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Molecular Cancer Therapeutics

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https://www.readbyqxmd.com/read/29339551/inhibition-of-flt3-and-pim-kinases-by-ec-70124-exerts-potent-activity-in-preclinical-models-of-acute-myeloid-leukemia
#1
Noelia Puente-Moncada, Paula Costales, Isaac Antolín, Luz Elena Núñez, Patricia Oro, Maria Ana Hermosilla, Jhudit Perez-Escuredo, Nicolas Rios-Lombardia, Ana M Sanchez-Sanchez, Elisa Luño, Carmen Rodriguez, Vanesa Martin, Francisco Moris
Internal tandem duplication (ITD) or tyrosine kinase domain mutations of FLT3 is the most frequent genetic alteration in acute myeloid leukemia (AML) and are associated with poor disease outcome. Despite considerable efforts to develop single-target FLT3 drugs, so far, the most promising clinical response has been achieved using the multikinase inhibitor midostaurin. Here we explore the activity of the indolocarbazole EC-70124, from the same chemical space as midostaurin, in preclinical models of AML, focusing on those bearing FLT3-ITD mutations...
January 16, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29339550/relative-target-affinities-of-t-cell-dependent-bispecific-antibodies-determine-biodistribution-in-a-solid-tumor-mouse-model
#2
Danielle Mandikian, Nene Takahashi, Amy A Lo, Ji Li, Jeffrey Eastham-Anderson, Dionysos Slaga, Jason Ho, Maria Hristopoulos, Robyn Clark, Klara Totpal, Kedan Lin, Sean B Joseph, Mark S Dennis, Saileta Prabhu, Teemu T Junttila, C Andrew Boswell
Anti-HER2/CD3, a T cell-dependent bispecific antibody (TDB) construct, induces T cell-mediated cell death in cancer cells expressing HER2 by cross-linking tumor HER2 with CD3 on cytotoxic T cells, thereby creating a functional cytolytic synapse. TDB design is a very challenging process that requires consideration of multiple parameters. While therapeutic antibody design strategy is commonly driven by striving for the highest attainable antigen binding affinity, little is known about how the affinity of each TDB arm can affect the targeting ability of the other arm and the consequent distribution and efficacy...
January 16, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29284644/cox-2-seh-dual-inhibitor-ptupb-potentiates-the-anti-tumor-efficacy-of-cisplatin
#3
Fuli Wang, Hongyong Zhang, Ai-Hong Ma, Weimin Yu, Maike Zimmermann, Jun Yang, Sung Hee Hwang, Daniel Zhu, Tzu-Yin Lin, Michael Malfatti, Kenneth W Turteltaub, Paul T Henderson, Susan Airhart, Bruce D Hammock, Jianlin Yuan, Ralph W de Vere White, Chong-Xian Pan
Cisplatin-based therapy is highly toxic, but moderately effective in most cancers. Concurrent inhibition of cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) results in anti-tumor activity, and has organ protective effects. The goal of this study was to determine the anti-tumor activity of PTUPB, an orally bioavailable COX-2/sEH dual inhibitor, in combination with cisplatin and gemcitabine (GC) therapy. NSG mice bearing bladder cancer patient-derived xenografts were treated with vehicle, PTUPB, cisplatin, GC or combinations thereof...
December 28, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29282301/inhibition-of-mdm2-by-a-rhein-derived-compound-aq-101-suppresses-cancer-development-in-scid-mice
#4
Lubing Gu, Hailong Zhang, Tao Liu, Alexander Draganov, Sha Yi, Binghe Wang, Muxiang Zhou
A novel small-molecule anthraquinone (AQ) analog, AQ-101, which was synthesized through chemical modification of the core structures of rhein, exhibited potent anticancer activity. In the present study, we evaluated the cancer-inhibiting mechanism of AQ-101 and tested the therapeutic potential of this compound for treating cancer in mice. We found that AQ-101 was able to induce MDM2 protein degradation through a self-ubiquitination and proteasome-mediated mechanism. This AQ-101-induced MDM2 downregulation led to activation of p53, which contributed to apoptosis of acute lymphoblastic leukemia (ALL), especially those with a wild-type p53 phenotype and MDM2 expression in vitro and in vivo...
December 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29282300/scavenger-receptor-type-b1-and-lipoprotein-nanoparticle-inhibit-myeloid-derived-suppressor-cells
#5
Michael P Plebanek, Debayan Bhaumik, Paul J Bryce, C Shad Thaxton
Myeloid derived suppressor cells (MDSCs) are innate immune cells that potently inhibit T cells. In cancer, novel therapies aimed to activate T cells can be rendered ineffective due to the activity of MDSCs. Thus, targeted inhibition of MDSCs may greatly enhance T cell-mediated anti-tumor immunity, but targeted mechanisms remain obscure. Here we show, for the first time, that scavenger receptor type B-1 (SCARB1), a high-affinity receptor for spherical high-density lipoprotein (HDL), is expressed by MDSCs. Furthermore, we demonstrate that SCARB1 is specifically targeted by synthetic high-density lipoprotein-like nanoparticles (HDL NP), which reduces MDSC activity...
December 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29282299/an-anti-gdnf-family-receptor-alpha-1-gfra1-antibody-drug-conjugate-for-the-treatment-of-hormone-receptor-positive-breast-cancer
#6
Sunil Bhakta, Lisa M Crocker, Yvonne Chen, Meredith Hazen, Melissa M Schutten, Dongwei Li, Coenraad Kuijl, Rachana Ohri, Fiona Zhong, Kirsten Achilles Poon, Mary Ann T Go, Eric Cheng, Robert Piskol, Ron Firestein, Aimee Fourie-O'Donohue, Katherine R Kozak, Helga Raab, Jo-Anne Hongo, Deepak Sampath, Mark S Dennis, Richard H Scheller, Paul Polakis, Jagath R Junutula
Luminal A (hormone receptor-positive) breast cancer constitutes 70% of total breast cancer patients. In an attempt to develop a targeted therapeutic for this cancer indication, we have identified and characterized Glial cell line-Derived Neurotrophic Factor (GDNF) Family Receptor Alpha 1 (GFRA1) antibody-drug conjugates (ADC) using a cleavable valine-citrulline-MMAE (vcMMAE) linker-payload. RNAseq and immunohistochemistry analysis confirmed the abundant expression of GFRA1 in luminal A breast cancer tissues, while minimal or no expression was observed in most normal tissues...
December 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29282298/%C3%AE-catenin-mrna-silencing-and-mek-inhibition-display-synergistic-efficacy-in-preclinical-tumor-models
#7
Shanthi Ganesh, Xue Shui, Kevin Craig, Martin Koser, Girish R Chopda, Wendy A Cyr, Chengjung Lai, Henryk Dudek, Weimin Wang, Bob Brown, Marc Abrams
Colorectal carcinomas (CRC) harbor well-defined genetic abnormalities including aberrant activation of Wnt/β-catenin and MAPK pathways, often simultaneously. While the MAPK pathway can be targeted using potent small molecule drugs, including BRAF and MEK inhibitors, β-catenin inhibition has been historically challenging. RNA interference (RNAi) approaches have advanced to the stage of clinical viability, and are especially well-suited for transcriptional modulators such as β-catenin. In this study, we report therapeutic effects of combined targeting of these pathways with pharmacological agents...
December 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29242243/an-infrared-dye-conjugated-virus-like-particle-for-the-treatment-of-primary-uveal-melanoma
#8
Rhonda C Kines, Isabella Varsavsky, Sanghamitra Choudhary, Debaditya Bhattacharya, Sean Spring, Roger J McLaughlin, Shin J Kang, Hans E Grossniklaus, Demitrios G Vavvas, Stephen Monks, John R MacDougall, Elisabet de Los Pinos, John T Schiller
The work outlined herein describes AU-011, a novel recombinant papillomavirus-like particle (VLP) drug conjugate and its initial evaluation as a potential treatment for primary uveal melanoma. The VLP is conjugated with a phthalocyanine photosensitizer, IRDye 700DX, that exerts its cytotoxic effect through photo-activation with a near-infrared laser. We assessed the anti-cancer properties of AU-011 in vitro utilizing a panel of human cancer cell lines and in vivo using murine subcutaneous and rabbit orthotopic xenograft models of uveal melanoma...
December 14, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29237807/molecularly-targeted-cancer-combination-therapy-with-near-infrared-photoimmunotherapy-and-near-infrared-photo-release-with-duocarmycin-antibody-conjugate
#9
Tadanobu Nagaya, Alexander P Gorka, Roger R Nani, Shuhei Okuyama, Fusa Ogata, Yasuhiro Maruoka, Peter L Choyke, Martin J Schnermann, Hisataka Kobayashi
Near infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photo-absorber conjugate (APC). However, the effect of NIR-PIT can be enhanced when combined with other therapies. NIR photocaging groups, based on the heptamethine cyanine scaffold, have been developed to release bioactive molecules near targets after exposure to light. Here, we investigated the combination of NIR-PIT employing panitumumab-IR700 (pan-IR700) and the NIR-releasing compound, CyEt-Panitumumab-Duocarmycin (CyEt-Pan-Duo)...
December 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29237806/afatinib-is-a-new-therapeutic-approach-in-chordoma-with-a-unique-ability-to-target-egfr-and-brachyury
#10
Paola Magnaghi, Barbara Salom, Liviana Cozzi, Nadia Amboldi, Dario Ballinari, Elena Tamborini, Fabio Gasparri, Alessia Montagnoli, Laura Raddrizzani, Alessio Somaschini, Roberta Bosotti, Christian Orrenius, Fabio Bozzi, Silvana Pilotti, Arturo Galvani, Josh Sommer, Silvia Stacchiotti, Antonella Isacchi
Chordomas are rare bone tumors with no approved therapy. These tumors express several activated tyrosine kinase receptors, which prompted attempts to treat patients with tyrosine kinase inhibitors. Although clinical benefit was observed in Phase II clinical trials with imatinib and sorafenib, and sporadically also with EGFR inhibitors, therapies evaluated to date have shown modest activity. With the goal of identifying new drugs with immediate therapeutic potential for chordoma patients, we collected clinically approved drugs and other advanced inhibitors of MET, PDGFRβ and EGFR tyrosine kinases, and assessed their anti-proliferative activity against a panel of chordoma cell lines...
December 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29237805/preclinical-evaluation-of-scc244-glumetinib-a-novel-potent-and-highly-selective-inhibitor-of-c-met-in-met-dependent-cancer-models
#11
Jing Ai, Yi Chen, Xia Peng, Yinchun Ji, Yong Xi, Yanyan Shen, Xinying Yang, Yi Su, Yi-Ming Sun, Yinglei Gao, Yuchi Ma, Bing Xiong, Jingkang Shen, Jian Ding, Meiyu Geng
Because the receptor tyrosine kinase c-Met plays a critical role in tumor growth, metastasis, tumor angiogenesis and drug resistance, the c-Met axis represents an attractive therapeutic target. Herein, we report the first preclinical characterization of SCC244, a novel, potent and highly selective inhibitor of c-Met kinase. SCC244 showed subnanomolar potency against c-Met kinase activity and high selectivity versus 312 other tested protein kinases, making it one of the most selective c-Met inhibitors described to date...
December 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29237804/inhibiting-nuclear-phospho-progesterone-receptor-enhances-antitumor-activity-of-onapristone-in-uterine-cancer
#12
Yan Huang, Wei Hu, Jie Huang, Fanrong Shen, Yunjie Sun, Cristina Ivan, Sunila Pradeep, Robert Dood, Monika Haemmerle, Dahai Jiang, Lingegowda S Mangala, Kyunghee Noh, Jean M Hansen, Heather J Dalton, Rebecca Previs, Archana S Nagaraja, Michael McGuire, Nicholas B Jennings, Russell R Broaddus, Robert L Coleman, Anil K Sood
While progesterone receptor (PR)-targeted therapies are modestly active in patients with uterine cancer, their underlying molecular mechanisms are not well understood. The clinical use of such therapies is limited because of the lack of biomarkers that predict response to PR-agonists (progestins) or PR-antagonists (onapristone). Thus, understanding the underlying molecular mechanisms of action will provide an advance in developing novel combination therapies for cancer patients. Nuclear translocation of PR has been reported to be ligand-dependent or -independent...
December 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29237803/anti-tumor-activity-of-entrectinib-a-pan-trk-ros1-and-alk-inhibitor-in-etv6-ntrk3-positive-acute-myeloid-leukemia
#13
Kristen M Smith, Patrick C Fagan, Elena Pomari, Giuseppe Germano, Chiara Frasson, Colin Walsh, Ian M Silverman, Paolo Bonvini, Gang Li
Activation of tropomyosin receptor kinase (TRK) family tyrosine kinases by chromosomal rearrangement has been shown to drive a wide range of solid tumors and hematologic malignancies. TRK fusions are actionable targets as evidenced by recent clinical trial results in solid tumors. Entrectinib (RXDX-101) is an investigational, orally available, CNS-active, highly potent and selective kinase inhibitor against TRKA/B/C, ROS1 and ALK kinase activities. Here, we demonstrate that TRK kinase inhibition by entrectinib selectively targets preclinical models of TRK fusion-driven hematologic malignancies...
December 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29237802/phase-1-dose-escalation-study-of-anti-ctla-4-antibody-ipilimumab-and-lenalidomide-in-patients-with-advanced-cancers
#14
Divya Sakamuri, Isabella C Glitza, Sonia L Betancourt Cuellar, Vivek Subbiah, Siqing Fu, Apostolia M Tsimberidou, Jennifer J Wheler, David S Hong, Aung Naing, Gerald S Falchook, Michelle A Fanale, Maria E Cabanillas, Filip Janku
Preclinical data suggest that combining a check point inhibition with immunomodulatory derivative can increase anticancer response. We designed a dose escalation study using a 3+3 design to determine the safety, maximum tolerated dose (MTD) or recommended phase 2 dose (R2PD) and dose limiting toxicities (DLT) of the anti-CTLA-4 antibody ipilimumab (1.5-3mg/kg intravenously every 28 days x 4) and lenalidomide (10-25mg orally daily for 21 of 28 days until disease progression or unacceptable toxicity) in advanced cancers...
December 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29167315/a-novel-yap1-inhibitor-targets-cscs-enriched-radiation-resistant-cells-and-exerts-strong-antitumor-activity-in-esophageal-adenocarcinoma
#15
Shumei Song, Min Xie, Ailing W Scott, Jiankang Jin, Lang Ma, Xiaochuan Dong, Heath D Skinner, Randy L Johnson, Sheng Ding, Jaffer A Ajani
Mounting evidence suggests that the Hippo co-activator Yes-associated protein 1 (YAP1) is a major mediator of cancer stem cell (CSC) properties, tumor progression, and therapy resistance as well as often a terminal node of many oncogenic pathways. Thus, targeting YAP1 may be a novel therapeutic strategy for many types of tumors with high YAP1 expression, including esophageal adenocarcinoma (EAC). However, effective YAP1 inhibitors are currently lacking. Here, we identify a small molecule (CA3) that not only has remarkable inhibitory activity on YAP1/Tead transcriptional activity but also demonstrates strong inhibitory effects on EAC cell growth especially on YAP1 high expressing EAC cells both in vitro and in vivo...
November 22, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29167314/wnt-%C3%AE-catenin-pathway-activation-mediates-adaptive-resistance-to-braf-inhibition-in-colorectal-cancer
#16
Guangming Chen, Chenxi Gao, Xuan Gao, Dennis Han Zhang, Shih-Fan Kuan, Timothy F Burns, Jing Hu
One of the most encouraging developments in oncology has been the success of BRAF inhibitors in BRAF-mutant melanoma. However, in contrast to its striking efficacy in BRAF-mutant melanomas, BRAF inhibitor monotherapy is ineffective in BRAF-mutant colorectal cancer (CRC). While many studies on BRAF inhibitor resistance in CRC have focused on mechanisms underlying the reactivation of the EGFR/RAS/RAF/MEK/ERK pathway, the current study focuses on identifying novel adaptive signaling mechanisms, a fresh angle on CRC resistance to BRAF inhibition...
November 22, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29167313/mechanism-informed-repurposing-of-minocycline-overcomes-resistance-to-topoisomerase-inhibition-for-peritoneal-carcinomatosis
#17
Huang-Chiao Huang, Joyce Liu, Yan Baglo, Imran Rizvi, Sriram Anbil, Michael Pigula, Tayyaba Hasan
Mechanism-inspired drug repurposing that augments standard treatments offers a cost-effective and a rapid route toward addressing the burgeoning problem of plateauing of effective therapeutics for drug-resistant micrometastases. We show that the antibiotic minocycline, by its ability to minimize DNA repair via reduced expression of tyrosyl-DNA phosphodiesterase-1 (Tdp1), removes a key process attenuating the efficacy of irinotecan, a frequently used chemotherapeutic against metastatic disease. Moreover, minocycline and irinotecan cooperatively mitigate each other's undesired cytokine inductions of VEGF and IL-8 respectively, thereby reinforcing the benefits of each modality...
November 22, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29167312/inhibition-of-o-glcnacase-sensitizes-apoptosis-and-reverses-bortezomib-resistance-in-mantle-cell-lymphoma-through-modification-of-truncated-bid
#18
Sudjit Luanpitpong, Nawin Chanthra, Montira Janan, Jirarat Poohadsuan, Parinya Samart, Yaowalak U-Pratya, Yon Rojanasakul, Surapol Issaragrisil
Aberrant energy metabolism represents a hallmark of cancer and contributes to numerous aggressive behaviors of cancer cells, including cell death and survival. Despite the poor prognosis of mantle cell lymphoma (MCL), due to the inevitable development of drug resistance, metabolic reprograming of MCL cells remains an unexplored area. Post-translational modification of proteins via O-GlcNAcylation is an ideal sensor for nutritional changes mediated by O-GlcNAc transferase (OGT) and is removed by O-GlcNAcase (OGA)...
November 22, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29158470/comparative-oncology-evaluation-of-intravenous-recombinant-oncolytic-vesicular-stomatitis-virus-therapy-in-spontaneous-canine-cancer
#19
Shruthi Naik, Gina D Galyon, Nathan J Jenks, Michael B Steele, Amber C Miller, Sara D Allstadt, Lukkana Suksanpaisan, Kah Whye Peng, Mark J Federspiel, Stephen J Russell, Amy K LeBlanc
Clinical translation of intravenous therapies to treat disseminated or metastatic cancer is imperative. Comparative oncology, the evaluation of novel cancer therapies in animals with spontaneous cancer, can be utilized to inform and accelerate clinical translation. Preclinical murine studies demonstrate that single shot systemic therapy with a VSV-IFNβ-NIS, a novel recombinant oncolytic Vesicular stomatitis virus (VSV), can induce curative remission in tumor bearing mice. Clinical translation of VSV-IFNβ-NIS therapy is dependent on comprehensive assessment of clinical toxicities, virus shedding, pharmacokinetics, and efficacy in clinically relevant models...
November 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29158469/molecular-basis-for-necitumumab-inhibition-of-egfr-variants-associated-with-acquired-cetuximab-resistance
#20
Atrish Bagchi, Jaafar N Haidar, Scott W Eastman, Michal Vieth, Michael Topper, Michelle D Iacolina, Jason M Walker, Amelie Forest, Yang Shen, Ruslan D Novosiadly, Kathryn M Ferguson
Acquired resistance to cetuximab, an antibody that targets the epidermal growth factor receptor (EGFR), impacts clinical benefit in head and neck, and colorectal cancers (CRC). One of the mechanisms of resistance to cetuximab is the acquisition of mutations that map to the cetuximab epitope on EGFR and prevent drug binding. We find that necitumumab, another FDA approved EGFR antibody, can bind to EGFR that harbors the most common cetuximab resistance substitution, S468R (or S492R, depending on the amino acid numbering system)...
November 20, 2017: Molecular Cancer Therapeutics
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