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The novel ATR inhibitor M1774 induces replication protein overexpression and broad synergy with DNA-targeted anticancer drugs Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-03-11 Ukhyun Jo, Yashuhiro Arakawa, Astrid Zimmermann, Daiki Taniyama, Makito Mizunuma, Lisa M. Jenkins, Tapan Maity, Suresh Kumar, Frank T. Zenke, Naoko Takebe, Yves Pommier
Ataxia Telangiectasia and Rad3-related (ATR) checkpoint kinase inhibitors are in clinical trials. Here we explored the molecular pharmacology and therapeutic combination strategies of the oral ATR inhibitor M1774 (Tuvusertib) with DNA damaging agents (DDAs). As single agent, M1774 suppressed cancer cell viability at nanomolar concentrations, showing greater activity than ceralasertib and berzosertib
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89Zr-ImmunoPET for the Specific Detection of EMP2-Positive Tumors Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-02-28 Ann M. Chan, Tove Olafsen, Jessica Tsui, Felix B. Salazar, Brian Aguirre, Kirstin A. Zettlitz, Michael Condro, Anna M. Wu, Jonathan Braun, Lynn K. Gordon, Negin Ashki, Julian Whitelegge, Shili Xu, Oluwatayo Ikotun, Jason Thanh. Lee, Madhuri Wadehra
Epithelial membrane protein-2 (EMP2) is upregulated in a number of tumors and therefore remains a promising target for monoclonal antibody (mAb)-based therapy. In the current study, image guided therapy for an anti-EMP2 mAb was evaluated by positron emission tomography (PET) in both syngeneic and immunodeficient cancer models expressing different levels of EMP2 in order to enable a better understanding
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ATPase copper transporting beta (ATP7B) is a novel target for improving the therapeutic efficacy of docetaxel by disulfiram/copper in human prostate cancer. Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-02-28 Liankun Song, Vyvyan Nguyen, Jun Xie, Shang JIa, Christopher J. Chang, Edward Uchio, Xiaolin Zi
Docetaxel has been the standard first-line chemotherapy for lethal metastatic prostate cancer (mPCa) since 2004, but resistance to docetaxel treatment is common. The molecular mechanisms of docetaxel resistance remain largely unknown and could be amenable to interventions that mitigate resistance. We have recently discovered that several docetaxel-resistant mPCa cell lines exhibit lower uptake of cellular
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Thio-2 inhibits key signaling pathways required for the development and progression of castration resistant prostate cancer. Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-02-27 Antje Neeb, Ines Figueiredo, Denisa Bogdan, Laura Cato, Jutta Stober, Juan M. Jiménez-Vacas, Victor Gourain, Irene I. Lee, Rebecca Seeger, Claudia Muhle-Goll, Bora Gurel, Jonathan Welti, Daniel Nava Rodrigues, Jan Rekowski, Xintao Qiu, Yija Jiang, Patrizio Di Micco, Borja Mateos, Stasė Bielskutė, Ruth Riisnaes, Ana Ferreira, Susana Miranda, Mateus Crespo, Lorenzo Buroni, Jian Ning, Suzanne Carreira
Therapies that abrogate persistent androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC) remain an unmet clinical need. The N-terminal domain (NTD) of the AR that drives transcriptional activity in CRPC remains a challenging therapeutic target. Herein we demonstrate that BAG-1 mRNA is highly expressed and associates with signaling pathways, including AR signaling, that are
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Structural Basis for Multivalent MUC16 Recognition and Robust Anti-Pancreatic Cancer Activity of Humanized Antibody AR9.6 Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-02-23 Eric N. Aguilar, Satish Sagar, Brandy R. Murray, Christabelle Rajesh, Eric K. Lei, Sarah A. Michaud, David R. Goodlett, Thomas C. Caffrey, Paul M. Grandgenett, Benjamin Swanson, Teresa M. Brooks, Adrian R. Black, Henk van Faassen, Greg Hussack, Kevin A. Henry, Michael A. Hollingsworth, Cory L. Brooks, Prakash Radhakrishnan
Mucin-16 (MUC16) is a target for antibody-mediated immunotherapy in pancreatic ductal adenocarcinoma (PDAC) amongst other malignancies. The MUC16 specific monoclonal antibody AR9.6 has shown promise for PDAC immunotherapy and imaging. Here, we report the structural and biological characterization of the humanized AR9.6 antibody (huAR9.6). The structure of huAR9.6 was determined in complex with a MUC16
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Mitochondrial and cytosolic one-carbon metabolism is a targetable metabolic vulnerability in cisplatin-resistant ovarian cancer Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-02-20 Adrianne Wallace-Povirk, Carrie O'Connor, Aamod S. Dekhne, Xun Bao, Md. Junayed Nayeen, Mathew Schneider, Jade M. Katinas, Jennifer Wong-Roushar, Seongho Kim, Lisa Polin, Jing Li, Jessica B. Back, Charles E. Dann, Aleem Gangjee, Zhanjun Hou, Larry H. Matherly
One-carbon (C1) metabolism is compartmentalized between the cytosol and mitochondria with the mitochondrial C1 pathway as the major source of glycine and C1 units for cellular biosynthesis. Expression of mitochondrial C1 genes including SLC25A32, serine hydroxymethyl transferase (SHMT) 2, 5,10-methylene tetrahydrofolate dehydrogenase 2, and 5,10-methylene tetrahydrofolate dehydrogenase 1-like was significantly
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Biomarkers for antibody-drug conjugates in solid tumors Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-02-16 Jalissa Katrini, Laura Boldrini, Celeste Santoro, Carmine Valenza, Dario Trapani, Giuseppe Curigliano
The clinical development and then the progressive entry in clinical practice of antibody-drug conjugates (ADCs) have marked a transformative advancement in the overall cancer treatment. ADCs have been extensively tested for a large number of tumors, reporting heterogeneous clinical efficacy and safety results. In some diseases, the advent of ADCs has yielded significant changes in the prognostic trajectory
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Molecular landscape of FaDu xenograft tumors in mice after a combinatorial treatment with radiation and an HSP90 inhibitor identifies adaptation-induced targets Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-02-15 Michelle Bylicky, Uma Shankavaram, Molykutty J. John-Aryankalayil, Sunita Chopra, Sarwat Naz, Anastasia L. Sowers, Rajani Choudhuri, Valerie Calvert, Emanuel F. Petricoin, Iris Eke, James B. Mitchell, C. Norman Coleman
Treatments involving radiation and chemotherapy alone or in combination have improved patient survival and quality of life. However, cancers frequently evade these therapies due to adaptation and tumor evolution. Given the complexity of predicting response based solely on the initial genetic profile of a patient, a pre-determined treatment course may miss critical adaptation that can cause resistance
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Design and evaluation of ZD06519, a novel camptothecin payload for antibody drug conjugates Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-02-14 Mark E. Petersen, Michael G. Brant, Manuel Lasalle, Samir Das, Renee Duan, Jodi Wong, Tong Ding, Kaylee J. Wu, Dayananda Siddappa, Chen Fang, Wen Zhang, Alex M. L. Wu, Truman Hirkala-Schaefer, Graham A. E. Garnett, Vincent Fung, Luying Yang, Andrea Hernandez Rojas, Samuel O. Lawn, Stuart D. Barnscher, Jamie R. Rich, Raffaele Colombo
In recent years, the field of antibody drug conjugates (ADCs) has seen a resurgence, largely driven by the clinical benefit observed in patients treated with ADCs incorporating camptothecin-based topoisomerase I inhibitor payloads. Herein, we present the development of a novel camptothecin ZD06519 (FD1), which has been specifically designed for its application as an ADC payload. A panel of camptothecin
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Development of a Novel DNA Mono-alkylator Platform for Antibody Drug Conjugates Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-02-14 Joshua D. Thomas, Aleksandr V. Yurkovetskiy, Mao Yin, Natalya D. Bodyak, Shuyi Tang, Marina Protopopova, Eugene Kelleher, Brian Jones, Liping Yang, Daniel Custar, Kalli C. Catcott, Damon R. Demady, Scott D. Collins, Ling Xu, Charlie Bu, LiuLiang Qin, Elena Ter-Ovanesyan, Marc Damelin, Dorin Toader, Timothy B. Lowinger
Although microtubule inhibitors (MTI) remain a therapeutically valuable payload option for antibody drug conjugates (ADCs), some cancers do not respond to MTI-based ADCs. Efforts to fill this therapeutic gap have led to a recent expansion of the ADC payload "toolbox" to include payloads with novel mechanisms of action such as topoisomerase inhibition and DNA crosslinking. We present here the development
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Interferon gamma induces higher neutrophil extracellular traps leading to tumor-killing activity in microsatellite stable colorectal cancer Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-02-13 Hao-Wei Teng, Tean-Ya Wang, Chun-Chi Lin, Zhen-Jie Tong, Hsiao-Wei Cheng, Hsiang-Tsui Wang
Many colorectal cancer (CRC) patients do not respond to immune checkpoint blockade (ICB) therapy, highlighting the urgent need to understand tumor resistance mechanisms. Recently, the link between the IFNγ signaling pathway integrity and ICB resistance in the CRC tumor microenvironment has been revealed. The immunosuppressive microenvironment poses a significant challenge to antitumor immunity in CRC
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Evaluating for correlations between metabolites in patients receiving immunotherapy for metastatic or recurrent NSCLC: an exploratory study based on two cohorts Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-02-13 Yanjun Xu, Kaibo Ding, Zhongsheng Peng, Ling Ding, Hui Li, Yun Fan
ICIs have demonstrated stunning clinical efficacy in NSCLC. However, most patients do not achieve long-term survival. Minimally invasive collected samples are attracting significant interest as new fields of biomarker study, and metabolomics is one of these growing fields. We focused on the added value of the metabolomic profile as a means of distinguishing long-term survival from short-term survival
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Trastuzumab-MMAU Antibody-Auristatin Conjugates: Valine-Glucoserine Linker with Stabilized Maleimide Conjugation Improves In Vivo Efficacy and Tolerability Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-02-07 Shalom D. Goldberg, Tero Satomaa, Olulanu Aina, Olli Aitio, Krista Burke, Vadim Dudkin, Brian Geist, Onyi Irrechukwu, Anna-Liisa Hänninen, Annamari Heiskanen, Jari Helin, Jukka O. Hiltunen, Jacqueline Kinyamu-Akunda, Donna M. Klein, Neeraj Kohli, Titta Kotiranta, Tuula Lähteenmäki, Ritva Niemelä, Virve Pitkänen, Henna Pynnönen, William Rittase, Kristen Wiley, Junguo Zhou, Juhani Saarinen
Purpose: Antibody-drug conjugates (ADCs) have shown impressive clinical activity with approval of many agents in hematological and solid tumors. However, challenges remain with both efficacy and safety of ADCs. This study describes novel trastuzumab-auristatin conjugates with the hydrophilic MMAE prodrug MMAU, and optimization of a glycopeptide linker leading to a wider therapeutic window. Experimental
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ADCT-602, a novel PBD dimer–containing antibody–drug conjugate for treating CD22-positive hematological malignancies Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-02-07 Francesca Zammarchi, Karin E. Havenith, Nikoleta Sachini, Narinder Janghra, Simon Chivers, Esohe Idusogie, Eugenio Gaudio, Chiara Tarantelli, Francois Bertelli, Kathleen Santos, Peter Tyrer, Simon Corbett, Filippo Spriano, Gaetanina Golino, Luciano Cascione, Francesco Bertoni, John A. Hartley, Patrick H. van Berkel
Relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) and lymphomas have poor patient outcomes; novel therapies are needed. CD22 is an attractive target for antibody–drug conjugates (ADCs), being highly expressed in R/R B-ALL with rapid internalization kinetics. ADCT-602 is a novel CD22-targeting ADC, consisting of humanized monoclonal antibody hLL2-C220, site-specifically conjugated
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Momordicine-I suppresses head and neck cancer growth by reprogrammimg immunosuppressive effect of the tumor-infiltrating macrophages and B lymphocytes Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-02-05 Subhayan Sur, Pradeep Bhartiya, Robert Steele, Michelle Brennan, Richard J. DiPaolo, Ratna B. Ray
Head and neck cancer (HNC) is prevalent worldwide, and treatment options are limited. Momordicine-I (M-I), a natural component from bitter melon, shows antitumor activity against these cancers, but its mechanism of action, especially in the tumor microenvironment (TME), remains unclear. In this study, we establish that M-I reduces HNC tumor growth in two different immunocompetent mouse models using
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Polyploidy in Cancer: causal mechanisms, cancer-specific consequences, and emerging treatments Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-02-05 Patrick J. Conway, Jonathan Dao, Dmytro Kovalskyy, Daruka Mahadevan, Eloise Dray
Drug resistance is the major determinant for metastatic disease and fatalities, across all cancers. Depending on the tissue of origin and the therapeutic course, a variety of biological mechanisms can support and sustain drug resistance. While genetic mutations and gene silencing through epigenetic mechanisms are major culprits in targeted therapy, drug efflux and polyploidization are more global mechanisms
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Macrophages as targets in hepatocellular carcinoma therapy Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-02-04 Yu-ting Liu, Zheng-wei Mao, Yuan Ding, Wei-lin Wang
Hepatocellular carcinoma (HCC) is a malignant tumor with a complex and diverse immunosuppressive microenvironment. Tumor-associated macrophages (TAMs) are an essential component of the tumor immune microenvironment. TAMs typically exist in two primary states: anti-tumor M1 macrophages and pro-tumor M2 macrophages. Remarkably, TAMs possess high plasticity, enabling them to switch between different subtypes
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Enhanced Anti-Pediatric Sarcomas Effect of Everolimus with Secukinumab by Targeting IL-17A Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-01-31 Dan Huang, Zhipeng Wu, Zhengyi Wu, Nuoya Li, Liang Hao, Kuangfan Li, Junquan Zeng, Bingbing Qiu, Shouhua Zhang, Jinlong Yan
In this study, we explored the therapeutic potential of everolimus, an mTOR inhibitor, in a patient-derived xenograft (PDX) of rhabdomyosarcoma, the most prevalent malignant pediatric sarcoma. Additionally, rhabdoid tumor cell line A-204 and Ewings sarcoma cell line A-673 were cultured to assess the in vitro effect of everolimus. Furthermore, the cell-derived xenograft (CDX) of A-673 was established
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Differential distribution of the DNA-PKcs inhibitor peposertib selectively radiosensitizes patient-derived melanoma brain metastasis xenografts Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-01-22 Jianxiong Ji, Sonja Dragojevic, Cameron M. Callaghan, Emily J. Smith, Surabhi Talele, Wenjuan Zhang, Margaret A. Connors, Ann C. Mladek, Zeng Hu, Katrina K. Bakken, Paige P. Sarkaria, Brett L. Carlson, Danielle M. Burgenske, Paul A. Decker, Mohammad Abdur Rashid, Mi-Hyeon Jang, Shiv K. Gupta, Jeanette E. Eckel-Passow, William F. Elmquist, Jann N. Sarkaria
Radioresistance of melanoma brain metastases limits the clinical utility of conventionally fractionated brain radiation in this disease, and strategies to improve radiation response could have significant clinical impact. The catalytic subunit of DNA-dependent protein kinase (DNA- PKcs) is critical for repair of radiation-induced DNA damage, and inhibitors of this kinase can have potent effects on
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Simvastatin overcomes resistance to tyrosine kinase inhibitors in patient-derived, oncogene-driven lung adenocarcinoma models Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-01-18 Weijie Ma, Sixi Wei, Qianping Li, Jie Zeng, Wenwu Xiao, Chihong Zhou, Ken Y. Yoneda, Amir A. Zeki, Tianhong Li
There is an unmet clinical need to develop novel strategies to overcome resistance to tyrosine kinase inhibitors (TKIs) in patients with oncogene-driven lung adenocarcinoma (LUAD). The objective of this study was to determine if simvastatin could overcome TKI resistance using the in vitro and in vivo LUAD models. Human LUAD cell lines, tumor cells, and patient-derived xenografts (PDXs) from TKI-resistant
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Cereblon-Based Bifunctional Degrader of SOS1, BTX-6654, Targets Multiple KRAS Mutations and Inhibits Tumor Growth Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-01-15 Kyle Begovich, Angela Schoolmeesters, Navin Rajapakse, Elena Martinez-Terroba, Maneesh Kumar, Arvind Shakya, Chon Lai, Steven Greene, Brandon Whitefield, Akinori Okano, Venkat Mali, Shenlin Huang, Aparajita H. Chourasia, Leah Fung
Mutations within the oncogene KRAS drive an estimated 25% of all cancers. Only allele-specific KRAS G12C inhibitors are currently available and are associated with the emergence of acquired resistance, partly due to upstream pathway reactivation. Given its upstream role in the activation of KRAS, Son of Sevenless homologue 1 (SOS1), has emerged as an attractive therapeutic target. Agents that target
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Raludotatug Deruxtecan, a CDH6-Targeting Antibody-Drug Conjugate with a DNA Topoisomerase I Inhibitor DXd, is Efficacious in Human Ovarian and Kidney Cancer Models Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-01-11 Hirokazu Suzuki, Shotaro Nagase, Chiemi Saito, Atsuko Takatsuka, Motoko Nagata, Kokichi Honda, Yuki Kaneda, Yumi Nishiya, Tomoyo Honda, Tomomichi Ishizaka, Kensuke Nakamura, Takashi Nakada, Yuki Abe, Toshinori Agatsuma
Cadherin-6 (CDH6) is expressed in several cancer types, but no CDH6-targeted therapy is currently clinically available. Here, we generated raludotatug deruxtecan (R-DXd; DS-6000), a novel CDH6-targeting antibody-drug conjugate with a potent DNA topoisomerase I inhibitor, and evaluated its properties, pharmacological activities, and safety profile. In vitro pharmacological activities and the mechanisms
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PROTACs: Current and Future Potential as a Precision Medicine Strategy to Combat Cancer Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-01-11 Kailee A. Rutherford, Kirk J. McManus
PROTACs (proteolysis targeting chimeras) are an emerging precision medicine strategy that targets key proteins for proteolytic degradation to ultimately induce cancer cell killing. These hetero-bifunctional molecules hijack the ubiquitin proteasome system to selectively add polyubiquitin chains onto a specific protein target to induce proteolytic degradation. Importantly, PROTACs have the capacity
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Elimusertib has anti-tumor activity in preclinical patient-derived pediatric solid tumor models Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-12-30 Fabian F. Pusch, Heathcliff Dorado Garcia, Robin Xu, Dennis Gürgen, Yi Bei, Lotte Brückner, Claudia Röefzaad, Jennifer von Stebut, Victor Bardinet, Rocío Chamorro Gonzalez, Angelika Eggert, Johannes H. Schulte, Patrick Hundsdörfer, Georg Seifert, Kerstin Haase, Beat W. Schäfer, Marco Wachtel, Anja A. Kühl, Michael V. Ortiz, Antje M. Wengner, Monika Scheer, Anton G. Henssen
The small molecule inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), elimusertib, is currently being tested clinically in various cancer entities in adults and children. Its preclinical anti-tumor activity in pediatric malignancies, however, is largely unknown. We here assessed the preclinical activity of elimusertib in 38 cell lines and 32 patient-derived xenograft (PDX) models derived
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The methyltransferases METTL7A and METTL7B confer resistance to thiol-based histone deacetylase inhibitors Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-12-28 Robert W. Robey, Christina M. Fitzsimmons, Wilfried M. Guiblet, William J.E. Frye, José M. González Dalmasy, Li Wang, Drake A. Russell, Lyn M. Huff, Andrew J. Perciaccante, Fatima Ali-Rahmani, Crystal C. Lipsey, Heidi M. Wade, Allison V. Mitchell, Siddhardha S. Maligireddy, David Terrero, Donna Butcher, Elijah F. Edmondson, Lisa M. Jenkins, Tatiana Nikitina, Victor B. Zhurkin, Amit K. Tiwari, Anthony
Histone deacetylase inhibitors (HDACis) are part of a growing class of epigenetic therapies used for the treatment of cancer. Although HDACis are effective in the treatment of T-cell lymphomas, treatment of solid tumors with this class of drugs has not been successful. Overexpression of the multidrug resistance protein P-glycoprotein (P-gp), encoded by ABCB1, is known to confer resistance to the HDACi
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A review of recent advances in the molecular mechanisms underlying brain metastasis in lung cancer Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-12-21 Chao Guan, Xiaoye Zhang, Li Yu
Brain metastasis from lung cancer is a prevalent mode of treatment failure associated with a poor prognosis. The incidence of brain metastasis has recently shown a dramatic increase. The early detection and risk stratification of lung cancer-related brain metastasis would be highly advantageous for patients. However, our current knowledge and comprehension of the underlying mechanisms driving brain
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Palazestrant (OP-1250), a Complete Estrogen Receptor Antagonist, Inhibits Wild-type and Mutant ER-positive Breast Cancer Models as Monotherapy and in Combination Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-12-16 Alison D. Parisian, Susanna A. Barratt, Leslie Hodges-Gallagher, Fabian E. Ortega, Guadalupe Peña, Judevin Sapugay, Brandon Robello, Richard Sun, David Kulp, Gopinath S. Palanisamy, David C. Myles, Peter J. Kushner, Cyrus L. Harmon
The estrogen receptor (ER) is a well-established target for the treatment of breast cancer, with the majority of patients presenting as ER-positive (ER+). Endocrine therapy is a mainstay of breast cancer treatment but the development of resistance mutations in response to aromatase inhibitors, poor pharmacokinetic properties of fulvestrant, agonist activity of tamoxifen, and limited benefit for elacestrant
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4’-Ethynyl-2’-Deoxycytidine (EdC) Preferentially Targets Lymphoma and Leukemia Subtypes by Inducing Replicative Stress Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-12-08 Marissa L. Calbert, Gurushankar Chandramouly, Clare M. Adams, Magali Saez-Ayala, Tatiana Kent, Mrityunjay Tyagi, V.S.S. Abhinav Ayyadevara, Yifan Wang, John J. Krais, John Gordon, Jessica Atkins, Monika M. Toma, Stéphane Betzi, Andrew S. Boghossian, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Aaron R. Goldman, Nicole Gorman, Ramkrishna Mitra, Wayne E. Childers, Xavier Graña, Tomasz Skorski
Anticancer nucleosides are effective against solid tumors and hematological malignancies, but typically are prone to nucleoside metabolism resistance mechanisms. Using a nucleoside-specific multiplexed high-throughput screening approach, we discovered 4’-ethynyl-2’-deoxycytidine (EdC) as a third-generation anticancer nucleoside prodrug with preferential activity against diffuse large B-cell lymphoma
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TAS0313 Plus Pembrolizumab for Post-Chemotherapy Immune Checkpoint Inhibitor-Naïve Locally Advanced or Metastatic Urothelial Carcinoma Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-12-07 Hiroyuki Nishiyama, Junji Yonese, Takashi Kawahara, Ryuji Matsumoto, Hideaki Miyake, Nobuaki Matsubara, Hiroji Uemura, Masatoshi Eto, Haruhito Azuma, Wataru Obara, Akito Terai, Satoshi Fukasawa, Shigetaka Suekane
We evaluated the efficacy and safety of TAS0313, a multi-epitope long peptide vaccine, plus pembrolizumab in post-chemotherapy immune checkpoint inhibitor-naïve patients with locally advanced/metastatic urothelial carcinoma. TAS0313 9 mg was administered subcutaneously followed by pembrolizumab 200 mg on Day 1, and as monotherapy on Day 8 and 15 of Cycles 1 and 2, and Day 1 of subsequent cycles in
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Combination therapy with EGFR tyrosine kinase inhibitors and TEAD inhibitor increases tumor suppression effects in EGFR mutation-positive lung cancer Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-12-06 Tatsuya Ogimoto, Hiroaki Ozasa, Takahiro Tsuji, Tomoko Funazo, Masatoshi Yamazoe, Kentaro Hashimoto, Hiroshi Yoshida, Kazutaka Hosoya, Hitomi Ajimizu, Takashi Nomizo, Hironori Yoshida, Masatsugu Hamaji, Toshi Menju, Akihiko Yoshizawa, Hiroshi Date, Toyohiro Hirai
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the first-line therapies for EGFR mutation-positive lung cancer. EGFR-TKIs have favorable therapeutic effects. However, a large proportion of patients with EGFR mutation-positive lung cancer subsequently relapse. Some cancer cells survive the initial treatment with EGFR-TKIs, and this initial survival may be associated with
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ERBB4-Mediated Signaling Is a Mediator of Resistance to PI3K and BTK Inhibitors in B-cell Lymphoid Neoplasms Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-12-06 Alberto J. Arribas, Sara Napoli, Luciano Cascione, Laura Barnabei, Giulio Sartori, Eleonora Cannas, Eugenio Gaudio, Chiara Tarantelli, Afua A. Mensah, Filippo Spriano, Antonella Zucchetto, Francesca M. Rossi, Andrea Rinaldi, Manuel Castro de Moura, Sandra Jovic, Roberta Bordone Pittau, Anastasios Stathis, Georg Stussi, Valter Gattei, Jennifer R. Brown, Manel Esteller, Emanuele Zucca, Davide Rossi,
BTK and PI3K inhibitors are among the drugs approved for the treatment of patients with lymphoid neoplasms. Although active, their ability to lead to long-lasting complete remission is rather limited, especially in the lymphoma setting. This indicates that tumor cells often develop resistance to the drugs. We started from a marginal zone lymphoma cell line, Karpas-1718, kept under prolonged exposure
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Roles of cGAS-STING pathway in radiotherapy combined with immunotherapy for hepatocellular carcinoma Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-12-05 Jianing Ma, Yuning Xin, Qiang Wang, Lijuan Ding
Although great strides have been made in the management and treatment of hepatocellular carcinoma (HCC), its prognosis is still poor yielding a high mortality. Immunotherapy is recommended for treating advanced HCC, but its efficiency is hampered due to hepatic immunosuppression. Stimulator of interferon genes (STING) pathway, serving as a critical cytoplasmic DNA-sensing process, is reported to initiate
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Darolutamide added to docetaxel augments antitumor effect in models of prostate cancer through cell cycle arrest at the G1-S transition Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-11-30 Stefan A.J. Buck, Annelies Van Hemelryk, Corrina de Ridder, Debra Stuurman, Sigrun Erkens-Schulze, Sem Van 't Geloof, Wilma J. Teubel, Stijn L.W. Koolen, Elena S. Martens-Uzunova, Martin E. van Royen, Ronald de Wit, Ron H. J. Mathijssen, Wytske M. van Weerden
Resistance to taxane chemotherapy is frequently observed in metastatic prostate cancer. The androgen receptor (AR) is a major driver of prostate cancer and a key regulator of the G1-S cell cycle checkpoint, promoting cancer cell proliferation by irreversible passage to the S-phase. We hypothesized that AR signaling inhibitor (ARSi) darolutamide in combination with docetaxel could augment antitumor
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XTX301, a tumor-activated Interleukin-12 has the potential to widen the therapeutic index of IL-12 treatment for solid tumors as evidenced by pre-clinical studies Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-11-30 Ekta Patel, Natalia V. Malkova, David Crowe, Magali Pederzoli-Ribeil, Damiano Fantini, Manoussa Fanny, Hanumantha Rao Madala, Kurt A. Jenkins, Oleg Yerov, Justin Greene, Wilson Guzman, Caitlin O'Toole, Jacob Taylor, Rebekah K. O’Donnell, Parker Johnson, Bernard B. Lanter, Brian Ames, Jia Chen, Sallyann Vu, Hsin-Jung Wu, Susan Cantin, Megan McLaughlin, Yu-Shan S. Hsiao, Dheeraj S. Tomar, Raphael Rozenfeld
Interleukin-12 (IL-12) is a proinflammatory cytokine, that has shown promising anti-tumor activity in humans by promoting the recruitment and activation of immune cells in tumors. However, the systemic administration of IL-12 has been accompanied by considerable toxicity, prompting interest in researching alternatives to drive preferential IL-12 bioactivity in the tumor. Here, we have generated XTX301
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Glucocorticoid receptor (GR) activation is associated with increased cAMP/PKA signaling in castrate-resistant prostate cancer Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-11-30 Lynda Bennett, Praveen Kumar. Jaiswal, Ryan V. Harkless, Tiha M. Long, Ning Gao, Brianna Vandenburg, Phillip Selman, Ishrat Durdana, Ricardo R. Lastra, Donald Vander Griend, Remi Adelaiye-Ogala, Russell Z. Szmulewitz, Suzanne D. Conzen
In castrate-resistant prostate cancer (CRPC), increased glucocorticoid receptor (GR) expression and ensuing transcriptional activity have been proposed as an oncogenic “bypass” mechanism in response to androgen receptor (AR) signaling inhibition (ARSi). Here, we report that GR transcriptional activity acquired following ARSi is associated with the upregulation of cyclic adenosine monophosphate (cAMP)-associated
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Targeting Dysregulated Ion Channels in Liver Tumors with Venom Peptides Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-11-28 Favour Achimba, Bulat Faezov, Brandon Cohen, Roland Dunbrack, Mande Holford
The regulation of cellular processes by ion channels has become central to the study of cancer mechanisms. Designing molecules that can modify ion channels specific to tumor cells is a promising area of targeted drug delivery and therapy. Despite their potential in drug discovery, venom peptides – a group of natural products – have largely remained understudied and under-characterized. In general,
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Circulating oncometabolite 2-hydroxyglutarate (2HG) as a potential biomarker for isocitrate dehydrogenase (IDH1/2) mutant cholangiocarcinoma Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-11-28 Cha Len Lee, Grainne M. O'Kane, Warren P. Mason, Wen-Jiang Zhang, Pavlina Spiliopoulou, Aaron R. Hansen, Robert C. Grant, Jennifer J. Knox, Tracy L. Stockley, Gelareh Zadeh, Eric X. Chen
Isocitrate dehydrogenase (IDH) enzymes catalyze the decarboxylation of isocitrate to alpha-ketoglutarate. IDH1/2 mutations preferentially convert αKG to R-2-hydroxyglutarate (R2HG), resulting in R2HG accumulation in tumor tissues. We investigated circulating 2-hydroxyglutate (2HG) as potential biomarkers for patients with IDH-mutant (IDHmt) cholangiocarcinoma (CCA). R2HG and S-2-hydroxyglutarate (S2HG)
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PUMA/RIP3 mediates chemotherapy response via necroptosis and local immune activation in colorectal cancer Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-11-23 Dongshi Chen, Kaylee Ermine, Yi-Jun Wang, Xiaojun Chen, Xinyan Lu, Peng Wang, Donna Beer-Stolz, Jian Yu, Lin Zhang
Induction of programmed cell death (PCD) is a key cytotoxic effect of anticancer therapies. PCD is not confined to caspase-dependent apoptosis, but includes necroptosis, a regulated form of necrotic cell death controlled by Receptor-Interacting Protein (RIP) kinases 1 and 3, and Mixed Lineage Kinase Domain-Like (MLKL) pseudo-kinase. Necroptosis functions as a defense mechanism against oncogenic mutations
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Interleukin 35: New Target for Immunotherapy Targeting the Tumor Microenvironment Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-11-21 Pengcheng Yi, Wenjun Yu, Yanhong Xiong, Yao Dong, Qiang Huang, Yue Lin, Yunfei Du, Fuzhou Hua
Interleukin 35 (IL-35) is a newly discovered inhibitory cytokine of the interleukin 12 family. More recently, IL-35 was found to be increased in the tumor microenvironment (TME) and peripheral blood of many cancer patients, indicating that it plays an important role in TME. Tumors secrete cytokines that recruit myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Treg) into the TME to promote
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Oncogenic cells of renal embryonic lineage sensitive to the small molecule inhibitor QC6352 display depletion of KDM4 levels and disruption of ribosome biogenesis Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-11-21 Prahalathan Pichavaram, Carolyn M. Jablonowski, Jie Fang, Andrew M. Fleming, Hyea Jin Gil, Andrew S. Boghossian, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Christopher L. Morton, Gerard P. Zambetti, Andrew M. Davidoff, Jun Yang, Andrew J. Murphy
The histone lysine demethylases KDM4A-C are involved in physiologic processes including stem cell identity and self-renewal during development, DNA-damage repair, and cell cycle progression. KDM4A-C are overexpressed and associated with malignant cell behavior in multiple human cancers and are therefore potential therapeutic targets. Given the role of KDM4A-C in development and cancer, we aimed to
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The antipsychotic drug penfluridol inhibits N-linked glycoprotein processing and enhances T-cell-mediated tumor immunity Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-11-15 Wenlong Xu, Yuqi Wang, Na Zhang, Xiaofeng Lin, Di Zhu, Cheng Shen, Xiaobo Wang, Haiyang Li, Jinjiang Xue, Qian Yu, Xinyi Lu, Lu Zhou, Qingli He, Zhijun Tang, Shaodan He, Jianjun Fan, Jianbo Pan, Jiangjiang Tang, Wei Jiang, Mingliang Ye, Fanghui Lu, Zengxia Li, Yongjun Dang
Aberrant N-linked glycosylation is a prominent feature of cancers. Perturbance of oligosaccharide structure on cell surfaces directly affects key processes in tumor development and progression. In spite of the critical role played by N-linked glycans in tumor biology, the discovery of small molecules that specifically disturbs the N-linked glycans is still under investigation. To identify more sac
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Radiation Synergizes with IL-2/IL-15 Stimulation to Enhance Innate Immune Activation and Antitumor Immunity Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-11-13 Xuefeng Li, Kristin Huntoon, Yifan Wang, DaeYong Lee, Shiyan Dong, Abin Antony, Carl Walkey, Betty Y.S. Kim, Wen Jiang
Ionizing radiation is known to possess immune modulatory properties. However, how radiotherapy (RT) may complement with different types of immunotherapies to boost antitumor responses is unclear. In mice implanted with EO771 syngeneic tumors, NL-201 a stable, highly potent CD25-independent agonist to interleukin (IL)-2 and IL-15 receptors with enhanced affinity for IL-2Rβγ was given with or without
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Novel Methionine Aminopeptidase 2 Inhibitor M8891 Synergizes with VEGF Receptor Inhibitors to Inhibit Tumor Growth of Renal Cell Carcinoma Models Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-11-09 Manja Friese-Hamim, Maria J. Ortiz-Ruiz, Olga Bogatyrova, Marina Keil, Felix Rohdich, Beatrix Blume, Birgitta Leuthner, Frank Czauderna, Diane Hahn, Julia Jabs, Frank Jaehrling, Timo Heinrich, Roland Kellner, Katherine Chan, Amy H. Y. Tong, Dirk Wienke, Jason Moffat, Andree Blaukat, Frank T. Zenke
N-terminal processing by methionine aminopeptidases (MetAP) is a crucial step in the maturation of proteins during protein biosynthesis. Small molecule inhibitors of MetAP2 have anti-angiogenic and antitumoral activity. Herein, we characterize the structurally novel MetAP2 inhibitor M8891. M8891 is a potent, selective, reversible small molecule inhibitor blocking the growth of human endothelial cells
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Genetic silencing of AKT induces melanoma cell death via mTOR suppression Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-11-06 Gennie L. Parkman, Tursun Turapov, David A. Kircher, William J. Burnett, Christopher M. Stehn, Kayla O'Toole, Katie M. Culver, Ashley T. Chadwick, Riley C. Elmer, Ryan Flaherty, Karly A. Stanley, Mona Foth, David H. Lum, Robert L. Judson-Torres, John E. Friend, Matthew W. VanBrocklin, Martin McMahon, Sheri L. Holmen
Aberrant activation of the PI3K-AKT pathway is common in many cancers including melanoma, and AKT1, 2 and 3 (AKT1-3) are bona fide oncoprotein kinases with well-validated downstream effectors. However, efforts to pharmacologically inhibit AKT have proven to be largely ineffective. In this study, we observed paradoxical effects following either pharmacologic or genetic inhibition of AKT1-3 in melanoma
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Improving Intracellular Delivery of an Antibody-Drug Conjugate Targeting Carcinoembryonic Antigen Increases Efficacy at Clinically Relevant Doses In Vivo Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-11-01 Ian Nessler, Baron Rubahamya, Anna Kopp, Scott Hofsess, Thomas M. Cardillo, Nalini Sathyanarayan, Jennifer Donnell, Serengulam V. Govindan, Greg M. Thurber
Solid tumor antibody-drug conjugates (ADCs) have experienced more clinical success in the last five years than the previous 18-year span since the first ADC approval in 2000. While recent advances in protein engineering, linker design, and payload variations have played a role in this success, high expression and readily internalized targets have also been crucial to solid tumor therapy. However, these
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TAS0612, a novel RSK, AKT, and S6K inhibitor, exhibits antitumor effects in preclinical tumor models Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-10-31 Koji Ichikawa, Satoshi Ito, Emi Kato, Naomi Abe, Takumitsu Machida, Junya Iwasaki, Gotaro Tanaka, Hikari Araki, Kentaro Wakayama, Hideki Jona, Tetsuya Sugimoto, Kazutaka Miyadera, Shuichi Ohkubo
The mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways are involved in cancer growth and survival; however, the clinical efficacy of single inhibitors of each pathway is limited or transient owing to resistance mechanisms, such as feedback signaling and/or re-expression of receptor-type tyrosine kinases (RTKs). This study identified a potent and novel kinase inhibitor
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Adoptive T cells therapy in solid tumors: state-of-the art, current challenges, and upcoming improvements Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-10-30 Aurore Dougé, Nathan EL GHAZZI, Richard Lemal, Paul Rouzaire
In solid tumors, three main complementary approaches of adoptive T cell therapies were successively developed: tumor infiltrating lymphocytes (TILs), chimeric antigen receptor (CAR) engineered T cells and high-affinity T cell receptor (TCR) engineered T cells. In this review, we summarized rational and main results of these three adoptive T cell therapies in solid tumors field and gave an overview
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SKP2 knockout in Rb1/p53 deficient mouse models of osteosarcoma induces immune infiltration and drives a transcriptional program with a favorable prognosis Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-10-24 Alexander Ferrena, Jichuan Wang, Ranxin Zhang, Burcu Karadal-Ferrena, Waleed Al-Hardan, Swapnil Singh, Hasibagan Borjihan, Edward L. Schwartz, Hongling Zhao, Maja H. Oktay, Rui Yang, David S. Geller, Bang H. Hoang, Deyou Zheng
Osteosarcoma (OS) is an aggressive bone malignancy with a poor prognosis. One putative proto-oncogene in OS is SKP2, encoding a substrate recognition factor of the SCF E3 ubiquitin ligase. We previously demonstrated that SKP2 knockout in murine OS improved survival and delayed tumorigenesis. Here we performed RNA-sequencing (RNA-seq) on tumors from a transgenic OS mouse model with conditional Trp53
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Dual CAR-T cells targeting CD19 and CD37 are effective in target antigen loss B cell tumor models. Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-10-13 Kanae Imai, Yuki Takeuchi, Seitaro Terakura, Shingo Okuno, Yoshitaka Adachi, Masahide Osaki, Koji Umemura, Ryo Hanajiri, Kazuyuki Shimada, Makoto Murata, Hitoshi Kiyoi
Chimeric antigen receptor T (CAR-T) cells targeting multiple antigens, may reduce the risk of immune escape following the loss of the target antigen and further increase the efficacy of treatment. We developed dual-targeting CAR-T cells that target CD19 and CD37 antigens and evaluated their antitumor effects. CD19/CD37 dual CAR-T cells were generated using co-transduction and simultaneous gene transfer
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Design and evaluation of phosphonamidate-linked exatecan constructs for highly loaded, stable, and efficacious Antibody-Drug-Conjugates Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-10-13 Saskia Schmitt, Paul Machui, Isabelle Mai, Sarah Herterich, Swetlana Wunder, Philipp Cyprys, Marcus Gerlach, Philipp Ochtrop, Christian P. R. Hackenberger, Dominik Schumacher, Jonas Helma, Annette M. Vogl, Marc-Andre Kasper
Topoisomerase I (TOP1) Inhibitors constitute an emerging payload class to engineer Antibody-Drug-Conjugates (ADCs) as next-generation biopharmaceutical for cancer treatment. Existing ADCs are utilizing camptothecin payloads with lower potency and suffer from limited stability in circulation. With this study, we introduce a novel camptothecin-based linker-payload platform based on the highly potent
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Delivery versus potency in treating brain tumors: BI-907828, a MDM2-p53 antagonist with limited BBB penetration but significant in vivo efficacy in glioblastoma Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-10-13 Wenjuan Zhang, Rachael A. Vaubel, Ju-Hee Oh, Ann C. Mladek, Surabhi Talele, Wenqiu Zhang, Katie L. Waller, Danielle M. Burgenske, Jann N. Sarkaria, William F. Elmquist
MDM2-p53 inhibition may be effective in glioblastoma. This study evaluates the PK/PD of BI-907828, a potent antagonist of MDM2, in GBM, and demonstrates a translational paradigm with a focus on a unified “Delivery – Potency – Efficacy” relationship in drug development for CNS tumors. BI-907828 was tested for cytotoxicity and MDM2-p53 pathway inhibition. Systemic pharmacokinetics and transport mechanisms
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An antibody-drug conjugate directed to tissue factor shows preclinical anti-tumor activity in head and neck cancer as a single agent and in combination with chemoradiotherapy Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-10-13 Jantine E. Bakema, Marijke Stigter-van Walsum, Jeffrey R. Harris, Sonja H. Ganzevles, Anantharaman Muthuswamy, Mischa Houtkamp, Theo S. Plantinga, Elisabeth Bloemena, Ruud H. Brakenhoff, Esther C.W. Breij, Rieneke van de Ven
Head and neck squamous cell carcinoma (HNSCC) is a solid tumor type that arises in the squamous epithelial cells lining of the mucosal surfaces of the upper aerodigestive tract¬. Long term survival of patients with advanced disease stage remains disappointing with current treatment options. We show that tissue factor is abundantly expressed on patient-derived HNSCC cell lines, xenograft tumor material
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CD38 x ICAM-1 Bispecific Antibody is a Novel Approach for Treating Multiple Myeloma and Lymphoma Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-10-11 Xiaocheng Chen, Oi Kwan Wong, Lauren Reiman, Daniel W. Sherbenou, Leonard Post
The cluster of differentiation 38 (CD38) is a well validated target for treating multiple myeloma (MM). Although anti-CD38 monoclonal antibodies have demonstrated outstanding initial responses in patients with multiple myeloma, nearly all patients eventually develop resistance and relapse. In addition, currently approved CD38 targeting therapies have failed to show monotherapy efficacy in lymphomas
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Bifunctional inhibitor reveals NEK2 as a therapeutic target and regulator of oncogenic pathways in lymphoma Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-10-11 Mason McCrury, Kennith Swafford, Sydnye L. Shuttleworth, Syed Hassan. Mehdi, Baku Acharya, Debasmita Saha, Kevin Naceanceno, Stephanie D. Byrum, Aaron J. Storey, Ying-Zhi Xu, Claire Doshier, Vijay Patel, Ginell R. Post, Annick De Loose, Analiz Rodriguez, Leonard D. Shultz, Fenghuang Zhan, Donghoon Yoon, Brendan Frett, Samantha Kendrick
Expression of the serine/threonine kinase NEK2 is essential for entry into mitosis via its role in facilitating centrosome separation. Its overactivity can lead to tumorigenesis and drug resistance through the activation of several oncogenic pathways including AKT. While the cancer-enabling activities of NEK2 are documented in many malignancies, including correlations with poor survival in myeloma
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Amelioration of Tumor-Promoting Microenvironment via Vascular Remodeling and CAF Suppression using E7130: Biomarker Analysis by Multi-modal Imaging Modalities Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-10-10 Ken Ito, Masayuki Yamaguchi, Taro Semba, Kimiyo Tabata, Moe Tamura, Muneo Aoyama, Takanori Abe, Osamu Asano, Yasuhiko Terada, Yasuhiro Funahashi, Hirofumi Fujii
E7130 is a novel anti-cancer agent created from total synthetic study of the natural compound norhalichondrin B. In addition to inhibiting microtubule dynamics, E7130 also ameliorates tumor-promoting aspects of the tumor microenvironment (TME) by suppressing cancer-associated fibroblasts (CAFs) and promoting remodeling of tumor vasculature. Here, we demonstrate TME amelioration by E7130 using multi-imaging
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Effects of Combined Therapeutic Targeting of AXL and ATR on Pleural Mesothelioma Cells Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-10-07 Soichi Hirai, Tadaaki Yamada, Yuki Katayama, Masaki Ishida, Hayato Kawachi, Yohei Matsui, Ryota Nakamura, Kenji Morimoto, Mano Horinaka, Toshiyuki Sakai, Yoshitaka Sekido, Shinsaku Tokuda, Koichi Takayama
Few treatment options exist for pleural mesothelioma (PM), which is a progressive malignant tumor. However, the efficacy of molecular-targeted monotherapy is limited, and further therapeutic strategies are warranted to treat PM. Recently, the cancer cell cycle checkpoint inhibitors have attracted attention because they disrupt cell cycle regulation. Here, we aimed to establish a novel combinational
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Neutrophil elastase remodels mammary tumors to facilitate lung metastasis Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-10-05 Amriti R. Lulla, Said Akli, Cansu Karakas, Joseph A. Caruso, Lucas D. Warma, Natalie W. Fowlkes, Xiayu Rao, Jing Wang, Kelly K. Hunt, Stephanie S. Watowich, Khandan Keyomarsi
Metastatic disease remains the leading cause of death due to cancer, yet the mechanism(s) of metastasis and its timely detection remain to be elucidated. Neutrophil elastase (NE), a serine protease secreted by neutrophils, is a crucial mediator of chronic inflammation and tumor progression. In this study, we used the PyMT model (NE+/+ and NE-/-) of breast cancer to interrogate the tumor-intrinsic and
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Development of a Novel CLDN18.2-directed Monoclonal Antibody and Antibody-drug Conjugate for Treatment of CLDN18.2 Positive Cancers Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-10-03 Neil A. O'Brien, Martina S.J. McDermott, Jun Zhang, Ke Wei Gong, Ming Lu, Benjamin Hoffstrom, Tong Luo, Raul Ayala, Kevin Chau, Min Liang, Athena M. Madrid, Timothy R. Donahue, John A. Glaspy, Leonard Presta, Dennis J. Slamon
Gastric and pancreatic cancers are malignancies of high unmet clinical need. Expression of CLDN18.2 in these cancers, coupled with its absence from most normal tissues, provides a potential therapeutic window against this target. We present preclinical development and characterization of a novel therapeutic monoclonal antibody (mAb) and antibody drug conjugate (ADC) targeting CLDN18.2. A humanized
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Brentuximab Vedotin-Driven Microtubule Disruption Results in Endoplasmic Reticulum Stress Leading to Immunogenic Cell Death and Antitumor Immunity Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-09-30 Ryan A. Heiser, Anthony T. Cao, Weiping Zeng, Michelle Ulrich, Patrick Younan, Martha E. Anderson, Esther S. Trueblood, Mechthild Jonas, Robert Thurman, Che-Leung Law, Shyra J. Gardai
Brentuximab vedotin, a CD30-directed antibody–drug conjugate (ADC), is approved for clinical use in multiple CD30-expressing lymphomas. The cytotoxic payload component of brentuximab vedotin is monomethyl auristatin E (MMAE), a highly potent microtubule-disrupting agent. Preclinical results provided here demonstrate that treatment of cancer cells with brentuximab vedotin or free MMAE leads to a catastrophic
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Site-specific Dolasynthen antibody-drug conjugates exhibit consistent pharmacokinetic profiles across a wide range of drug to antibody ratios Mol. Cancer Ther. (IF 5.7) Pub Date : 2023-09-29 Susan M. Clardy, Alex Uttard, Bingfan Du, Kalli C. Catcott, Kelly L. Lancaster, Elizabeth Ditty, Jack Sadowsky, Jeffrey Zurita, Naniye Malli, Liuliang Qin, Stephen P. Bradley, Kenneth Avocetien, Tyler Carter, Dokyong Kim, Mark Nazzaro, Ling Xu, Thomas H. Pillow, Neelie T. Zacharias, Gail D. Lewis, Rebecca K. Rowntree, Radha Iyengar, David H. Lee, Marc Damelin, Dorin Toader, Timothy B. Lowinger
Key defining attributes of an antibody-drug conjugate (ADC) include the choice of the targeting antibody, linker, payload, and the drug-to-antibody ratio (DAR). Historically, most ADC platforms have used the same DAR for all targets, regardless of target characteristics. However, recent studies and modeling suggest that the optimal DAR can depend on target expression level and intratumoral heterogeneity