-Guiu, August Vidal, Alberto Villanueva, Francesc Viñals

    Epithelial ovarian cancer is characterized by a low recovery rate because the disease is typically diagnosed at an advanced stage, by which time, most patients (80%) already exhibit disseminated neoplasia. The cytokine receptor CXCR4 has been implicated in the development of metastasis in various tumor types. Using a patient-derived tissue macroarray and mRNA expression analysis we observed high CXCR4 levels in high-grade serous epithelial ovarian carcinomas, the most metastatic tumor, compared with those in endometrioid carcinomas. CXCR4 inhibition by treatment with the CXCR4 antagonist AMD3100 or by expression of shRNA anti-CXCR4 similarly inhibited angiogenesis in several models of ovarian carcinomas orthotopically grown in nude mice, but the effect on tumor growth was correlated with the levels of CXCR4 expression. Moreover, CXCR4 inhibition completely blocked dissemination and metastasis. This effect was associated with reduced levels of active Src, active ERKs, the inhibition of EMT transition and block of hematogenous ovarian cancer dissemination decreasing circulating human tumoral cells (CTCs). In tumors, CXCR4-expressing cells also had more mesenchymal characteristics. In conclusion, our results indicate that CXCR4 expression confers a proinvasive phenotype to ovarian carcinoma cells. Thus anti-CXCR4 therapy is a possible agent for a complementary treatment of advanced disseminated epithelial high-grade serous ovarian cancer patients.

    更新日期:2017-11-19
  • CAT-02-106, a site-specifically conjugated anti-CD22 antibody bearing an MDR1-resistant maytansine payload yields excellent efficacy and safety in preclinical models
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Penelope M Drake, Adam Carlson, Jesse M McFarland, Stefanie Banas, Robyn M Barfield, Wesley Zmolek, Yun Cheol Kim, Betty C.B. Huang, Romas Kudirka, David Rabuka

    Hematologically-derived tumors make up ~10% of all newly-diagnosed cancer cases in the U.S. Of these, the non-Hodgkin lymphoma (NHL) designation describes a diverse group of cancers that collectively rank among the top 10 most commonly diagnosed cancers worldwide. Although long-term survival trends are improving, there remains a significant unmet clinical need for treatments to help patients with relapsed or refractory disease, one cause of which is drug efflux through upregulation of xenobiotic pumps, such as MDR1. CD22 is a clinically-validated target for the treatment of NHL, but no anti-CD22 agents have yet been approved for this indication. Recent approval of an anti-CD22 antibody-drug conjugate (ADC) for the treatment of relapsed/refractory ALL supports the rationale for targeting this protein. An opportunity exists for a next-generation anti-CD22 antibody-drug conjugate (ADC) to address unmet medical needs in the relapsed/refractory NHL population. We describe a site-specifically-conjugated antibody-drug conjugate, made using aldehyde tag technology, targeted against CD22 and bearing a noncleavable maytansine payload that is resistant to MDR1-mediated efflux. The construct was efficacious against CD22+ NHL xenografts and could be repeatedly dosed in cynomolgus monkeys at 60 mg/kg with no observed significantly adverse effects. Exposure to total ADC at these doses (as assessed by AUC0-inf) indicated that the exposure needed to achieve efficacy was below tolerable limits. Together, the data suggest that this drug has the potential to be used effectively in patients with CD22+ tumors that have developed MDR1-related resistance to prior therapies.

    更新日期:2017-11-16
  • Characterization of SGN-CD123A, a potent CD123-directed antibody-drug conjugate for acute myeloid leukemia
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Fu Li, May Kung Sutherland, Changpu Yu, Roland B Walter, Lori Westendorf, John Valliere-Douglass, Lucy Pan, Ashley Cronkite, Django Sussman, Kerry Klussman, Michelle Ulrich, Martha E. Anderson, Ivan J. Stone, Weiping Zeng, Mechthild Jonas, Timothy S. Lewis, Maitrayee Goswami, Sa A Wang, Peter D. Senter, Che-Leung Law, Eric J. Feldman, Dennis R. Benjamin

    Treatment choices for acute myeloid leukemia (AML) patients resistant to conventional chemotherapies are limited and novel therapeutic agents are needed. Interleukin-3 receptor alpha (IL-3Rα, or CD123) is expressed on the majority of AML blasts and there is evidence that its expression is increased on leukemic relative to normal hematopoietic stem cells, which makes it an attractive target for antibody-based therapy. Here we report the generation and preclinical characterization of SGN-CD123A, an antibody-drug conjugate utilizing the pyrrolobenzodiazepine dimer (PBD) linker and a humanized CD123 antibody with engineered cysteines for site-specific conjugation. Mechanistically, SGN-CD123A induces activation of DNA damage response pathways, cell cycle changes, and apoptosis in AML cells. In vitro, SGN-CD123A mediated potent cytotoxicity of 11/12 CD123+ AML cell lines and 20/23 primary samples from AML patients, including those with unfavorable cytogenetic profiles or FLT3 mutations. In vivo, SGN-CD123A treatment led to AML eradication in a disseminated disease model, remission in a subcutaneous xenograft model, and significant growth delay in a multidrug resistance xenograft model. Moreover, SGN-CD123A also resulted in durable complete remission of a patient-derived xenograft AML model. When combined with a FLT3 inhibitor quizartinib, SGN-CD123A enhanced the activity of quizartinib against two FLT3-mutated xenograft models. Overall, these data demonstrate that SGN-CD123A is a potent anti-leukemic agent, supporting an ongoing trial to evaluate its safety and efficacy in AML patients ([NCT02848248][1]). [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02848248&atom=%2Fmolcanther%2Fearly%2F2017%2F11%2F15%2F1535-7163.MCT-17-0742.atom

    更新日期:2017-11-16
  • Pharmacologic inhibition of the menin-MLL interaction leads to transcriptional repression of PEG10 and blocks hepatocellular carcinoma
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Katarzyna Kempinska, Bhavna Malik, Dmitry Borkin, Szymon Klossowski, Shirish Shukla, Hongzhi Miao, Jingya Wang, Tomasz Cierpicki, Jolanta Grembecka

    Hepatocellular carcinoma (HCC) accounts for ~85% of malignant liver tumors and results in 600,000 deaths each year, emphasizing the need for new therapies. Upregulation of menin was reported in HCC patients and high levels of menin correlate with poor patient prognosis. The protein-protein interaction between menin and histone methyltransferase Mixed Lineage Leukemia 1 (MLL1) plays an important role in the development of HCC, implying that pharmacologic inhibition of this interaction could lead to new therapeutic strategy for the HCC patients. Here, we demonstrate that the menin-MLL inhibitor MI-503 shows anti-tumor activity in in vitro and in vivo models of HCC and reveal the potential mechanism of menin contribution to HCC. Treatment with MI-503 selectively kills various HCC cell lines and this effect is significantly enhanced by a combination of MI-503 with sorafenib, the standard of care therapy for HCC. Furthermore, MI-503 reduces sphere formation and cell migration in in vitro HCC models. When applied in vivo, MI-503 gives a strong anti-tumor effect both as a single agent and in combination with sorafenib in mice xenograft models of HCC. Mechanistically, treatment with MI-503 downregulates expression of several genes known to play a critical role in proliferation and migration of HCC cells, including PEG10, and displaces the menin-MLL1 complex from the PEG10 promoter, resulting in reduced H3K4 methylation and transcriptional repression. Overall, our studies reveal a mechanistic link between menin and genes involved in HCC and demonstrate that pharmacologic inhibition of the menin-MLL interaction might represent a promising therapeutic approach for HCC.

    更新日期:2017-11-16
  • JQ1 induces DNA damage and apoptosis, and inhibits tumor growth in a patient-derived xenograft model of cholangiocarcinoma
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Patrick L Garcia, Aubrey L Miller, Tracy L Gamblin, Leona N Council, John D Christein, J. Pablo Arnoletti, Marty J Heslin, Sushanth Reddy, Joseph H Richardson, Xiangqin Cui, Robert C. A. M. van Waardenburg, James E. Bradner, Eddy S. Yang, Karina J Yoon

    Cholangiocarcinoma (CCA) is a fatal disease with a five-year survival of <30%. For a majority of patients chemotherapy is the only therapeutic option, and virtually all patients relapse. Gemcitabine is the frontline agent for treatment of CCA. Patients treated with gemcitabine monotherapy survive ~8 months. Combining this agent with cisplatin increases survival by ~3 months, but neither regimen produces durable remissions. The molecular etiology of this disease is poorly understood. To facilitate molecular characterization and development of effective therapies for CCA, we established a panel of patient-derived xenograft (PDX) models of CCA. We used two of these models to investigate the anti-tumor efficacy and mechanism of action of the bromodomain inhibitor JQ1, an agent that has not been evaluated for the treatment of CCA. The data show that JQ1 suppressed the growth of the CCA PDX model CCA2, and demonstrate that growth suppression was concomitant with inhibition of c-Myc protein expression. A second model (CCA1) was JQ1-insensitive, with tumor progression and c-Myc expression unaffected by exposure to this agent. Also selective to CCA2 tumors, JQ1 induced DNA damage and apoptosis, and downregulated multiple c-Myc transcriptional targets that regulate cell cycle progression and DNA repair. These findings suggest that c-Myc inhibition and several of its transcriptional targets may contribute to the mechanism of action of JQ1 in this tumor type. We conclude that BET inhibitors such as JQ1 warrant further investigation for the treatment of CCA.

    更新日期:2017-11-16
  • Targeted Delivery of STAT-3 Modulator to Breast Cancer Stem Like Cells Down-regulates a Series of Stem-ness Genes
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Santosh K Misra, Arun De, Dipanjan Pan

    Cancer stem cells are known to be controlled by pathways that are dormant in normal adult cells, e.g. PTEN, which is a negative regulator of transcription factor STAT3. STAT3 regulates genes that are involved in stem cell self-renewal and thus represents a novel therapeutic target of enormous clinical significance. Studies on breast cancer stem cells (BCSCs) have been also significantly correlated with STATs. We describe here for the first time a novel strategy to selectively target CSCs and to induce downregulation of STAT3 downstream target genes reducing expression of series of 'stem-ness genes' in treated tumors. In vitro and in vivo experiments were performed to evaluate functional activity with gene and protein expression studies. The results of the study indicate that this targeted delivery approach deactivates STAT3 causing a reduction of CD44+/CD24-ve cancer stem cell populations with aptly tracked gene and protein regulations of "stem-ness" characteristics.

    更新日期:2017-11-15
  • Evaluation of CDK12 Protein Expression as a Potential Novel Biomarker for DNA Damage Response Targeted Therapies in Breast Cancer
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Kalnisha Naidoo, Patty T. Wai, Sarah L Maguire, Frances Daley, Syed Haider, Divya Kriplani, James Campbell, Hasan Mirza, Anita Grigoriadis, Andrew Tutt, Paul M Moseley, Tarek M. A. Abdel-Fatah, Stephen YT Chan, Srinivasan Madhusudan, Emad A Rakha, Ian O Ellis, Christopher J. Lord, Yinyin Yuan, Andrew R Green, Rachael Natrajan

    Disruption of Cyclin Dependent Kinase 12 (CDK12) is known to lead to defects in DNA repair and sensitivity to platinum salts and poly(ADP-ribose) polymerase 1/2 inhibitors. However, CDK12 has also been proposed as an oncogene in breast cancer. We therefore aimed to assess the frequency and distribution of CDK12 protein expression by immunohistochemistry (IHC) in independent cohorts of breast cancer and correlate this with outcome and genomic status. We found that 21% of primary unselected breast cancers were CDK12 high, and 10.5% were absent, by IHC. CDK12 positivity correlated with HER2 positivity but was not an independent predictor of breast cancer specific survival taking HER2 status into account, however absent CDK12 protein expression significantly correlated with a triple negative phenotype. Interestingly, CDK12 protein absence was associated with reduced expression of a number of DDR proteins including ATR, Ku70/Ku80, PARP1, DNA-PK and gamma-H2AX, suggesting a novel mechanism of CDK12 associated DDR dysregulation in breast cancer. Our data suggest that diagnostic IHC quantification of CDK12 in BC is feasible, with CDK12 absence possibly signifying defective DDR function. This may have important therapeutic implications, particularly for triple negative breast cancers.

    更新日期:2017-11-15
  • Response and resistance to paradox breaking BRAF inhibitor in melanomas in vivo and ex vivo
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Edward J. Hartsough, Curtis H. Kugel, Michael J. Vido, Adam C. Berger, Timothy J. Purwin, Allison Goldberg, Michael A. Davies, Matthew J. Schiewer, Karen E. Knudsen, Gideon Bollag, Andrew E. Aplin

    FDA-approved BRAF inhibitors produce high response rates and improve overall survival in patients with BRAF V600E/K mutant melanoma, but are linked to pathologies associated with paradoxical ERK1/2 activation in wild-type BRAF cells. To overcome this limitation, a next-generation paradox breaking RAF inhibitor (PLX8394) has been designed. Here we show that by using a quantitative reporter assay, PLX8394 rapidly suppressed ERK1/2 reporter activity and growth of mutant BRAF melanoma xenografts. Ex vivo treatment of xenografts and use of a patient-derived explant system (PDeX) revealed that PLX8394 suppressed ERK1/2 signaling and elicited apoptosis more effectively than the FDA-approved BRAF inhibitor, vemurafenib. Furthermore, PLX8394 was efficacious against vemurafenib-resistant BRAF splice-variant expressing tumors and reduced splice-variant homodimerization. Importantly, PLX8394 did not induce paradoxical activation of ERK1/2 in wild-type BRAF cell lines or PDeX. Continued in vivo dosing of xenografts with PLX8394 led to the development of acquired resistance via ERK1/2 reactivation through heterogeneous mechanisms; however, resistant cells were found to have differential sensitivity to ERK1/2 inhibitor. These findings highlight the efficacy of a paradox-breaking selective BRAF inhibitor and the use of PDeX system to test efficacy of therapeutic agents.

    更新日期:2017-11-15
  • Therapeutic Impact of Nanoparticle Therapy Targeting Tumor Associate Macrophages
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Courtney Penn, Kun Yang, Hong Zong, Jae-Young Lim, Alex Cole, Dongli Yang, James Baker, Sascha N. Goonewardena, Ronald J. Buckanovich

    Antiangiogenic therapies, despite initial encouragement, have demonstrated a limited benefit in ovarian cancer. Laboratory studies suggest anti-angiogenic therapy induced hypoxia can induce tumor "stemness' as resistance to antiangiogenic therapy develops and limits the therapeutic benefit. Resistance to antiangiogenic therapy and an induction of tumor stemness may be mediated by proangiogenic tumor associated macrophages (TAMs). As such TAMs have been proposed as a therapeutic target. We demonstrate here that ovarian TAMs express high levels of the folate receptor-2 (FOLR2) and can be selectively targeted using G5-dendrimer nanoparticles using methotrexate as both a ligand and a toxin. G5-methotrexate (G5-MTX) Nps deplete tumor associated macrophages in both solid tumor and ascites models of ovarian cancer. As a therapeutic these nanoparticles are more effective than cisplatin. Importantly, these nanoparticles could (i) overcome resistance to anti-angiogenic therapy, (ii) prevent antiangiogenic therapy induced increases in cancer stem-like cells in both murine and human tumor cell models, and (iii) prevent anti-angiogenic therapy induced increases in VEGF-C (iv) prevent anti-angiogenic therapy induce BRCA1 gene expression. Combine this work strongly supports the development of TAM targeted nanoparticle therapy.

    更新日期:2017-11-15
  • Clinical application of circulating tumor DNA in the genetic analysis of patients with advanced GIST
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Hao Xu, Liang Chen, Yang Shao, Dongqin Zhu, Xiaofei Zhi, Qiang Zhang, Fengyuan Li, Jianghao Xu, Xisheng Liu, Zekuan Xu

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of digestive tract. In the past, tissue biopsy was the main method for the diagnosis of GISTs. While circulating tumor DNA (ctDNA) detection by next-generation sequencing (NGS) may be a feasible and replaceable method for diagnosis of GISTs. We retrospectively analyzed the data for ctDNA and tissue DNA detection from 32 advanced GIST patients. We found that NGS obviously increased the positive rate of ctDNA detection. ctDNA detection identified rare mutations that were not detected in tissue DNA detection. Tumor size and Ki-67 were significant influencing factors of the positive rate of ctDNA detection and concordance between ctDNA and tissue DNA detection. In all patients, the concordance rate between ctDNA and tissue DNA detection was 71.9%, with moderate concordance. But the concordance was strong for patients with tumor size>10cm or Ki-67>5%. Tumor size, mitotic figure, Ki-67 and ctDNA mutation type were the significant influencing factors of prognosis, but only tumor size and ctDNA mutation type were the independent prognostic factors for advanced GIST patients. We confirmed that ctDNA detection by NGS is a feasible and promising method for the diagnosis and prognosis of advanced GIST patients.

    更新日期:2017-11-15
  • The Mutational Landscape of Gastrointestinal Malignancies as Reflected by Circulating Tumor DNA
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Paul Riviere, Paul T Fanta, Sadakatsu Ikeda, Joel Baumgartner, Gregory M Heestand, Razelle Kurzrock

    We aimed to assess the utility of a novel, non-invasive method of detecting genomic alterations in patients with gastrointestinal malignancies i.e., the use of liquid biopsies to obtain blood-derived circulating tumor DNA (ctDNA) through an analysis of the genomic landscape of ctDNA (68 genes) from 213 patients with advanced gastrointestinal cancers. The most common cancer types were colorectal adenocarcinoma (N=55 (26%)), appendiceal adenocarcinoma (N=46 (22%)), hepatocellular carcinoma (N=31 (15%)), and pancreatic ductal adenocarcinoma (N=25 (12%)). The majority of patients (58%) had >1 characterized alteration (excluded variants of unknown significance). The median number of characterized alterations was 1 (range, 0-13). The number of detected alterations per patient varied between different cancer types: in hepatocellular carcinoma, 74% of patients (23/31) had >1 characterized alteration(s) versus 24% of appendiceal adenocarcinoma patients (11/46). The median percent ctDNA among characterized alterations was 2.50% (interquartile range, 0.76-8.96%). Overall, 95% of patients (117/123) had distinct molecular portfolios with 143 unique characterized alterations within 56 genes. Overall concordance rates of 96%, 94%, 95%, and 91%, respectively, were found between ctDNA and tissue-biopsy (N = 105 patients) in the four most common alterations (KRAS amplification, MYC amplification, KRAS G12V, and EGFR amplification). Of the 123 patients with characterized alterations, >99% (122/123) had one or more alterations potentially actionable by experimental or approved drugs. These observations suggest that many patients with gastrointestinal tumors, including difficult-to-biopsy malignancies like hepatocellular cancers, frequently have discernible and pharmacologically tractable ctDNA alterations.

    更新日期:2017-11-15
  • IMMU-140, a novel SN-38-antibody-drug conjugate targeting HLA-DR, mediates dual cytotoxic effects in hematological cancers and malignant melanoma
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Thomas M. Cardillo, Serengulam V. Govindan, Maria B. Zalath, Diane L Rossi, Yang Wang, Chien-Hsing Chang, David M. Goldenberg

    HLA-DR is a member of the MHC class II antigen family expressed on hematological and solid tumors.  Antibodies directed against HLA-DR have demonstrated some clinical success, but toxicities limited development.  IMMU-140 is an anti-HLA-DR antibody-drug conjugate comprised of the active metabolite of irinotecan, SN-38, conjugated to a humanized anti-HLA-DR IgG4 antibody (IMMU-114); the IgG4 naked antibody is devoid of immune functions. Our aim was to determine if SN-38, the metabolite of a drug not commonly used in hematopoietic cancers, would be effective and safe when targeted to HLA-DR-expressing tumors.  In vitro , IMMU-140 had dual-therapeutic mechanisms, as evidenced by its retention of non-overlapping anti-HLA-DR non-classical apoptotic signaling and classical apoptosis mediated by its SN-38 payload.   In seven human disease models (acute lymphocytic leukemia [ALL], chronic lymphocytic leukemia [CLL], multiple myeloma [MM], acute myeloid leukemia [AML], diffuse large B-cell lymphoma [DLBCL], Hodgkin lymphoma [HL], and melanoma), IMMU-140 provided significant therapeutic efficacy compared to controls, in vivo and in 3D spheroid models.  Except for MM and HL, IMMU-140 imparted significantly improved antitumor effects compared to parental IMMU-114.  Even in intractable AML and ALL, where IMMU-114 only had modest antitumor effects,   IMMU-140 therapy mediated >80% improvement in survival.  Therapy was well-tolerated, as demonstrated by no marked loss in body weight.  Combined with doxorubicin, IMMU-140 produced significantly greater antitumor effects in HL than with monotherapy and without any added toxicity.   The dual-therapeutic action of IMMU-140 resulted in promising therapeutic activity in a range of hematopoietic tumors and melanoma, and therefore warrants clinical development.

    更新日期:2017-11-15
  • Ceritinib enhances the efficacy of trametinib in BRAF/NRAS-wild type melanoma cell lines
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Daniel Verduzco, Brent M. Kuenzi, Fumi Kinose, Vernon K. Sondak, Zeynep Eroglu, Uwe Rix, Keiran S. M. Smalley

    Targeted therapy options are currently lacking for the heterogeneous population of patients whose melanomas lack BRAF or NRAS mutations (~35% of cases). We undertook a chemical biology screen to identify potential novel drug targets for this understudied group of tumors. Screening a panel of 8 BRAF/NRAS-WT melanoma cell lines against 240 targeted drugs identified ceritinib and trametinib as potential hits with single agent activity. Ceritinib enhanced the efficacy of trametinib across the majority of the BRAF/NRAS-WT cell lines, and the combination showed increased cytotoxicity in both 3D spheroid culture and long-term colony formation experiments. Co-administration of ceritinib and trametinib led to robust inhibition of tumor growth in an in vivo xenograft BRAF/NRAS-WT melanoma model; this was not due to ALK inhibition by ceritinib. Mechanistic studies showed the ceritinib-trametinib combination to increase suppression of MAPK and TORC1 signaling. Similar results were seen when BRAF/NRAS-WT melanoma cells were treated with a combination of trametinib and the TORC1/2 inhibitor INK128. We next used mass spectrometry-based chemical proteomics and identified known and new ceritinib targets, such as IGF1R and ACK1, respectively. Validation studies suggested that ceritinib could suppress mTORC1 signaling in the presence of trametinib through inhibition of IGF1R and/or ACK1 in a cell line-dependent manner. Together our studies demonstrated that combining a specific inhibitor (trametinib) with a more broadly targeted agent (ceritinib) has efficacy against tumors with heterogeneous mutational profiles.

    更新日期:2017-11-15
  • Highlights of This Issue
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    American Association for Cancer Research

    ### [Harney and Karagiannis et al. Page 2486][1] Cytotoxic chemotherapy is known to induce pro-metastatic changes resulting in poor survival. Harney, Karagiannis and colleagues show that the TIE2 kinase inhibitor rebastinib reduces primary tumor growth and metastasis in a preclinical breast cancer

    更新日期:2017-11-10
  • Inhibition of the V-ATPase by Archazolid A: A New Strategy to Inhibit EMT
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Henriette Merk, Philipp Messer, Maximilian A. Ardelt, Don C. Lamb, Stefan Zahler, Rolf Müller, Angelika M. Vollmar, Johanna Pachmayr

    Epithelial–mesenchymal transition (EMT) induces tumor-initiating cells (TIC), which account for tumor recurrence, metastasis, and therapeutic resistance. Strategies to interfere with EMT are rare but urgently needed to improve cancer therapy. By using the myxobacterial natural compound Archazolid A as a tool, we elucidate the V-ATPase, a multimeric proton pump that regulates lysosomal acidification, as a crucial player in EMT and identify the inhibition of V-ATPase by Archazolid A as a promising strategy to block EMT. Genetic knockdown and pharmacologic inhibition of the V-ATPase by Archazolid A interfere with the EMT process and inhibit TIC generation, as shown by a reduced formation of mammospheres and decreased cell motility. As an underlying mechanism, V-ATPase inhibition by Archazolid A disturbs the turnover of E-cadherin: Archazolid abrogates E-cadherin loss during EMT by interfering with its internalization and recycling. Our study elucidates V-ATPase as essential player in EMT by regulating E-cadherin turnover. Archazolid A is suggested as a promising therapeutic agent to block EMT and the generation of TICs. Mol Cancer Ther; 16(11); 2329–39. ©2017 AACR . This article is featured in Highlights of This Issue, [p. 2327][1] [1]: /lookup/volpage/16/2327?iss=11

    更新日期:2017-11-10
  • A Bifunctional MAPK/PI3K Antagonist for Inhibition of Tumor Growth and Metastasis
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Stefanie Galbán, April A. Apfelbaum, Carlos Espinoza, Kevin Heist, Henry Haley, Karan Bedi, Mats Ljungman, Craig J. Galbán, Gary D. Luker, Marcian Van Dort, Brian D. Ross

    Responses to targeted therapies frequently are brief, with patients relapsing with drug-resistant tumors. For oncogenic MEK and BRAF inhibition, drug resistance commonly occurs through activation of PI3K/AKT/mTOR signaling and immune checkpoint modulation, providing a robust molecular target for concomitant therapy. Here, we evaluated the efficacy of a bifunctional kinase inhibitor (ST-162) that concurrently targets MAPK and PI3K signaling pathways. Treatment with ST-162 produced regression of mutant KRAS- or BRAF-addicted xenograft models of colorectal cancer and melanoma and stasis of BRAF/PTEN–mutant melanomas. Combining ST-162 with immune checkpoint blockers further increased efficacy in a syngeneic KRAS-mutant colorectal cancer model. Nascent transcriptome analysis revealed a unique gene set regulated by ST-162 related to melanoma metastasis. Subsequent mouse studies revealed ST-162 was a potent inhibitor of melanoma metastasis to the liver. These findings highlight the significant potential of a single molecule with multikinase activity to achieve tumor control, overcome resistance, and prevent metastases through modulation of interconnected cell signaling pathways. Mol Cancer Ther; 16(11); 2340–50. ©2017 AACR .

    更新日期:2017-11-10
  • Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib)
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Ursula A. Germann, Brinley F. Furey, William Markland, Russell R. Hoover, Alex M. Aronov, Jeffrey J. Roix, Michael Hale, Diane M. Boucher, David A. Sorrell, Gabriel Martinez-Botella, Matthew Fitzgibbon, Paul Shapiro, Michael J. Wick, Ramin Samadani, Kathryn Meshaw, Anna Groover, Gary DeCrescenzo, Mark Namchuk, Caroline M. Emery, Saurabh Saha, Dean J. Welsch

    Aberrant activation of signaling through the RAS–RAF–MEK–ERK (MAPK) pathway is implicated in numerous cancers, making it an attractive therapeutic target. Although BRAF and MEK-targeted combination therapy has demonstrated significant benefit beyond single-agent options, the majority of patients develop resistance and disease progression after approximately 12 months. Reactivation of ERK signaling is a common driver of resistance in this setting. Here we report the discovery of BVD-523 (ulixertinib), a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and ERK1/2 selectivity. In vitro BVD-523 treatment resulted in reduced proliferation and enhanced caspase activity in sensitive cells. Interestingly, BVD-523 inhibited phosphorylation of target substrates despite increased phosphorylation of ERK1/2. In in vivo xenograft studies, BVD-523 showed dose-dependent growth inhibition and tumor regression. BVD-523 yielded synergistic antiproliferative effects in a BRAF V600E-mutant melanoma cell line xenograft model when used in combination with BRAF inhibition. Antitumor activity was also demonstrated in in vitro and in vivo models of acquired resistance to single-agent and combination BRAF/MEK–targeted therapy. On the basis of these promising results, these studies demonstrate BVD-523 holds promise as a treatment for ERK-dependent cancers, including those whose tumors have acquired resistance to other treatments targeting upstream nodes of the MAPK pathway. Assessment of BVD-523 in clinical trials is underway ([NCT01781429][1], [NCT02296242][2], and [NCT02608229][3]). Mol Cancer Ther; 16(11); 2351–63. ©2017 AACR . [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01781429&atom=%2Fmolcanther%2F16%2F11%2F2351.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02296242&atom=%2Fmolcanther%2F16%2F11%2F2351.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02608229&atom=%2Fmolcanther%2F16%2F11%2F2351.atom

    更新日期:2017-11-10
  • Animacroxam, a Novel Dual-Mode Compound Targeting Histone Deacetylases and Cytoskeletal Integrity of Testicular Germ Cell Cancer Cells
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Gustav Steinemann, Alexandra Dittmer, Weronika Kuzyniak, Björn Hoffmann, Mark Schrader, Rainer Schobert, Bernhard Biersack, Bianca Nitzsche, Michael Höpfner

    Novel approaches for the medical treatment of advanced solid tumors, including testicular germ cell tumors (TGCT), are desperately needed. Especially, TGCT patients not responding to cisplatin-based therapy need therapeutic alternatives, as there is no effective medical treatment available for this particular subgroup. Here, we studied the suitability of the novel dual-mode compound animacroxam for TGCT treatment. Animacroxam consists of an HDAC-inhibitory hydroxamate moiety coupled to a 4,5-diarylimidazole with inherent cytoskeleton disrupting potency. Animacroxam revealed pronounced antiproliferative, cell-cycle arresting, and apoptosis-inducing effects in TGCT cell lines with different cisplatin sensitivities. The IC50 values of animacroxam ranged from 0.22 to 0.42 μmol/L and were not correlated to the cisplatin sensitivity of the tumor cells. No unspecific cytotoxicity of animacroxam was observed in either cisplatin-sensitive or resistant TGCT cells, even at doses as high as 10 μmol/L. Furthermore, animacroxam induced the formation of actin stress fibers in cancer cells, thereby confirming the cytoskeleton-disrupting and antimigratory properties of its imidazole moiety. When compared with the clinically established HDAC inhibitor vorinostat, the novel dual-mode compound animacroxam exhibited superior antitumoral efficacy in vitro . Animacroxam also reduced the tumor size of TGCT tumors in vivo , as evidenced by performing xenograft experiments on tumor bearing chorioallantoic membranes of fertilizes chicken eggs (CAM assay). The in vivo experiments also revealed a very good tolerability of the compound, and hence, animacroxam may be a promising candidate for innovative treatment of TGCT in general and the more so for platinum-insensitive or refractory TGCT. Mol Cancer Ther; 16(11); 2364–74. ©2017 AACR .

    更新日期:2017-11-10
  • The p97 Inhibitor CB-5083 Is a Unique Disrupter of Protein Homeostasis in Models of Multiple Myeloma
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Ronan Le Moigne, Blake T. Aftab, Stevan Djakovic, Eugen Dhimolea, Eduardo Valle, Megan Murnane, Emily M. King, Ferdie Soriano, Mary-Kamala Menon, Zhi Yong Wu, Stephen T. Wong, Grace J. Lee, Bing Yao, Arun P. Wiita, Christine Lam, Julie Rice, Jinhai Wang, Marta Chesi, P. Leif Bergsagel, Marianne Kraus, Christoph Driessen, Szerenke Kiss von Soly, F. Michael Yakes, David Wustrow, Laura Shawver, Han-Jie Zhou, Thomas G. Martin, Jeffrey L. Wolf, Constantine S. Mitsiades, Daniel J. Anderson, Mark Rolfe

    Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system, and CB-5083, a first-in-class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematologic and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma cell lines and a number of in vivo multiple myeloma models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response, and apoptosis. CB-5083 decreases viability in multiple myeloma cell lines and patient-derived multiple myeloma cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs, which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant multiple myeloma models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with multiple myeloma standard-of-care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several multiple myeloma disease models and provide the rationale for clinical evaluation as monotherapy and in combination in multiple myeloma. Mol Cancer Ther; 16(11); 2375–86. ©2017 AACR .

    更新日期:2017-11-10
  • Combination Therapy with c-Met and Src Inhibitors Induces Caspase-Dependent Apoptosis of Merlin-Deficient Schwann Cells and Suppresses Growth of Schwannoma Cells
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Marisa A. Fuse, Stephani Klingeman Plati, Sarah S. Burns, Christine T. Dinh, Olena Bracho, Denise Yan, Rahul Mittal, Rulong Shen, Julia N. Soulakova, Alicja J. Copik, Xue Zhong Liu, Fred F. Telischi, Long-Sheng Chang, Maria Clara Franco, Cristina Fernandez-Valle

    Neurofibromatosis type 2 (NF2) is a nervous system tumor disorder caused by inactivation of the merlin tumor suppressor encoded by the NF2 gene. Bilateral vestibular schwannomas are a diagnostic hallmark of NF2. Mainstream treatment options for NF2-associated tumors have been limited to surgery and radiotherapy; however, off-label uses of targeted molecular therapies are becoming increasingly common. Here, we investigated drugs targeting two kinases activated in NF2-associated schwannomas, c-Met and Src. We demonstrated that merlin-deficient mouse Schwann cells (MD-MSC) treated with the c-Met inhibitor, cabozantinib, or the Src kinase inhibitors, dasatinib and saracatinib, underwent a G1 cell-cycle arrest. However, when MD-MSCs were treated with a combination of cabozantinib and saracatinib, they exhibited caspase-dependent apoptosis. The combination therapy also significantly reduced growth of MD-MSCs in an orthotopic allograft mouse model by greater than 80% of vehicle. Moreover, human vestibular schwannoma cells with NF2 mutations had a 40% decrease in cell viability when treated with cabozantinib and saracatinib together compared with the vehicle control. This study demonstrates that simultaneous inhibition of c-Met and Src signaling in MD-MSCs triggers apoptosis and reveals vulnerable pathways that could be exploited to develop NF2 therapies. Mol Cancer Ther; 16(11); 2387–98. ©2017 AACR .

    更新日期:2017-11-10
  • Dual Inhibition of Hedgehog and c-Met Pathways for Pancreatic Cancer Treatment
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Agnieszka A. Rucki, Qian Xiao, Stephen Muth, Jianlin Chen, Xu Che, Jennifer Kleponis, Rajni Sharma, Robert A. Anders, Elizabeth M. Jaffee, Lei Zheng

    Pancreatic ductal adenocarcinoma (PDAC) is one of the most chemotherapy- and radiotherapy-resistant tumors. The c-Met and Hedgehog (Hh) pathways have been shown previously by our group to be key regulatory pathways in the primary tumor growth and metastases formation. Targeting both the HGF/c-Met and Hh pathways has shown promising results in preclinical studies; however, the benefits were not readily translated into clinical trials with PDAC patients. In this study, utilizing mouse models of PDAC, we showed that inhibition of either HGF/c-Met or Hh pathways sensitize the PDAC tumors to gemcitabine, resulting in decreased primary tumor volume as well as significant reduction of metastatic tumor burden. However, prolonged treatment of single HGF/c-Met or Hh inhibitor leads to resistance to these single inhibitors, likely because the single c-Met treatment leads to enhanced expression of Shh, and vice versa. Targeting both the HGF/c-Met and Hh pathways simultaneously overcame the resistance to the single-inhibitor treatment and led to a more potent antitumor effect in combination with the chemotherapy treatment. Mol Cancer Ther; 16(11); 2399–409. ©2017 AACR .

    更新日期:2017-11-10
  • Targeting TAO Kinases Using a New Inhibitor Compound Delays Mitosis and Induces Mitotic Cell Death in Centrosome Amplified Breast Cancer Cells
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Chuay-Yeng Koo, Caterina Giacomini, Marta Reyes-Corral, Yolanda Olmos, Ignatius A. Tavares, Charles M. Marson, Spiros Linardopoulos, Andrew N. Tutt, Jonathan D.H. Morris

    Thousand-and-one amino acid kinases (TAOK) 1 and 2 are activated catalytically during mitosis and can contribute to mitotic cell rounding and spindle positioning. Here, we characterize a compound that inhibits TAOK1 and TAOK2 activity with IC50 values of 11 to 15 nmol/L, is ATP-competitive, and targets these kinases selectively. TAOK inhibition or depletion in centrosome-amplified SKBR3 or BT549 breast cancer cell models increases the mitotic population, the percentages of mitotic cells displaying amplified centrosomes and multipolar spindles, induces cell death, and inhibits cell growth. In contrast, nontumorigenic and dividing bipolar MCF-10A breast cells appear less dependent on TAOK activity and can complete mitosis and proliferate in the presence of the TAOK inhibitor. We demonstrate that TAOK1 and TAOK2 localize to the cytoplasm and centrosomes respectively during mitosis. Live cell imaging shows that the TAOK inhibitor prolongs the duration of mitosis in SKBR3 cells, increases mitotic cell death, and reduces the percentages of cells exiting mitosis, whereas MCF-10A cells continue to divide and proliferate. Over 80% of breast cancer tissues display supernumerary centrosomes, and tumor cells frequently cluster extra centrosomes to avoid multipolar mitoses and associated cell death. Consequently, drugs that stimulate centrosome declustering and induce multipolarity are likely to target dividing centrosome-amplified cancer cells preferentially, while sparing normal bipolar cells. Our results demonstrate that TAOK inhibition can enhance centrosome declustering and mitotic catastrophe in cancer cells, and these proteins may therefore offer novel therapeutic targets suitable for drug inhibition and the potential treatment of breast cancers, where supernumerary centrosomes occur. Mol Cancer Ther; 16(11); 2410–21. ©2017 AACR .

    更新日期:2017-11-10
  • Targeting Phosphatidylinositol 3-Kinase Signaling Pathway for Therapeutic Enhancement of Vascular-Targeted Photodynamic Therapy
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Daniel Kraus, Pratheeba Palasuberniam, Bin Chen

    Vascular-targeted photodynamic therapy (PDT) selectively disrupts vascular function by inducing oxidative damages to the vasculature, particularly endothelial cells. Although effective tumor eradication and excellent safety profile are well demonstrated in both preclinical and clinical studies, incomplete vascular shutdown and angiogenesis are known to cause tumor recurrence after vascular-targeted PDT. We have explored therapeutic enhancement of vascular-targeted PDT with PI3K signaling pathway inhibitors because the activation of PI3K pathway was involved in promoting endothelial cell survival and proliferation after PDT. Here, three clinically relevant small-molecule inhibitors (BYL719, BKM120, and BEZ235) of the PI3K pathway were evaluated in combination with verteporfin-PDT. Although all three inhibitors were able to synergistically enhance PDT response in endothelial cells, PDT combined with dual PI3K/mTOR inhibitor BEZ235 exhibited the strongest synergism, followed in order by combinations with pan-PI3K inhibitor BKM120 and p110α isoform-selective inhibitor BYL719. Combination treatments of PDT and BEZ235 exhibited a cooperative inhibition of antiapoptotic Bcl-2 family protein Mcl-1 and induced more cell apoptosis than each treatment alone. In addition to increasing treatment lethality, BEZ235 combined with PDT effectively inhibited PI3K pathway activation and consequent endothelial cell proliferation after PDT alone, leading to a sustained growth inhibition. In the PC-3 prostate tumor model, combination treatments improved treatment outcomes by turning a temporary tumor regrowth delay induced by PDT alone to a more long-lasting treatment response. Our study strongly supports the combination of vascular-targeted PDT and PI3K pathway inhibitors, particularly mTOR inhibitors, for therapeutic enhancement. Mol Cancer Ther; 16(11); 2422–31. ©2017 AACR .

    更新日期:2017-11-10
  • mTOR Kinase Inhibition Effectively Decreases Progression of a Subset of Neuroendocrine Tumors that Progress on Rapalog Therapy and Delays Cardiac Impairment
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Melissa A. Orr-Asman, Zhengtao Chu, Min Jiang, Mariah Worley, Kathleen LaSance, Sheryl E. Koch, Vinicius S. Carreira, Hanan M. Dahche, David R. Plas, Kakajan Komurov, Xiaoyang Qi, Carol A. Mercer, Lowell B. Anthony, Jack Rubinstein, Hala E. Thomas

    Inhibition of mTOR signaling using the rapalog everolimus is an FDA-approved targeted therapy for patients with lung and gastroenteropancreatic neuroendocrine tumors (NET). However, patients eventually progress on treatment, highlighting the need for additional therapies. We focused on pancreatic NETs (pNET) and reasoned that treatment of these tumors upon progression on rapalog therapy, with an mTOR kinase inhibitor (mTORKi), such as CC-223, could overcome a number of resistance mechanisms in tumors and delay cardiac carcinoid disease. We performed preclinical studies using human pNET cells in vitro and injected them subcutaneously or orthotopically to determine tumor progression and cardiac function in mice treated with either rapamycin alone or switched to CC-223 upon progression. Detailed signaling and RNA sequencing analyses were performed on tumors that were sensitive or progressed on mTOR treatment. Approximately 57% of mice bearing pNET tumors that progressed on rapalog therapy showed a significant decrease in tumor volume upon a switch to CC-223. Moreover, mice treated with an mTORKi exhibited decreased cardiac dilation and thickening of heart valves than those treated with placebo or rapamycin alone. In conclusion, in the majority of pNETs that progress on rapalogs, it is possible to reduce disease progression using an mTORKi, such as CC-223. Moreover, CC-223 had an additional transient cardiac benefit on valvular fibrosis compared with placebo- or rapalog-treated mice. These results provide the preclinical rationale to further develop mTORKi clinically upon progression on rapalog therapy and to further test their long-term cardioprotective benefit in those NET patients prone to carcinoid syndrome. Mol Cancer Ther; 16(11); 2432–41. ©2017 AACR .

    更新日期:2017-11-10
  • Potency-matched Dual Cytokine-Antibody Fusion Proteins for Cancer Therapy
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Roberto De Luca, Alex Soltermann, Francesca Pretto, Catherine Pemberton-Ross, Giovanni Pellegrini, Sarah Wulhfard, Dario Neri

    A novel biopharmaceutical, consisting of the F8 mAb (specific to a splice isoform of fibronectin) simultaneously fused to both TNF and IL2, was found to react with the majority of solid tumors and hematologic malignancies in mouse and man, but not with healthy adult tissues. The product selectively localized to neoplastic lesions in vivo , as evidenced by quantitative biodistribution studies using radioiodinated protein preparations. When the potency of the cytokine payloads was matched by a single-point mutation, the resulting fusion protein (IL2-F8-TNFmut) eradicated soft-tissue sarcomas in immunocompetent mice, which did not respond to individual antibody–cytokine fusion proteins or by standard doxorubicin treatment. Durable complete responses were also observed in mice bearing CT26, C1498, and F9 tumors. The simultaneous delivery of multiple proinflammatory payloads to the cancer site conferred protective immunity against subsequent tumor challenges. A fully human homolog of IL2-F8-TNFmut, which retained selectivity similar to its murine counterpart when tested on human material, may open new clinical applications for the immunotherapy of cancer. Mol Cancer Ther; 16(11); 2442–51. ©2017 AACR .

    更新日期:2017-11-10
  • Vessel-Targeted Chemophototherapy with Cationic Porphyrin-Phospholipid Liposomes
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Dandan Luo, Jumin Geng, Nasi Li, Kevin A. Carter, Shuai Shao, G. Ekin Atilla-Gokcumen, Jonathan F. Lovell

    Cationic liposomes have been used for targeted drug delivery to tumor blood vessels, via mechanisms that are not fully elucidated. Doxorubicin (Dox)-loaded liposomes were prepared that incorporate a cationic lipid; 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), along with a small amount of porphyrin-phospholipid (PoP). Near-infrared (NIR) light caused release of entrapped Dox via PoP-mediated DOTAP photo-oxidation. The formulation was optimized to enable extremely rapid NIR light-triggered Dox release (i.e., in 15 seconds), while retaining reasonable serum stability. In vitro , cationic PoP liposomes readily bound to both MIA PaCa-2 human pancreatic cancer cells and human vascular endothelial cells. When administered intravenously, cationic PoP liposomes were cleared from circulation within minutes, with most accumulation in the liver and spleen. Fluorescence imaging revealed that some cationic PoP liposomes also localized at the tumor blood vessels. Compared with analogous neutral liposomes, strong tumor photoablation was induced with a single treatment of cationic PoP liposomes and laser irradiation (5 mg/kg Dox and 100 J/cm2 NIR light). Unexpectedly, empty cationic PoP liposomes (lacking Dox) induced equally potent antitumor phototherapeutic effects as the drug loaded ones. A more balanced chemo- and phototherapeutic response was subsequently achieved when antitumor studies were repeated using higher drug dosing (7 mg/kg Dox) and a low fluence phototreatment (20 J/cm2 NIR light). These results demonstrate the feasibility of vessel-targeted chemophototherapy using cationic PoP liposomes and also illustrate synergistic considerations. Mol Cancer Ther; 16(11); 2452–61. ©2017 AACR .

    更新日期:2017-11-10
  • Wilms Tumor NCAM-Expressing Cancer Stem Cells as Potential Therapeutic Target for Polymeric Nanomedicine
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Ela Markovsky, Einav Vax, Dikla Ben-Shushan, Anat Eldar-Boock, Rachel Shukrun, Eilam Yeini, Iris Barshack, Revital Caspi, Orit Harari-Steinberg, Naomi Pode-Shakked, Benjamin Dekel, Ronit Satchi-Fainaro

    Cancer stem cells (CSC) form a specific population within the tumor that has been shown to have self-renewal and differentiation properties, increased ability to migrate and form metastases, and increased resistance to chemotherapy. Consequently, even a small number of cells remaining after therapy can repopulate the tumor and cause recurrence of the disease. CSCs in Wilms tumor, a pediatric renal cancer, were previously shown to be characterized by neural cell adhesion molecule (NCAM) expression. Therefore, NCAM provides a specific biomarker through which the CSC population in this tumor can be targeted. We have recently developed an NCAM-targeted nanosized conjugate of paclitaxel bound to a biodegradable polyglutamic acid polymer. In this work, we examined the ability of the conjugate to inhibit Wilms tumor by targeting the NCAM-expressing CSCs. Results show that the conjugate selectively depleted the CSC population of the tumors and effectively inhibited tumor growth without causing toxicity. We propose that the NCAM-targeted conjugate could be an effective therapeutic for Wilms tumor. Mol Cancer Ther; 16(11); 2462–72. ©2017 AACR .

    更新日期:2017-11-10
  • Inhibition of Discoidin Domain Receptor 1 Reduces Collagen-mediated Tumorigenicity in Pancreatic Ductal Adenocarcinoma
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Kristina Y. Aguilera, Huocong Huang, Wenting Du, Moriah M. Hagopian, Zhen Wang, Stefan Hinz, Tae Hyun Hwang, Huamin Wang, Jason B. Fleming, Diego H. Castrillon, Xiaomei Ren, Ke Ding, Rolf A. Brekken

    The extracellular matrix (ECM), a principal component of pancreatic ductal adenocarcinoma (PDA), is rich in fibrillar collagens that facilitate tumor cell survival and chemoresistance. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that specifically binds fibrillar collagens and has been implicated in promoting cell proliferation, migration, adhesion, ECM remodeling, and response to growth factors. We found that collagen-induced activation of DDR1 stimulated protumorigenic signaling through protein tyrosine kinase 2 (PYK2) and pseudopodium-enriched atypical kinase 1 (PEAK1) in pancreatic cancer cells. Pharmacologic inhibition of DDR1 with an ATP-competitive orally available small-molecule kinase inhibitor (7rh) abrogated collagen-induced DDR1 signaling in pancreatic tumor cells and consequently reduced colony formation and migration. Furthermore, the inhibition of DDR1 with 7rh showed striking efficacy in combination with chemotherapy in orthotopic xenografts and autochthonous pancreatic tumors where it significantly reduced DDR1 activation and downstream signaling, reduced primary tumor burden, and improved chemoresponse. These data demonstrate that targeting collagen signaling in conjunction with conventional cytotoxic chemotherapy has the potential to improve outcome for pancreatic cancer patients. Mol Cancer Ther; 16(11); 2473–85. ©2017 AACR . This article is featured in Highlights of This Issue, [p. 2327][1] [1]: /lookup/volpage/16/2327?iss=11

    更新日期:2017-11-10
  • The Selective Tie2 Inhibitor Rebastinib Blocks Recruitment and Function of Tie2Hi Macrophages in Breast Cancer and Pancreatic Neuroendocrine Tumors
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Allison S. Harney, George S. Karagiannis, Jeanine Pignatelli, Bryan D. Smith, Ece Kadioglu, Scott C. Wise, Molly M. Hood, Michael D. Kaufman, Cynthia B. Leary, Wei-Ping Lu, Gada Al-Ani, Xiaoming Chen, David Entenberg, Maja H. Oktay, Yarong Wang, Lawrence Chun, Michele De Palma, Joan G. Jones, Daniel L. Flynn, John S. Condeelis

    Tumor-infiltrating myeloid cells promote tumor progression by mediating angiogenesis, tumor cell intravasation, and metastasis, which can offset the effects of chemotherapy, radiation, and antiangiogenic therapy. Here, we show that the kinase switch control inhibitor rebastinib inhibits Tie2, a tyrosine kinase receptor expressed on endothelial cells and protumoral Tie2-expressing macrophages in mouse models of metastatic cancer. Rebastinib reduces tumor growth and metastasis in an orthotopic mouse model of metastatic mammary carcinoma through reduction of Tie2+ myeloid cell infiltration, antiangiogenic effects, and blockade of tumor cell intravasation mediated by perivascular Tie2Hi/Vegf-AHi macrophages in the tumor microenvironment of metastasis (TMEM). The antitumor effects of rebastinib enhance the efficacy of microtubule inhibiting chemotherapeutic agents, either eribulin or paclitaxel, by reducing tumor volume, metastasis, and improving overall survival. Rebastinib inhibition of angiopoietin/Tie2 signaling impairs multiple pathways in tumor progression mediated by protumoral Tie2+ macrophages, including TMEM-dependent dissemination and angiopoietin/Tie2-dependent angiogenesis. Rebastinib is a promising therapy for achieving Tie2 inhibition in cancer patients. Mol Cancer Ther; 16(11); 2486–501. ©2017 AACR . This article is featured in Highlights of This Issue, [p. 2327][1] [1]: /lookup/volpage/16/2327?iss=11

    更新日期:2017-11-10
  • Autophagy Inhibition Improves Sunitinib Efficacy in Pancreatic Neuroendocrine Tumors via a Lysosome-dependent Mechanism
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Tabea Wiedmer, Annika Blank, Sophia Pantasis, Lea Normand, Ruben Bill, Philippe Krebs, Mario P. Tschan, Ilaria Marinoni, Aurel Perren

    Increasing the efficacy of approved systemic treatments in metastasized pancreatic neuroendocrine tumors (PanNET) is an unmet medical need. The antiangiogenic tyrosine kinase inhibitor sunitinib is approved for PanNET treatment. In addition, sunitinib is a lysosomotropic drug and such drugs can induce lysosomal membrane permeabilization as well as autophagy. We investigated sunitinib-induced autophagy as a possible mechanism of PanNET therapy resistance. Sunitinib accumulated in lysosomes and induced autophagy in PanNET cell lines. Adding the autophagy inhibitor chloroquine reduced cell viability in cell lines and in primary cells isolated from PanNET patients. The same treatment combination reduced tumor burden in the Rip1Tag2 transgenic PanNET mouse model. The combination of sunitinib and chloroquine reduced recovery and induced apoptosis in vitro , whereas single treatments did not. Knockdown of key autophagy proteins in combination with sunitinib showed similar effect as chloroquine. Sunitinib also induced lysosomal membrane permeabilization, which further increased in the presence of chloroquine or knockdown of lysosome-associated membrane protein (LAMP2). Both combinations led to cell death. Our data indicate that chloroquine increases sunitinib efficacy in PanNET treatment via autophagy inhibition and lysosomal membrane permeabilization. We suggest that adding chloroquine to sunitinib treatment will increase efficacy of PanNET treatment and that such patients should be included in respective ongoing clinical trials. Mol Cancer Ther; 16(11); 2502–15. ©2017 AACR .

    更新日期:2017-11-10
  • Sphingosine-1-Phosphate Receptor-1 Promotes Environment-Mediated and Acquired Chemoresistance
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Veronica Lifshitz, Saul J. Priceman, Wenzhao Li, Gregory Cherryholmes, Heehyoung Lee, Adar Makovski-Silverstein, Lucia Borriello, Yves A. DeClerck, Hua Yu

    Drug resistance is a major barrier for the development of effective and durable cancer therapies. Overcoming this challenge requires further defining the cellular and molecular mechanisms underlying drug resistance, both acquired and environment-mediated drug resistance (EMDR). Here, using neuroblastoma (NB), a childhood cancer with high incidence of recurrence due to resistance to chemotherapy, as a model we show that human bone marrow–mesenchymal stromal cells induce tumor expression of sphingosine-1-phosphate receptor-1 (S1PR1), leading to their resistance to chemotherapy. Targeting S1PR1 by shRNA markedly enhances etoposide-induced apoptosis in NB cells and abrogates EMDR, while overexpression of S1PR1 significantly protects NB cells from multidrug-induced apoptosis via activating JAK–STAT3 signaling. Elevated S1PR1 expression and STAT3 activation are also observed in human NB cells with acquired resistance to etoposide. We show in vitro and in human NB xenograft models that treatment with FTY720, an FDA-approved drug and antagonist of S1PR1, dramatically sensitizes drug-resistant cells to etoposide. In summary, we identify S1PR1 as a critical target for reducing both EMDR and acquired chemoresistance in NB. Mol Cancer Ther; 16(11); 2516–27. ©2017 AACR .

    更新日期:2017-11-10
  • PPAR{gamma} Ligand-induced Annexin A1 Expression Determines Chemotherapy Response via Deubiquitination of Death Domain Kinase RIP in Triple-negative Breast Cancers
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Luxi Chen, Yi Yuan, Shreya Kar, Madhu M. Kanchi, Suruchi Arora, Ji E. Kim, Pei F. Koh, Einas Yousef, Ramar P. Samy, Muthu K. Shanmugam, Tuan Z. Tan, Sung W. Shin, Frank Arfuso, Han M. Shen, Henry Yang, Boon C. Goh, Joo I. Park, Louis Gaboury, Peter E. Lobie, Gautam Sethi, Lina H.K. Lim, Alan P. Kumar

    Metastatic breast cancer is still incurable so far; new specifically targeted and more effective therapies for triple-negative breast cancer (TNBC) are required in the clinic. In this study, our clinical data have established that basal and claudin-low subtypes of breast cancer (TNBC types) express significantly higher levels of Annexin A1 (ANXA1) with poor survival outcomes. Using human cancer cell lines that model the TNBC subtype, we observed a strong positive correlation between expression of ANXA1 and PPARγ. A similar correlation between these two markers was also established in our clinical breast cancer patients' specimens. To establish a link between these two markers in TNBC, we show de novo expression of ANXA1 is induced by activation of PPARγ both in vitro and in vivo and it has a predictive value in determining chemosensitivity to PPARγ ligands. Mechanistically, we show for the first time PPARγ-induced ANXA1 protein directly interacts with receptor interacting protein-1 (RIP1), promoting its deubiquitination and thereby activating the caspase-8–dependent death pathway. We further identified this underlying mechanism also involved a PPARγ-induced ANXA1-dependent autoubiquitination of cIAP1, the direct E3 ligase of RIP1, shifting cIAP1 toward proteosomal degradation. Collectively, our study provides first insight for the suitability of using drug-induced expression of ANXA1 as a new player in RIP1-induced death machinery in TNBCs, presenting itself both as an inclusion criterion for patient selection and surrogate marker for drug response in future PPARγ chemotherapy trials. Mol Cancer Ther; 16(11); 2528–42. ©2017 AACR .

    更新日期:2017-11-10
  • TDP1 is Critical for the Repair of DNA Breaks Induced by Sapacitabine, a Nucleoside also Targeting ATM- and BRCA-Deficient Tumors
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Muthana Al Abo, Hiroyuki Sasanuma, Xiaojun Liu, Vinodh N. Rajapakse, Shar-yin Huang, Evgeny Kiselev, Shunichi Takeda, William Plunkett, Yves Pommier

    2'- C -cyano-2'-deoxy-1-β-d-arabino-pentofuranosylcytosine (CNDAC) is the active metabolite of the anticancer drug, sapacitabine. CNDAC is incorporated into the genome during DNA replication and subsequently undergoes β-elimination that generates single-strand breaks with abnormal 3′-ends. Because tyrosyl-DNA phosphodiesterase 1 (TDP1) selectively hydrolyzes nonphosphorylated 3′-blocking ends, we tested its role in the repair of CNDAC-induced DNA damage. We show that cells lacking TDP1 (avian TDP1−/− DT40 cells and human TDP1 KO TSCER2 and HCT116 cells) exhibit marked hypersensitivity to CNDAC. We also identified BRCA1, FANCD2, and PCNA in the DNA repair pathways to CNDAC. Comparing CNDAC with the chemically related arabinosyl nucleoside analog, cytosine arabinoside (cytarabine, AraC) and the topoisomerase I inhibitor camptothecin (CPT), which both generate 3′-end blocking DNA lesions that are also repaired by TDP1, we found that inactivation of BRCA2 renders cells hypersensitive to CNDAC and CPT but not to AraC. By contrast, cells lacking PARP1 were only hypersensitive to CPT but not to CNDAC or AraC. Examination of TDP1 expression in the cancer cell line databases (CCLE, GDSC, NCI-60) and human cancers (TCGA) revealed a broad range of expression of TDP1 , which was correlated with PARP1 expression, TDP1 gene copy number and promoter methylation. Thus, this study identifies the importance of TDP1 as a novel determinant of response to CNDAC across various cancer types (especially non–small cell lung cancers), and demonstrates the differential involvement of BRCA2, PARP1, and TDP1 in the cellular responses to CNDAC, AraC, and CPT. Mol Cancer Ther; 16(11); 2543–51. ©2017 AACR .

    更新日期:2017-11-10
  • Synthetic Lethality Interaction Between Aurora Kinases and CHEK1 Inhibitors in Ovarian Cancer
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Ana Alcaraz-Sanabria, Cristina Nieto-Jiménez, Verónica Corrales-Sánchez, Leticia Serrano-Oviedo, Fernando Andrés-Pretel, Juan Carlos Montero, Miguel Burgos, Juan Llopis, Eva María Galán-Moya, Atanasio Pandiella, Alberto Ocaña

    Ovarian cancer is characterized by frequent mutations at TP53. These tumors also harbor germline mutations at homologous recombination repair genes, so they rely on DNA-damage checkpoint proteins, like the checkpoint kinase 1 (CHEK1) to induce G2 arrest. In our study, by using an in silico approach, we identified a synthetic lethality interaction between CHEK1 and mitotic aurora kinase A (AURKA) inhibitors. Gene expression analyses were used for the identification of relevant biological functions. OVCAR3, OVCAR8, IGROV1, and SKOV3 were used for proliferation studies. Alisertib was tested as AURKA inhibitor and LY2603618 as CHEK1 inhibitor. Analyses of cell cycle and intracellular mediators were performed by flow cytometry and Western blot analysis. Impact on stem cell properties was evaluated by flow cytometry analysis of surface markers and sphere formation assays. Gene expression analyses followed by functional annotation identified a series of deregulated genes that belonged to cell cycle, including AURKA/B, TTK kinase, and CHEK1. AURKA and CHEK1 were amplified in 8.7% and 3.9% of ovarian cancers, respectively. AURKA and CHEK1 inhibitors showed a synergistic interaction in different cellular models. Combination of alisertib and LY2603618 triggered apoptosis, reduced the stem cell population, and increased the effect of taxanes and platinum compounds. Finally, expression of AURKA and CHEK1 was linked with detrimental outcome in patients. Our data describe a synthetic lethality interaction between CHEK1 and AURKA inhibitors with potential translation to the clinical setting. Mol Cancer Ther; 16(11); 2552–62. ©2017 AACR .

    更新日期:2017-11-10
  • T790M-Selective EGFR-TKI Combined with Dasatinib as an Optimal Strategy for Overcoming EGFR-TKI Resistance in T790M-Positive Non-Small Cell Lung Cancer
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Satomi Watanabe, Takeshi Yoshida, Hisato Kawakami, Naoki Takegawa, Junko Tanizaki, Hidetoshi Hayashi, Masayuki Takeda, Kimio Yonesaka, Junji Tsurutani, Kazuhiko Nakagawa

    T790M mutation–selective EGFR tyrosine kinase inhibitors (EGFR-TKI) have demonstrated clinical benefits in non–small cell lung cancer (NSCLC) patients harboring T790M mutation, which is the major cause of resistance to EGFR-TKI. However, their efficacy is limited, possibly due to the emergence of apoptosis resistance in T790M-positive NSCLC. We previously identified Src family kinases as cooncogenic drivers along with T790M and found that the Src inhibitor dasatinib combined with an irreversible or a preclinical T790M-selective EGFR-TKI enhanced antitumor activity in T790M-positive cells. In the current study, we evaluated the efficacy of dasatinib combined with the clinically relevant T790M-selective EGFR-TKI ASP8273 or osimertinib in EGFR mutation–positive NSCLC with or without T790M mutation. A cell viability assay revealed that dasatinib had synergistic effects with these TKIs in T790M-positive cells and simultaneously inhibited Src, Akt, and Erk, which remained activated upon single-agent treatment. Dasatinib also increased the rate of apoptosis in T790M-positive cells induced by T790M-selective EGFR-TKIs, as determined by the Annexin-V binding assay; this was associated with downregulation of the antiapoptotic Bcl-2 family member Bcl-xL, a finding that was confirmed in mice bearing T790M-positive xenografts. Our results suggest that Bcl-xL plays a key role in the apoptosis resistance of T790M-positive NSCLC, and that dasatinib combined with clinically relevant T790M-selective EGFR-TKIs is potentially effective in overcoming resistance to first-generation EGFR-TKIs in NSCLC patients with acquired T790M. Mol Cancer Ther; 16(11); 2563–71. ©2017 AACR .

    更新日期:2017-11-10
  • Characterization of In Vivo Resistance to Osimertinib and JNJ-61186372, an EGFR/Met Bispecific Antibody, Reveals Unique and Consensus Mechanisms of Resistance
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Kristina B. Emdal, Antje Dittmann, Raven J. Reddy, Rebecca S. Lescarbeau, Sheri L. Moores, Sylvie Laquerre, Forest M. White

    Approximately 10% of non–small cell lung cancer (NSCLC) patients in the United States and 40% of NSCLC patients in Asia have activating epidermal growth factor receptor (EGFR) mutations and are eligible to receive targeted anti-EGFR therapy. Despite an extension of life expectancy associated with this treatment, resistance to EGFR tyrosine kinase inhibitors and anti-EGFR antibodies is almost inevitable. To identify additional signaling routes that can be cotargeted to overcome resistance, we quantified tumor-specific molecular changes that govern resistant cancer cell growth and survival. Mass spectrometry–based quantitative proteomics was used to profile in vivo signaling changes in 41 therapy-resistant tumors from four xenograft NSCLC models. We identified unique and tumor-specific tyrosine phosphorylation rewiring in tumors resistant to treatment with the irreversible third-generation EGFR-inhibitor, osimertinib, or the novel dual-targeting EGFR/Met antibody, JNJ-61186372. Tumor-specific increases in tyrosine-phosphorylated peptides from EGFR family members, Shc1 and Gab1 or Src family kinase (SFK) substrates were observed, underscoring a differential ability of tumors to uniquely escape EGFR inhibition. Although most resistant tumors within each treatment group displayed a marked inhibition of EGFR as well as SFK signaling, the combination of EGFR inhibition (osimertinib) and SFK inhibition (saracatinib or dasatinib) led to further decrease in cell growth in vitro . This result suggests that residual SFK signaling mediates therapeutic resistance and that elimination of this signal through combination therapy may delay onset of resistance. Overall, analysis of individual resistant tumors captured unique in vivo signaling rewiring that would have been masked by analysis of in vitro cell population averages. Mol Cancer Ther; 16(11); 2572–85. ©2017 AACR .

    更新日期:2017-11-10
  • EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Dorothy Brach, Danielle Johnston-Blackwell, Allison Drew, Trupti Lingaraj, Vinny Motwani, Natalie M. Warholic, Igor Feldman, Christopher Plescia, Jesse J. Smith, Robert A. Copeland, Heike Keilhack, Elayne Chan-Penebre, Sarah K. Knutson, Scott A. Ribich, Alejandra Raimondi, Michael J. Thomenius

    The EZH2 small-molecule inhibitor tazemetostat (EPZ-6438) is currently being evaluated in phase II clinical trials for the treatment of non-Hodgkin lymphoma (NHL). We have previously shown that EZH2 inhibitors display an antiproliferative effect in multiple preclinical models of NHL, and that models bearing gain-of-function mutations in EZH2 were consistently more sensitive to EZH2 inhibition than lymphomas with wild-type (WT) EZH2 . Here, we demonstrate that cell lines bearing EZH2 mutations show a cytotoxic response, while cell lines with WT- EZH2 show a cytostatic response and only tumor growth inhibition without regression in a xenograft model. Previous work has demonstrated that cotreatment with tazemetostat and glucocorticoid receptor agonists lead to a synergistic antiproliferative effect in both mutant and wild-type backgrounds, which may provide clues to the mechanism of action of EZH2 inhibition in WT- EZH2 models. Multiple agents that inhibit the B-cell receptor pathway (e.g., ibrutinib) were found to have synergistic benefit when combined with tazemetostat in both mutant and WT- EZH2 backgrounds of diffuse large B-cell lymphomas (DLBCL). The relationship between B-cell activation and EZH2 inhibition is consistent with the proposed role of EZH2 in B-cell maturation. To further support this, we observe that cell lines treated with tazemetostat show an increase in the B-cell maturation regulator, PRDM1 /BLIMP1, and gene signatures corresponding to more advanced stages of maturation. These findings suggest that EZH2 inhibition in both mutant and wild-type backgrounds leads to increased B-cell maturation and a greater dependence on B-cell activation signaling. Mol Cancer Ther; 16(11); 2586–97. ©2017 AACR .

    更新日期:2017-11-10
  • Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Aaron M. Goodman, Shumei Kato, Lyudmila Bazhenova, Sandip P. Patel, Garrett M. Frampton, Vincent Miller, Philip J. Stephens, Gregory A. Daniels, Razelle Kurzrock

    Immunotherapy induces durable responses in a subset of patients with cancer. High tumor mutational burden (TMB) may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non–small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients ( N = 151) were analyzed for response rate (RR), progression-free survival (PFS), and overall survival (OS). Higher TMB was independently associated with better outcome parameters (multivariable analysis). The RR for patients with high (≥20 mutations/mb) versus low to intermediate TMB was 22/38 (58%) versus 23/113 (20%; P = 0.0001); median PFS, 12.8 months vs. 3.3 months ( P ≤ 0.0001); median OS, not reached versus 16.3 months ( P = 0.0036). Results were similar when anti-PD-1/PD-L1 monotherapy was analyzed ( N = 102 patients), with a linear correlation between higher TMB and favorable outcome parameters; the median TMB for responders versus nonresponders treated with anti-PD-1/PD-L1 monotherapy was 18.0 versus 5.0 mutations/mb ( P < 0.0001). Interestingly, anti-CTLA4/anti-PD-1/PD-L1 combinations versus anti-PD-1/PD-L1 monotherapy was selected as a factor independent of TMB for predicting better RR (77% vs. 21%; P = 0.004) and PFS ( P = 0.024). Higher TMB predicts favorable outcome to PD-1/PD-L1 blockade across diverse tumors. Benefit from dual checkpoint blockade did not show a similarly strong dependence on TMB. Mol Cancer Ther; 16(11); 2598–608. ©2017 AACR . This article is featured in Highlights of This Issue, [p. 2327][1] [1]: /lookup/volpage/16/2327?iss=11

    更新日期:2017-11-10
  • TTK Inhibitors as a Targeted Therapy for CTNNB1 ({beta}-catenin) Mutant Cancers
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Guido J.R. Zaman, Jeroen A.D.M. de Roos, Marion A.A. Libouban, Martine B.W. Prinsen, Jos de Man, Rogier C. Buijsman, Joost C.M. Uitdehaag

    The spindle assembly checkpoint kinase TTK (Mps1) is a key regulator of chromosome segregation and is the subject of novel targeted therapy approaches by small-molecule inhibitors. Although the first TTK inhibitors have entered phase I dose escalating studies in combination with taxane chemotherapy, a patient stratification strategy is still missing. With the aim to identify a genomic biomarker to predict the response of tumor cells to TTK inhibitor therapy, we profiled a set of preclinical and clinical TTK inhibitors from different chemical series on a panel of 66 genetically characterized cell lines derived from different tumors (Oncolines). Cell lines harboring activating mutations in the CTNNB1 gene, encoding the Wnt pathway signaling regulator β-catenin, were on average up to five times more sensitive to TTK inhibitors than cell lines wild-type for CTNNB1 . The association of CTNNB1 -mutant status and increased cancer cell line sensitivity to TTK inhibition was confirmed with isogenic cell line pairs harboring either mutant or wild-type CTNNB1 . Treatment of a xenograft model of a CTNNB1 -mutant cell line with the TTK inhibitor NTRC 0066-0 resulted in complete inhibition of tumor growth. Mutations in CTNNB1 occur at relatively high frequency in endometrial cancer and hepatocellular carcinoma, which are known to express high TTK levels. We propose mutant CTNNB1 as a prognostic drug response biomarker, enabling the selection of patients most likely to respond to TTK inhibitor therapy in proof-of-concept clinical trials. Mol Cancer Ther; 16(11); 2609–17. ©2017 AACR .

    更新日期:2017-11-10
  • Estrogen Receptor {beta} Is a Novel Target in Acute Myeloid Leukemia
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Sarah-Grace Rota, Alessia Roma, Iulia Dude, Christina Ma, Robert Stevens, Janet MacEachern, Joanna Graczyk, Shaundrei Mabriel G. Espiritu, Praveen N. Rao, Mark D. Minden, Elena Kreinin, David A. Hess, Andrew C. Doxey, Paul A. Spagnuolo

    Acute myeloid leukemia (AML) is a devastating disease characterized by poor patient outcome and suboptimal chemotherapeutics. Here, a high-throughput screen identified diosmetin, a citrus flavonoid, with anti-AML activity. Diosmetin imparted selective toxicity against leukemia and leukemia stem cells in vitro and in vivo with no effect on normal hematopoietic stem cells. Mechanistically, we demonstrated that diosmetin targets estrogen receptor (ER) β. ERβ expression conferred cell sensitivity, as patient-derived AML cells with high levels of ERβ were sensitive, whereas cells with low ERβ were insensitive to diosmetin. Knockdown of ERβ confirmed resistance, whereas overexpression enhanced sensitivity to diosmetin, which was demonstrated to be mediated by reactive oxygen species signaling. In summary, these studies highlight targeting of ERβ with diosmetin as a potential novel therapeutic strategy for the treatment of AML. Mol Cancer Ther; 16(11); 2618–26. ©2017 AACR .

    更新日期:2017-11-10
  • Oncolytic Reactivation of KSHV as a Therapeutic Approach for Primary Effusion Lymphoma
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-11-01
    Feng Zhou, Michiko Shimoda, Laura Olney, Yuanzhi Lyu, Khiem Tran, Guochun Jiang, Kazushi Nakano, Ryan R. Davis, Clifford G. Tepper, Emanual Maverakis, Mel Campbell, Yuanpei Li, Satya Dandekar, Yoshihiro Izumiya

    Primary effusion lymphoma (PEL) is an aggressive subtype of non-Hodgkin lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Currently, treatment options for patients with PEL are limited. Oncolytic viruses have been engineered as anticancer agents and have recently shown increased therapeutic promise. Similarly, lytic activation of endogenous viruses from latently infected tumor cells can also be applied as a cancer therapy. In theory, such a therapeutic strategy would induce oncolysis by viral replication, while simultaneously stimulating an immune response to viral lytic cycle antigens. We examined the combination of the FDA-approved drug ingenol-3-angelate (PEP005) with epigenetic drugs as a rational therapeutic approach for KSHV-mediated malignancies. JQ1, a bromodomain and extra terminal (BET) protein inhibitor, in combination with PEP005, not only robustly induced KSHV lytic replication, but also inhibited IL6 production from PEL cells. Using the dosages of these agents that were found to be effective in reactivating HIV (as a means to clear latent virus with highly active antiretroviral therapy), we were able to inhibit PEL growth in vitro and delay tumor growth in a PEL xenograft tumor model. KSHV reactivation was mediated by activation of the NF-κB pathway by PEP005, which led to increased occupancy of RNA polymerase II onto the KSHV genome. RNA-sequencing analysis further revealed cellular targets of PEP005, JQ1, and the synergistic effects of both. Thus, combination of PEP005 with a BET inhibitor may be considered as a rational therapeutic approach for the treatment of PEL. Mol Cancer Ther; 16(11); 2627–38. ©2017 AACR .

    更新日期:2017-11-10
  • HIF2{alpha} targeted RNAi therapeutic inhibits clear cell renal cell carcinoma
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    So C. Wong, Weijun Cheng, Holly Hamilton, Anthony L Nicholas, Darren H Wakefield, Aaron Almeida, Andrei V Blokhin, Jeffrey Carlson, Zane C Neal, Vladimir Subbotin, Guofeng Zhang, Julia Hegge, Stephanie Bertin, Vladimir S Trubetskoy, David B Rozema, David L Lewis, Steven B. Kanner

    Targeted therapy against VEGF and mTOR pathways has been established as the standard-of-care for metastatic clear cell renal cell carcinoma (ccRCC); however, these treatments frequently fail and most patients become refractory requiring subsequent alternative therapeutic options. Therefore, development of innovative and effective treatments is imperative. About 80-90% of ccRCC tumors express an inactive mutant form of the von Hippel-Lindau protein (pVHL), an E3 ubiquitin ligase that promotes target protein degradation. Strong genetic and experimental evidence supports the correlate that pVHL functional loss leads to the accumulation of the transcription factor hypoxia-inducible factor 2α (HIF2α) and that an over-abundance of HIF2α functions as a tumorigenic driver of ccRCC. In this report, we describe an RNAi therapeutic for HIF2α that utilizes a targeting ligand that selectively binds to integrins αvβ3 and αvβ5 frequently over-expressed in ccRCC. We demonstrate that functional delivery of a HIF2α specific RNAi trigger resulted in HIF2α gene silencing and subsequent tumor growth inhibition and degeneration in an established orthotopic ccRCC xenograft model.

    更新日期:2017-11-10
  • Selective and concentrated accretion of SN-38 with a CEACAM5-targeting antibody-drug conjugate (ADC), labetuzumab govitecan (IMMU-130)
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Robert M. Sharkey, Serengulam V. Govindan, Thomas M. Cardillo, Jennifer Donnell, Jing Xia, Edmund A Rossi, Chien-Hsing Chang, David M. Goldenberg

    Labetuzumab govitecan (IMMU-130), an antibody-drug conjugate (ADC) with an average of 7.6 SN-38/IgG, was evaluated for its potential to enhance delivery of SN-38 to human colonic tumor xenografts. Mice bearing LS174T or GW-39 human colonic tumor xenografts were injected with irinotecan or IMMU-130 (SN-38 equivalents ~500 µg or ~16 µg, respectively). Serum and homogenates of tumors, liver, and small intestine were extracted, and SN-38, SN-38G (glucuronidated SN-38), and irinotecan concentrations determined by reversed-phase HPLC. Irinotecan cleared quickly from serum, with only 1-2% injected dose/mL after 5 min; overall, ~20% was converted to SN-38 andSN-38G. At 1 h with IMMU-130, 45-63% injected dose/mL of the SN-38 was in the serum, with >90% bound to the ADC over 3 days, and with low levels of SN-38G. Total SN-38 levels decreased more quickly than the IgG, confirming a gradual SN-38 release from the ADC. Area under the curve analysis found SN-38 levels were ~11- and 16-fold higher in LS174T and GW-39 tumors, respectively, in IMMU-130-treated animals. This delivery advantage is amplified >30-fold when normalized to SN-38 equivalents injected for each product. Levels of SN-38 and SN-38G were appreciably lower in the liver and small intestinal contents in animals given IMMU-130. Based on the SN-38 equivalents administered, IMMU-130 potentially delivers >300-fold more SN-38 to CEA-producing tumors compared to irinotecan, while also reducing levels of SN-38 and SN-38G in normal tissues. These observations are consistent with preclinical and clinical data showing efficacy and improved safety.

    更新日期:2017-11-10
  • Ceramide nanoliposomes as a MLKL-dependent, necroptosis-inducing, chemotherapeutic reagent in ovarian cancer
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Xuewei Zhang, Kazuyuki Kitatani, Masafumi Toyoshima, Masumi Ishibashi, Toshinori Usui, Junko Minato, Mahy Egiz, Shogo Shigeta, Todd Fox, Tye Deering, Mark Kester, Nobuo Yaegashi

    Ceramides are bioactive lipids that mediate cell death in cancer cells and ceramide-based therapy is now being tested in dose-escalating phase 1 clinical trials as a cancer treatment. Multiple nanoscale delivery systems for ceramide have been proposed to overcome the inherent toxicities, poor pharmacokinetics and difficult biophysics associated with ceramide. Using the ceramide nanoliposomes (CNL) we now investigate the therapeutic efficacy and signaling mechanisms of this nanoscale delivery platform in refractory ovarian cancer. Treatment of ovarian cancer cells with CNL decreased the number of living cells through necroptosis but not apoptosis. Mechanistically, dying SKOV3 ovarian cancer cells exhibit activation of pseudokinase mixed lineage kinase domain-like (MLKL) as evidenced by oligomerization and relocalization to the blebbing membranes, showing necroptotic characteristics. Knock-down of MLKL, but not its upstream protein kinases such as receptor-interacting protein kinases, with siRNA significantly abolished CNL-induced cell death. Monomeric MLKL protein expression inversely correlated with the IC50 values of CNL in distinct ovarian cancer cell lines, suggesting MLKL as a possible determinant for CNL-induced cell death. Finally, systemic CNL administration suppressed metastatic growth in an ovarian cancer cell xenograft model. Taken together, these results suggest that MLKL is a novel pro-necroptotic target for ceramide in ovarian cancer models.

    更新日期:2017-11-10
  • Histone deacetylase inhibition enhances the antitumor activity of a MEK inhibitorin lung cancer cells harboring RAS mutations
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Tadaaki Yamada, Joseph M Amann, Azusa Tanimoto, Hirokazu Taniguchi, Takehito Shukuya, Cynthia Timmers, Seiji Yano, Konstantin Shilo, David P Carbone

    Non-small-cell lung cancer (NSCLC) can be identified by precise molecular subsets based on genomic alterations that drive tumorigenesis and include mutations in EGFR, KRAS, and various ALK fusions. However, despite effective treatments for EGFR and ALK, promising therapeutics have not been developed for patients with KRAS mutations. It has been reported that one way the RAS-ERK pathway contributes to tumorigenesis is by affecting stability and localization of FOXO3a protein, an important regulator of cell death and the cell cycle. This is through regulation of apoptotic proteins BIM and FASL and cell cycle regulators p21Cip1 and p27 Kip1. We now show that a HDAC inhibitor affects the expression and localization of FOXO proteins and wanted to determine if the combination of a MEK inhibitor with a HDAC inhibitor would increase the sensitivity of NSCLC with KRAS mutation. Combined treatment with a MEK inhibitor and a HDAC inhibitor showed synergistic effects on cell metabolic activity of RAS mutated lung cancer cells through activation of FOXOs, with a subsequent increase in BIM and cell cycle inhibitors. Moreover, in a mouse xenograft model, the combination of belinostat and trametinib significantly decreases tumor formation through FOXOs by increasing BIM and the cell cycle inhibitors p21Cip1 and p27 Kip1. These results demonstrate that control of FOXOs localization and expression is critical in RAS driven lung cancer cells, suggesting that the dual molecular targeted therapy for MEK and HDACs may be promising as novel therapeutic strategy in NSCLC with specific populations of RAS mutations.

    更新日期:2017-11-10
  • miR-20a regulates Fas expression in osteosarcoma cells by modulating Fas promoter activity and can be therapeutically targeted to inhibit lung metastases
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Yuanzheng Yang, Gangxiong Huang, Zhichao Zhou, Jason G. Fewell, Eugenie S. Kleinerman

    The metastatic potential of osteosarcoma cells is inversely correlated to cell surface Fas expression. Downregulation of Fas allows osteosarcoma cells to escape Fas ligand-mediated apoptosis when they enter a Fas ligand-positive microenvironment such as the lung. We have previously demonstrated that miR-20a, encoded by the miR-17-92 cluster, downregulates Fas expression in osteosarcoma. We further demonstrated an inverse correlation between Fas expression and miR-20a expression. However, the mechanism of Fas regulation by miR-20a was still unclear. The purpose of the current study was to evaluate the mechanism of Fas regulation by miR-20a in vitro and test the effect of targeting miR-20a in vivo. We investigated whether miR-20a's downregulation of Fas was mediated by binding to the 3' untranslated region (3'-UTR) of Fas mRNA with the consequent induction of mRNA degradation or translational suppression. We identified and mutated two miR-20a binding sites on the Fas mRNA 3'-UTR. Using luciferase reporter assays, we demonstrated that miR-20a did not bind to either the wild-type or mutated Fas 3'-UTR. By contrast, overexpression of miR-20a resulted in downregulation of Fas promoter activity. Similarly, the inhibition of miR-20a increased Fas promoter activity. The critical region identified on the Fas promoter was between -240 bp and 150 bp. Delivery of anti-miR-20a in vivo using nanoparticles in mice with established osteosarcoma lung metastases resulted in upregulation of Fas and tumor growth inhibition. Taken together, our data suggest that miR-20a regulates Fas expression through the modulation of the Fas promoter and that targeting miR-20a using anti-miR-20a has therapeutic potential.

    更新日期:2017-11-10
  • ALK inhibitor response in melanomas expressing EML4-ALK fusions and alternate ALK isoforms
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Kasey L. Couts, Judson Bemis, Jacqueline A. Turner, Stacey M. Bagby, Danielle Murphy, Jason Christiansen, Jennifer D Hintzsche, Anh Le, Todd M Pitts, Keith Wells, Allison Applegate, Carol Amato, Pratik Multani, Edna Chow-Maneval, John J. Tentler, Yiqun G. Shellman, Matthew J. Rioth, Aik-Choon Tan, Rene Gonzalez, Theresa Medina, Robert C. Doebele, William A Robinson

    Oncogenic ALK fusions occur in several types of cancer and can be effectively treated with ALK inhibitors; however, ALK fusions and treatment response have not been characterized in malignant melanomas. Recently, a novel isoform of ALK (ALKATI) was reported in 11% of melanomas but the response of melanomas expressing ALKATI to ALK inhibition has not been well characterized. We analyzed 45 melanoma patient-derived xenograft models for ALK mRNA and protein expression. ALK expression was identified in 11 out of 45 (24.4%) melanomas. Ten melanomas express wild type (wt) ALK and/or ALKATI and one mucosal melanoma expresses multiple novel EML4-ALK fusion variants. Melanoma cells expressing different ALK variants were tested for response to ALK inhibitors. Whereas the melanoma expressing EML4-ALK were sensitive to ALK inhibitors in vitro and in vivo, the melanomas expressing wt ALK or ALKATI were not sensitive to ALK inhibitors. Additionally, a patient with mucosal melanoma expressing ALKATI was treated with an ALK/ROS1/TRK inhibitor (entrectinib) on a phase I trial but did not respond. Our results demonstrate ALK fusions occur in malignant melanomas and respond to targeted therapy whereas melanomas expressing ALKATI do not respond to ALK inhibitors. Targeting ALK fusions is an effective therapeutic option for a subset of melanoma patients, but additional clinical studies are needed to determine the efficacy of targeted therapies in melanomas expressing wt ALK or ALKATI.

    更新日期:2017-11-10
  • Caveolae-mediated endocytosis as a novel mechanism of resistance to trastuzumab emtansine (T-DM1)
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Matthew Sung, Xingzhi Tan, Bingwen Lu, Jonathan Golas, Christine Hosselet, Fang Wang, Laurie Tylaska, Lindsay King, Dahui Zhou, Russell Dushin, Jeremy S. Myers, Edward Rosfjord, Judy Lucas, Hans-Peter Gerber, Frank Loganzo

    Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) that has demonstrated clinical benefit for patients with HER2+ metastatic breast cancer, however its clinical activity is limited by inherent or acquired drug resistance. The molecular mechanisms that drive clinical resistance to T-DM1, especially in HER2+ tumors, are not well understood. We used HER2+ cell lines to develop models of T-DM1 resistance utilizing a cyclical dosing schema in which cells received T-DM1 in an "on-off" routine until a T-DM1 resistant population was generated. T-DM1 resistant N87 cells (N87-TM) were cross-resistant to a panel of trastuzumab-ADCs (T-ADCs) with non-cleavable-linked auristatins. N87-TM cells do not have a decrease in HER2 protein levels or an increase in drug transporter protein (e.g. MDR1) expression compared to parental N87 cells. Intriguingly, T-ADCs utilizing auristatin payloads attached via an enzymatically cleavable linker overcome T-DM1 resistance in N87-TM cells. Importantly, N87-TM cells implanted into athymic mice formed T-DM1 refractory tumors which remain sensitive to T-ADCs with cleavable-linked auristatin payloads. Comparative proteomic profiling suggested enrichment in proteins that mediate caveolae formation and endocytosis in the N87-TM cells. Indeed, N87-TM cells internalize T-ADCs into intracellular caveolin-1 (CAV1) positive puncta and alter their trafficking to the lysosome compared to N87 cells. T-DM1 colocalization into intracellular CAV1 positive puncta correlated with reduced response to T-DM1 in a panel of HER2+ cell lines. Together, these data suggest caveolae-mediated endocytosis of T-DM1 may serve as a novel predictive biomarker for patient response to T-DM1.

    更新日期:2017-11-10
  • Overcoming resistance to cetuximab with honokiol, a small-molecule polyphenol
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Hannah E Pearson, Mari Iida, Rachel A Orbuch, Nellie K McDaniel, Kwangok P. Nickel, Randall J. Kimple, Jack Arbiser, Deric L. Wheeler

    Overexpression and activation of the Epidermal Growth Factor Receptor (EGFR) have been linked to poor prognosis in several human cancers. Cetuximab is a monoclonal antibody against EGFR, that is used for the treatment in head and neck squamous cell carcinoma (HNSCC) and metastatic colorectal cancer. Unfortunately, most tumors have intrinsic or acquire resistance to cetuximab during the course of therapy. Honokiol is a natural compound found in the bark and leaves of the Chinese Magnolia tree and is established to have several anti-cancer properties without appreciable toxicity. In this study, we hypothesized that combining cetuximab and honokiol treatments could overcome acquired resistance to cetuximab. We previously developed a model of acquired resistance to cetuximab in non-small cell lung cancer cell line. Treatment of cetuximab resistant clones with honokiol and cetuximab resulted in a robust anti-proliferative response. Immunoblot analysis revealed the HER family and their signaling pathways were downregulated after combination treatment, most notably the proliferation (MAPK) and survival (AKT) pathways. Additionally, we found a decrease in phosphorylation of DRP1 and reactive oxygen species after combination treatment in cetuximab resistant clones which may signify a change in mitochondrial function. Furthermore, we utilized cetuximab resistant HNSCC patient derived xenografts (PDX) to test the benefit of combinatorial treatment in vivo. There was significant growth delay in PDX tumors after combination treatment with a subsequent down-regulation of active MAPK, AKT, and DRP1 signaling as seen in vitro. Collectively these data suggest that honokiol is a promising natural compound in overcoming acquired resistance to cetuximab.

    更新日期:2017-11-10
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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