-
First-in-human stage III/IV melanoma clinical trial of immune priming agent IFx-Hu2.0 Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-04-24 Joseph Markowitz, Michael Shamblott, Andrew S. Brohl, Amod A. Sarnaik, Zeynep Eroglu, Nikhil I. Khushalani, Christopher W. Dukes, Alejandra Chamizo, Marina Bastawrous, Edward T. Garcia, Ashraf Delhawi, Pei-Ling Chen, Deanryan B. De Aquino, Vernon K. Sondak, Ahmad A. Tarhini, Youngchul Kim, Patricia Lawman, Shari Pilon-Thomas
IFx-Hu2.0 was designed to encode part of the Emm55 protein contained within a plasmid in a formulation intended for transfection into mammalian cells. IFx-Hu2.0 promotes both adaptive and innate immune responses in animal studies. Furthermore, previous studies have demonstrated safety/efficacy in equine, canine, and murine species. We present the first-in-human study of IFx-Hu2.0, administered by intralesional
-
Enhancing standard of care chemotherapy efficacy using DNA-dependent protein kinase (DNA-PK) inhibition in preclinical models of Ewing sarcoma Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-04-24 Victor J. Collins, Katelyn R. Ludwig, Ariana E. Nelson, Soumya Sundara Rajan, Choh Yeung, Ksenia Vulikh, Kristine A. Isanogle, Arnulfo Mendoza, Simone Difilippantonio, Baktiar O. Karim, Natasha J. Caplen, Christine M. Heske
Disruption of DNA damage repair via impaired homologous recombination is characteristic of Ewing sarcoma (EWS) cells. We hypothesize that this disruption results in increased reliance on non-homologous end joining (NHEJ) to repair DNA damage. In this study, we investigated if pharmacological inhibition of the enzyme responsible for NHEJ, the DNA-PK holoenzyme, alters the response of EWS cells to genotoxic
-
Anti-tumor activity of a novel LAIR1 antagonist in combination with anti-PD-1 to treat collagen-rich solid tumors Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-04-22 B. Leticia Rodriguez, Jiawei Huang, Laura Gibson, Jared J. Fradette, Hung-I H. Chen, Kikuye Koyano, Czrina Cortez, Betty Li, Carmence Ho, Amir M. Ashique, Vicky Y. Lin, Suzanne Crawley, Julie M. Roda, Peirong Chen, Bin Fan, Jeong Kim, James Sissons, Jonathan Sitrin, Daniel D. Kaplan, Don L. Gibbons, Lee B. Rivera
We recently reported that resistance to PD-1-blockade in a refractory lung cancer-derived model involved increased collagen deposition and the collagen-binding inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), and thus we hypothesized that LAIR1 and collagen cooperated to suppress therapeutic response. Here, we report LAIR1 is associated with tumor stroma and is highly
-
A selective Fibroblast Growth Factor Receptor 1/2 PROTAC degrader with antitumor activity Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-04-22 Ying Kong, Xinyue Zhao, Zhaofu Wang, Siqi Yuan, Sheng Chen, Shidi Lou, Shichao Ma, Yunfeng Li, Xinghao Wang, Yangfeng Ge, Guobin Li, Hongbing Yang, Mengxi Zhao, Dandan Li, Hailong Zhang, Wenfu Tan, Juan Wang
The aberrant activation of fibroblast growth factor receptor (FGFR) acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is largely compromised due to low selectivity and side effects. Here, we report the selective FGFR1/2-targeting proteolysis targeting chimeric (PROTAC), BR-cpd7 that displays
-
A bispecific antibody that targets the membrane-proximal region of mesothelin and retains high anticancer activity in the presence of shed mesothelin Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-04-22 Anirban Chakraborty, Masanori Onda, Tara O'Shea, Junxia Wei, Xiufen Liu, Tapan K. Bera, Ira Pastan
Mesothelin (MSLN) is a cell-surface protein that is expressed on many cancers, which makes it a popular target for antibody-based cancer therapy. However, MSLN is shed from cancer cells at high levels via proteases that cleave at its membrane-proximal C-terminal region. Shed MSLN accumulates in patient fluids and tumors and can block antibody-based MSLN-targeting drugs from killing cancer cells. A
-
SMG5 Inhibition Restrains Hepatocellular Carcinoma Growth and Enhances Sorafenib Sensitivity Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-04-22 Nan Fang, Bing Liu, Qiuzhong Pan, Tingting Gong, Meixiao Zhan, Jingjing Zhao, Qijing Wang, Yan Tang, Yongqiang Li, Jia He, Tong Xiang, Fengze Sun, Ligong Lu, Jianchuan Xia
Hepatocellular carcinoma (HCC) has a pathogenesis that remains elusive with restricted therapeutic strategies and efficacy. This study aimed to investigate the role of SMG5, a crucial component in nonsense-mediated mRNA decay (NMD) that degrades mRNA containing a premature termination codon (PTC), in HCC pathogenesis and therapeutic resistance. We demonstrated an elevated expression of SMG5 in HCC
-
INA03, a potent transferrin-competitive antibody-drug conjugate against CD71, for a safer acute leukemia treatment Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-04-20 Manuela Bratti, Elisa Stubbs, Sergii Kolodych, Herve Souchet, Lois Kelly, Johanna Merlin, Michelle Marchal, Remy Castellano, Emmanuelle Josselin, Hélène Pasquer, Lina Benajiba, Alexandre Puissant, Oleksandr Koniev, Yves Collette, Coralie Belanger, Olivier Hermine, Renato C. Monteiro, Pierre Launay
Innovative strategies to enhance efficacy and overcome drug resistance in hematologic cancers such as antibody-drug conjugates (ADCs) have shifted the paradigm of conventional care by delivering promising outcomes in cancer therapies with a significant reduction in the risk of relapse. The transferrin receptor 1, CD71, known to be overexpressed in malignant cells, is considered a potent anti-tumoral
-
The SOS1 Inhibitor MRTX0902 Blocks KRAS Activation and Demonstrates Antitumor Activity in Cancers Dependent on KRAS Nucleotide Loading Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-04-20 Niranjan Sudhakar, Larry Yan, Fadia Qiryaqos, Lars D. Engstrom, Jade Laguer, Andrew Calinisan, Allan Hebbert, Laura Waters, Krystal Moya, Vickie Bowcut, Laura Vegar, John M. Ketcham, Anthony Ivetac, Christopher R. Smith, J David. Lawson, Lisa Rahbaek, Jeffrey Clarine, Natalie Nguyen, Barbara Saechao, Cody Parker, Adam J. Elliott, Darin Vanderpool, Leo He, Laura D. Hover, Julio Fernandez-Banet, Silvia
KRAS is the most frequently mutated oncogene in human cancer and facilitates uncontrolled growth through hyperactivation of the RTK/MAPK pathway. The Son of Sevenless homolog 1 (SOS1) protein functions as a guanine nucleotide exchange factor (GEF) for the RAS subfamily of small GTPases and represents a druggable target in the pathway. Using a structure-based drug discovery approach, MRTX0902 was identified
-
Assessment of Patient-Derived Xenograft Growth and Antitumor Activity: The NCI PDXNet Consensus Recommendations Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-04-20 Funda Meric-Bernstam, Michael W. Lloyd, Soner Koc, Yvonne A. Evrard, Lisa Meier. McShane, Michael T. Lewis, Kurt W. Evans, Dali Li, Lawrence V. Rubinstein, Alana L. Welm, Dennis A. Dean, Anuj Srivastava, Jeffrey W. Grover, Min Jin Ha, Huiqin Chen, Xuelin Huang, Kaushik Varadarajan, Jing Wang, Jack A. Roth, Bryan E. Welm, Ramaswamy Govindan, Li Ding, Salma Kaochar, Nicholas Mitsiades, Luis G. Carvajal-Carmona
Although patient-derived xenografts (PDXs) are commonly used for preclinical modeling in cancer research, a standard approach to in vivo tumor growth analysis and assessment of antitumor activity is lacking, complicating comparison of different studies and determination of whether a PDX experiment has produced evidence needed to consider a new therapy promising. We present consensus recommendations
-
Near-infrared Photoimmunotherapy Targeting Cancer-Associated Fibroblasts in Patient-Derived Xenografts using a Humanized anti-Fibroblast Activation Protein Antibody Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-04-18 Teruki Kobayashi, Kazuhiro Noma, Seitaro Nishimura, Takuya Kato, Noriyuki Nishiwaki, Toshiaki Ohara, Tomoyoshi Kunitomo, Kento Kawasaki, Masaaki Akai, Satoshi Komoto, Hajime Kashima, Satoru Kikuchi, Hiroshi Tazawa, Yasuhiro Shirakawa, Peter L. Choyke, Hisataka Kobayashi, Toshiyoshi Fujiwara
Esophageal cancer remains a highly aggressive malignancy with a poor prognosis, despite ongoing advancements in treatments such as immunotherapy. The tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), plays a crucial role in driving the aggressiveness of esophageal cancer. In a previous study utilizing human-derived xenograft models, we successfully developed a novel cancer
-
Optimizing the design and geometry of T cell engaging bispecific antibodies targeting CEA in colorectal cancer Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-04-18 Abdullah Elsayed, Louis Plüss, Larissa Nideroest, Giulia Rotta, Marina Thoma, Nathan Zangger, Frederik Peissert, Stefanie K. Pfister, Christian Pellegrino, Sheila Dakhel Plaza, Roberto De Luca, Markus G. Manz, Annette Oxenius, Emanuele Puca, Cornelia Halin, Dario Neri
Metastatic colorectal cancer (mCRC) remains a leading cause of cancer-related deaths, with a 5-year survival rate of only 15%. T cell engaging bispecific antibodies (TCBs) represent a class of biopharmaceuticals that redirect cytotoxic T cells towards tumor cells, thereby turning immunologically "cold" tumors "hot." The carcinoembryonic antigen (CEA) is an attractive tumor-associated antigen (TAA)
-
Proton FLASH radiotherapy ameliorates radiation-induced salivary gland dysfunction and oral mucositis and increases survival in a mouse model of head and neck cancer Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-04-09 Priyanka Chowdhury, Anastasia Velalopoulou, Ioannis I. Verginadis, George Morcos, Phoebe E. Loo, Michele M. Kim, Seyyedeh Azar Oliaei Motlagh, Khayrullo Shoniyozov, Eric S. Diffenderfer, Emilio A. Ocampo, Mary Putt, Charles-Antoine Assenmacher, Enrico Radaelli, Jiawei Lu, Ling Qin, Hengxi Liu, Nektaria Maria Leli, Swati Girdhani, Nicolas Denef, Francois Vander Stappen, Keith A. Cengel, Theresa M. Busch
Head and neck cancer radiotherapy often damages salivary glands and oral mucosa, severely negatively impacting patients’ quality of life. The ability of FLASH- Proton Radiation therapy (F-PRT) to decrease normal tissue toxicity while maintaining tumor control compared to Standard Proton Radiation therapy (S-PRT) has been previously demonstrated for several tissues. However, its potential in ameliorating
-
Discovery of a long half-life AURKA inhibitor to treat MYC-amplified solid tumors as a monotherapy and in combination with everolimus Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-04-09 Chun-Ping Chang, Teng-Kuang Yeh, Chiung-Tong CHEN, Wan-Ping Wang, Yen-Ting Chen, Chia-Hua Tsai, Yan-Fu Chen, Yi-Yu Ke, Jing-Ya Wang, Ching-Ping Chen, Tsung-Chih Hsieh, Mine-Hsine Wu, Chen-Lung Huang, Ya-Ping Chen, Hong Zhuang, Ya-Hui Chi
Aurora kinase inhibitors such as alisertib can destabilize MYC-family oncoproteins and have demonstrated compelling anti-tumor efficacy. In this study, we report 6K465, a novel pyrimidine-based Aurora A (AURKA) inhibitor that reduces levels of c-MYC and N-MYC oncoproteins more potently than alisertib. In an analysis of the antiproliferative effect of 6K465, the sensitivities of small cell lung cancer
-
A novel dual ATM/DNA-PK inhibitor, XRD-0394, potently radiosensitizes and potentiates PARP and topoisomerase I inhibitors Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-04-08 Tona M. Gilmer, Chun-Hsiang Lai, Kexiao Guo, Katherine Deland, Kathleen A. Ashcraft, Amy E. Stewart, Yaode Wang, Jianmin Fu, Kris C. Wood, David G. Kirsch, Michael B. Kastan
A majority of cancer patients receive radiation therapy as part of their treatment regimens whether using external beam therapy or locally-delivered radioisotopes. While often effective, some tumors are inadequately controlled with radiation and radiation therapy has significant short-term and long-term toxicities for cancer survivors. Insights into molecular mechanisms involved in cellular responses
-
Pharmacological Characterization of SDX-7320/Evexomostat: a Novel Methionine Aminopeptidase Type 2 Inhibitor with Anti-Tumor and Anti-Metastatic Activity Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-03-26 Peter Cornelius, Benjamin A. Mayes, John S. Petersen, David J. Turnquist, Pierre J. Dufour, Andrew J. Dannenberg, James M. Shanahan, Bradley J. Carver
Methionine aminopeptidase type 2 (MetAP2) is a ubiquitous, evolutionarily conserved metalloprotease fundamental to protein biosynthesis which catalyzes removal of the N-terminal methionine residue from nascent polypeptides. MetAP2 is an attractive target for cancer therapeutics based upon its over-expression in multiple human cancers, the importance of MetAP2-specific substrates whose biological activity
-
Ultrasensitive response explains the benefit of combination chemotherapy despite drug antagonism Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-03-26 Sarah C. Patterson, Amy E. Pomeroy, Adam C. Palmer
Most aggressive lymphomas are treated with combination chemotherapy, commonly as multiple cycles of concurrent drug administration. Concurrent administration is in theory optimal when combination therapies have synergistic (more than additive) drug interactions. We investigated pharmacodynamic interactions in the standard 4-drug ‘CHOP’ regimen in Peripheral T-Cell Lymphoma (PTCL) cell lines and found
-
Inhibition of MALT1 and BCL2 induces synergistic anti-tumor activity in models of B cell lymphoma Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-03-20 Joshua P. Plotnik, Adam E. Richardson, Haopeng Yang, Estela Rojas, Velitchka Bontcheva, Colleen Dowell, Sydney Parsons, Ashley Wilson, Vida Ravanmehr, Christine Will, Paul Jung, Haizhong Zhu, Sarathy Karunan. Partha, Sanjay C. Panchal, Raghuveer Singh Mali, Frederick J. Kohlhapp, Ryan A. McClure, Cyril Y. Ramathal, Mariam D. George, Manisha Jhala, Nathaniel L. Elsen, Wei Qiu, Russell A. Judge, Chin
The activated B cell (ABC) subset of diffuse large B cell lymphoma (DLBCL) is characterized by chronic B cell receptor signaling and associated with poor outcomes when treated with standard therapy. In ABC-DLBCL, MALT1 is a core enzyme that is constitutively activated by stimulation of the B cell receptor or gain-of-function mutations in upstream components of the signaling pathway, making it an attractive
-
The CDK4/6 inhibitor Palbociclib synergizes with ATRA to induce differentiation in AML Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-03-20 Linhui Hu, Qian Li, Jiyu Wang, Huiping Wang, Xiyang Ren, Keke Huang, Yangyang Wang, Xue Liang, Lianfang Pu, Shudao Xiong, Zhimin Zhai
Differentiation therapy based on ATRA almost cured acute promyelocytic leukemia (APL). However, it is disappointing that ATRA is not effective against other acute myeloid leukemia (AML) subtypes. Developing new and effective anti-AML therapies that promote leukemia differentiation is necessary. The CDK4/6-cyclin D pathway is a key initiator of the G1/S phase transition, which determines cell fate.
-
A Compound that Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer Mol. Cancer Ther. (IF 5.7) Pub Date : 2024-03-20 Takuma Uo, Kayode K. Ojo, Cynthia C. T. Sprenger, Kathryn Soriano Epilepsia, B. Gayani K. Perera, Mamatha Damodarasamy, Shihua Sun, Soojin Kim, Hannah H. Hogan, Matthew A. Hulverson, Ryan Choi, Grant R. Whitman, Lynn K. Barrett, Samantha A. Michaels, Linda H. Xu, Vicky L. Sun, Samuel L.M. Arnold, Haley J. Pang, Matthew M. Nguyen, Anna-Lena B.G. Vigil, Varun Kamat, Lucas B. Sullivan, Ian R. Sweet, Ram
Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Non-specific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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,
-
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)
-
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
-
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
-
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
-
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