journal
https://read.qxmd.com/read/38530117/ultrasensitive-response-explains-the-benefit-of-combination-chemotherapy-despite-drug-antagonism
#1
JOURNAL ARTICLE
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 that CHOP consistently exhibits antagonism and not synergy. We tested whether staggered treatment schedules could improve tumor cell kill by avoiding antagonism, using in vitro models of concurrent or staggered treatments...
March 26, 2024: Molecular Cancer Therapeutics
https://read.qxmd.com/read/38530115/pharmacological-characterization-of-sdx-7320-evexomostat-a-novel-methionine-aminopeptidase-type-2-inhibitor-with-anti-tumor-and-anti-metastatic-activity
#2
JOURNAL ARTICLE
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 may be altered following MetAP2 inhibition, and additionally, that MetAP2 was identified as the target for the anti-angiogenic natural product, fumagillin...
March 26, 2024: Molecular Cancer Therapeutics
https://read.qxmd.com/read/38507743/the-cdk4-6-inhibitor-palbociclib-synergizes-with-atra-to-induce-differentiation-in-aml
#3
JOURNAL ARTICLE
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. Herein, we investigated whether the CDK4/6 inhibitor palbociclib would synergize with ATRA to promote leukemia differentiation in vitro and in vivo...
March 20, 2024: Molecular Cancer Therapeutics
https://read.qxmd.com/read/38507740/inhibition-of-malt1-and-bcl2-induces-synergistic-anti-tumor-activity-in-models-of-b-cell-lymphoma
#4
JOURNAL ARTICLE
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 Pan, Anthony Mastracchio, Jared Henderson, Jonathan A Meulbroek, Michael R Green, William N Pappano
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 therapeutic target. We discovered a novel small molecule inhibitor, ABBV-MALT1, that potently shuts down B cell signaling selectively in ABC-DLBCL preclinical models leading to potent cell growth and xenograft inhibition...
March 20, 2024: Molecular Cancer Therapeutics
https://read.qxmd.com/read/38507737/a-compound-that-inhibits-glycolysis-in-prostate-cancer-controls-growth-of-advanced-prostate-cancer
#5
JOURNAL ARTICLE
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 Vidadala, Dustin J Maly, Wesley C Van Voorhis, Stephen R Plymate
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 of a novel small molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro...
March 20, 2024: Molecular Cancer Therapeutics
https://read.qxmd.com/read/38490257/characteristics-of-carcinoembryonic-antigen-related-cell-adhesion-molecules-and-their-relationship-to-cancer
#6
JOURNAL ARTICLE
Ru-Xue Ma, Yan-Wei Hu, Jian-Rui Wei
Carcinoembryonic antigen related cell adhesion molecules (CEACAMs), such as carcinoembryonic antigen (CEA) and the oncofetal glycoprotein family, are tumor markers. The CEACAMs consist of 12 different human CEACAMs and 5 different murine CEACAMs. The CEACAM family of proteins participates in multiple biological processes that include the immune response, angiogenesis, and cancer. CEACAMs play a significant role in cancer initiation and development. Increasing evidence suggests that family members may be new cancer biomarkers and targets in that CEACEAMs tend to be aberrantly expressed and therefore may have potential diagnostic and therapeutic importance...
March 16, 2024: Molecular Cancer Therapeutics
https://read.qxmd.com/read/38471796/evaluation-of-the-role-of-axl-in-fusion-positive-pediatric-rhabdomyosarcoma-identifies-the-small-molecule-inhibitor-bemcentinib-bgb324-as-potent-chemosensitizer
#7
JOURNAL ARTICLE
Sara G Danielli, Jakob Wurth, Sarah Morice, Samanta Kisele, Didier Surdez, Olivier Delattre, Peter K Bode, Marco Wachtel, Beat W Schafer
Rhabdomyosarcoma (RMS) is a highly aggressive pediatric cancer with features of skeletal muscle differentiation. Over 80% of the high-risk patients ultimately fail to respond to chemotherapy treatment, leading to limited therapeutic options and dismal prognostic rates. The lack of response - and subsequent tumor recurrence - is driven in part by stem cell-like cells, the tumor subpopulation that is enriched after treatment, and characterized by expression of the AXL receptor tyrosine kinase (AXL). AXL mediates survival, migration and therapy resistance in several cancer types; however, its function in RMS remains unclear...
March 13, 2024: Molecular Cancer Therapeutics
https://read.qxmd.com/read/38466804/the-novel-atr-inhibitor-m1774-induces-replication-protein-overexpression-and-broad-synergy-with-dna-targeted-anticancer-drugs
#8
JOURNAL ARTICLE
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, but less potency than gartisertib and elimusertib in the small-cell lung cancer H146, H82, and DMS114 cell lines...
March 11, 2024: Molecular Cancer Therapeutics
https://read.qxmd.com/read/38442920/patient-derived-tumor-xenograft-study-with-cdk4-6-inhibitor-plus-akt-inhibitor-for-the-management-of-metastatic-castration-resistant-prostate-cancer
#9
JOURNAL ARTICLE
Adam M Kase, Justyna Gleba, James L Miller, Erin Miller, Joachim Petit, Michael T Barrett, Yumei Zhou, Ephraim E Parent, Hancheng Cai, Joshua A Knight, Jacob Orme, Jordan Reynolds, William F Durham, Thomas M Metz, Nathalie Meurice, Brandy Edenfield, Aylin Alasonyalilar Demirer, Ahmet Bilgili, Peyton G Hickman, Matthew L Pawlush, Laura Marlow, Daniel P Wickland, Winston Tan, John A Copland
Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive malignancy with poor outcomes. To investigate novel therapeutic strategies, we characterized three new metastatic prostate cancer PDTX models and developed 3D spheroids from each to investigate molecular targeted therapy combinations including CDK4/6 inhibitors (CDK4/6i) with AKT inhibitors (ATKi). Metastatic prostate cancer tissue was collected and three PDTX models were established and characterized using WES. PDTX 3-D spheroids were developed from these three PDTXs to show resistance patterns and test novel molecular targeted therapies...
March 6, 2024: Molecular Cancer Therapeutics
https://read.qxmd.com/read/38417139/atpase-copper-transporting-beta-atp7b-is-a-novel-target-for-improving-the-therapeutic-efficacy-of-docetaxel-by-disulfiram-copper-in-human-prostate-cancer
#10
JOURNAL ARTICLE
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 copper and uniquely express higher levels of a copper exporter protein ATP7B. Knock-down of ATP7B by silencing RNAs (siRNAs) sensitized docetaxel resistant-mPCa cells to the growth inhibitory and apoptotic effects of docetaxel...
February 28, 2024: Molecular Cancer Therapeutics
https://read.qxmd.com/read/38417138/89zr-immunopet-for-the-specific-detection-of-emp2-positive-tumors
#11
JOURNAL ARTICLE
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 of its tumor uptake and off target accumulation and clearance. The therapeutic efficacy of the anti-EMP2 mAb was initially evaluated in high- and low-expressing tumors, and the mAb reduced tumor load for the high EMP2 expressing 4T1 and HEC-1-A tumors...
February 28, 2024: Molecular Cancer Therapeutics
https://read.qxmd.com/read/38412481/thio-2-inhibits-key-signaling-pathways-required-for-the-development-and-progression-of-castration-resistant-prostate-cancer
#12
JOURNAL ARTICLE
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, Stefan Bräse, Nicole Jung, Simone Gräßle, Amanda Swain, Xavier Salvatella, Stephen R Plymate, Bissan Al-Lazikani, Henry W Long, Wei Yuan, Myles Brown, Andrew C B Cato, Johann S de Bono, Adam Sharp
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 implicated in the development and progression of CRPC. In addition, interrogation of geometric and physiochemical properties of the BAG domain of BAG-1 isoforms identifies it to be a tractable but challenging drug target...
February 27, 2024: Molecular Cancer Therapeutics
https://read.qxmd.com/read/38394685/structural-basis-for-multivalent-muc16-recognition-and-robust-anti-pancreatic-cancer-activity-of-humanized-antibody-ar9-6
#13
JOURNAL ARTICLE
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 SEA (Sea urchin sperm, Enterokinase, Agrin) domain. Binding of huAR9.6 to recombinant, shed, and cell-surface MUC16 was characterized, and anti-PDAC activity was evaluated in vitro and in vivo...
February 23, 2024: Molecular Cancer Therapeutics
https://read.qxmd.com/read/38377173/mitochondrial-and-cytosolic-one-carbon-metabolism-is-a-targetable-metabolic-vulnerability-in-cisplatin-resistant-ovarian-cancer
#14
JOURNAL ARTICLE
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 elevated in primary epithelial ovarian cancer (EOC) specimens compared to normal ovaries. 5-Substituted pyrrolo[3,2-d]pyrimidine antifolates (AGF347, AGF359, AGF362) inhibited proliferation of cisplatin sensitive (A2780, CaOV3, IGROV1) and resistant (A2780-E80, SKOV3) EOC cells...
February 20, 2024: Molecular Cancer Therapeutics
https://read.qxmd.com/read/38354417/design-and-evaluation-of-zd06519-a-novel-camptothecin-payload-for-antibody-drug-conjugates
#15
JOURNAL ARTICLE
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 analogs with different substituents at the C-7 and C-10 positions of the camptothecin core were prepared and tested in vitro...
February 14, 2024: Molecular Cancer Therapeutics
https://read.qxmd.com/read/38354416/development-of-a-novel-dna-mono-alkylator-platform-for-antibody-drug-conjugates
#16
JOURNAL ARTICLE
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 of a novel DNA mono-alkylator ADC platform that exhibits sustained tumor growth suppression at single doses in MTI-resistant tumors and is well-tolerated in the rat upon repeat dosing...
February 14, 2024: Molecular Cancer Therapeutics
https://read.qxmd.com/read/38359816/molecular-landscape-of-fadu-xenograft-tumors-in-mice-after-a-combinatorial-treatment-with-radiation-and-an-hsp90-inhibitor-identifies-adaptation-induced-targets
#17
JOURNAL ARTICLE
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 or induce new targets for drug- and immunotherapy. To address the timescale for these evasive mechanisms, using a mouse xenograft tumor model we investigated the rapidity of gene expression (mRNA), molecular pathway, and phosphoproteome changes after radiation, an HSP90 inhibitor or combination...
February 13, 2024: Molecular Cancer Therapeutics
https://read.qxmd.com/read/38346939/interferon-gamma-induces-higher-neutrophil-extracellular-traps-leading-to-tumor-killing-activity-in-microsatellite-stable-colorectal-cancer
#18
JOURNAL ARTICLE
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 development. Tumor-associated neutrophils (TANs) found in tumor tissues exhibit an immunosuppressive phenotype and are associated with CRC patient prognosis...
February 13, 2024: Molecular Cancer Therapeutics
https://read.qxmd.com/read/38346938/evaluating-for-correlations-between-metabolites-in-patients-receiving-immunotherapy-for-metastatic-or-recurrent-nsclc-an-exploratory-study-based-on-two-cohorts
#19
JOURNAL ARTICLE
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 in NSCLC patients treated with ICIs.: We prospectively recruited 97 patients with stage IV NSCLC who were treated with anti-PD-1 inhibitor, including patients treated with monoimmunotherapy as second-line treatment (Cohort 1), and patients treated with combination immunotherapy as first-line treatment (Cohort 2)...
February 13, 2024: Molecular Cancer Therapeutics
https://read.qxmd.com/read/38324336/adct-602-a-novel-pbd-dimer-containing-antibody-drug-conjugate-for-treating-cd22-positive-hematological-malignancies
#20
JOURNAL ARTICLE
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 to the pyrrolobenzodiazepine dimer-based payload tesirine. In preclinical studies, ADCT-602 demonstrated potent, specific cytotoxicity in CD22-positive lymphomas and leukemias...
February 7, 2024: Molecular Cancer Therapeutics
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