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Molecular Cancer Therapeutics

Jeremy Karlin, Jasmine Allen, Syed F Ahmad, Gareth Hughes, Victoria Sheridan, Rajesh Odedra, Paul Farrington, Elaine B Cadogan, Lucy C Riches, Antonio Garcia-Trinidad, Andrew G Thomason, Bhavika Patel, Jennifer Vincent, Alan Lau, Kurt G Pike, Thomas A Hunt, Amrita Sule, Nicholas C K Valerie, Laura Biddlestone-Thorpe, Jenna Kahn, Jason M Beckta, Nitai Mukhopadhyay, Bernard Barlaam, Sebastien L Degorce, Jason Kettle, Nicola Colclough, Joanne Wilson, Aaron Smith, Ian P Barrett, Li Zheng, Tianwei Zhang, Yingchun Wang, Kan Chen, Martin Pass, Stephen T Durant, Kristoffer Valerie
Inhibition of ataxia-telangiectasia mutated (ATM) during radiotherapy of glioblastoma multiforme (GBM) may improve tumor control by short-circuiting the response to radiation-induced DNA damage. A major impediment for clinical implementation is that current inhibitors have limited CNS bioavailability, thus, the goal was to identify ATM inhibitors (ATMi) with improved CNS penetration. Drug screens and refinement of lead compounds identified AZ31 and AZ32. The compounds were then tested in vivo for efficacy and impact on tumor and healthy brain...
May 16, 2018: Molecular Cancer Therapeutics
Wakako Yano, Tatsushi Yokogawa, Takeshi Wakasa, Keisuke Yamamura, Akio Fujioka, Kunihiro Yoshisue, Eiji Matsushima, Seiji Miyahara, Hitoshi Miyakoshi, Junko Taguchi, Khoon Tee Chong, Yayoi Takao, Masayoshi Fukuoka, Kenichi Matsuo
5-Fluorouracil (5-FU) is an antimetabolite and exerts antitumor activity via intracellularly and physiologically complicated metabolic pathways. In this study, we designed a novel small molecule inhibitor, TAS-114, which targets the intercellular metabolism of 5-FU to enhance antitumor activity and modulates catabolic pathway to improve the systemic availability of 5-FU. TAS-114 strongly and competitively inhibited deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase), a gatekeeper protein preventing aberrant base incorporation into DNA, and enhanced the cytotoxicity of fluoropyrimidines in cancer cells; however, it had little intrinsic activity...
May 10, 2018: Molecular Cancer Therapeutics
Michela Bardini, Luca Trentin, Francesca Rizzo, Margherita Vieri, Angela M Savino, Patricia Garrido Castro, Grazia Fazio, Eddy H J Van Roon, Mark Kerstjens, Nicholas N Smithers, Rab K Prinjha, Geertruy Te Kronnie, Giuseppe Basso, Ronald W Stam, Rob Pieters, Andrea Biondi, Giovanni Cazzaniga
MLL-rearranged acute lymphoblastic leukemia occurring in infants is a rare but very aggressive leukemia, typically associated with a dismal prognosis. Despite the development of specific therapeutic protocols, infant patients with MLL-rearranged ALL still suffer from a low cure rate. At present, novel therapeutic approaches are urgently needed. Recently, the use of small molecule inhibitors targeting the epigenetic regulators of the MLL complex emerged as a promising strategy for the development of a targeted therapy...
May 10, 2018: Molecular Cancer Therapeutics
Laetitia Marzi, Keli Agama, Junko Murai, Simone Difilippantonio, Amy James, Cody J Peer, William D Figg, Daniel Beck, Mohamed S A Elsayed, Mark Cushman, Yves Pommier
Contrary to other anticancer targets, topoisomerase I (TOP1) is targeted by only one chemical class of FDA-approved drugs: topotecan and irinotecan, the derivatives of the plant alkaloid, camptothecin. The indenoisoquinolines LMP400, LMP744 and LMP776 are novel non-camptothecin TOP1 inhibitors in clinical trial, which overcome the limitations of camptothecins. To further improve metabolic stability, their methoxy groups have been replaced by a fluorine, as in the fluoroindenoisoquinolines NSC 781517 (LMP517), NSC 779135 (LMP135) and NSC 779134 (LMP134)...
May 10, 2018: Molecular Cancer Therapeutics
Shinichi Hasako, Miki Terasaka, Naomi Abe, Takao Uno, Hirokazu Ohsawa, Akihiro Hashimoto, Ryoto Fujita, Kenji Tanaka, Takashige Okayama, Renu Wadhwa, Kazutaka Miyadera, Yoshimi Aoyagi, Kazuhiko Yonekura, Kenichi Matsuo
Activating mutations in the epidermal growth factor receptor (EGFR) gene are important targets in cancer therapy because they are key drivers of non-small-cell lung cancer (NSCLC). Whereas almost all common EGFR mutations, such as exon 19 deletions and the L858R point mutation in exon 21, are sensitive to EGFR-tyrosine kinase inhibitor (TKI) therapies, NSCLC driven by EGFR exon 20 insertion mutations is associated with poor clinical outcomes due to dose-limiting toxicity, demonstrating the need for a novel therapy...
May 10, 2018: Molecular Cancer Therapeutics
Vanessa Buatois, Zoë Johnson, Susana Salgado-Pires, Anne Papaïoannou, Eric Hatterer, Xavier Chauchet, Françoise Richard, Leticia Barba, Bruno Daubeuf, Laura Cons, Lucile Broyer, Matilde D'Asaro, Thomas Matthes, Simon LeGallou, Thierry Fest, Karin Tarte, Robert K Clarke Hinojosa, Eulàlia Genescà Ferrer, José María Ribera, Aditi Dey, Katharine Bailey, Adele K Fielding, Linda Eissenberg, Julie Ritchey, Michael Rettig, John F DiPersio, Marie H Kosco-Vilbois, Krzysztof Masternak, Nicolas Fischer, Limin Shang, Walter G Ferlin
CD47, a ubiquitously expressed innate immune checkpoint receptor that serves as a universal "don't eat me" signal of phagocytosis, is often up-regulated by hematological and solid cancers to evade immune surveillance. Development of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hemotoxicity including anemia. To overcome such liabilities, we have developed a fully human bispecific antibody, NI-1701, designed to co-engage CD47 and CD19 selectively on B cells...
May 9, 2018: Molecular Cancer Therapeutics
Arthur Winer, Sylvia Adams, Paolo Mignatti
The matrix metalloproteinases (MMP) are a family of proteolytic enzymes that degrade multiple components of the extracellular matrix. A large body of experimental and clinical evidence has implicated MMPs in tumor invasion, neoangiogenesis, and metastasis, and therefore they represent ideal pharmacologic targets for cancer therapy. From the 1990s to early 2000s, synthetic inhibitors of MMPs (MMPI) were studied in various cancer types. Unexpectedly, despite strongly promising preclinical data, all trials were unsuccessful in reducing tumor burden or improving overall survival; in addition, MMPIs had unforeseen, severe side effects...
May 7, 2018: Molecular Cancer Therapeutics
Hiroki Ide, Satoshi Inoue, Taichi Mizushima, Guiyang Jiang, Kuang-Hsiang Chuang, Mototsugu Oya, Hiroshi Miyamoto
Although radiotherapy often with chemotherapy has been shown to offer a survival benefit comparable to that of radical cystectomy in select patients with bladder cancer, the development of radiosensitization strategies may significantly enhance its application. Notably, emerging preclinical evidence has indicated the involvement of androgen receptor (AR) signaling in urothelial cancer progression. We here assessed whether AR signals could contribute to modulating radiosensitivity in bladder cancer cells. Ionizing radiation reduced the numbers of viable cells or colonies of AR-negative lines more significantly than those of AR-positive lines...
May 2, 2018: Molecular Cancer Therapeutics
Jordan M Thompson, Alejandro Alvarez, Monika K Singha, Matthew W Pavesic, Quy H Nguyen, Luke J Nelson, David A Fruman, Olga V Razorenova
Clear Cell Renal Cell Carcinoma (CC-RCC) is a devastating disease with limited therapeutic options available for advance stages. The objective of this study was to investigate HMG-CoA Reductase inhibitors, also known as statins, as potential therapeutics for CC-RCC. Importantly, treatment with statins was found to be synthetically lethal with the loss of the von Hippel-Lindau (VHL) tumor suppressor gene, which occurs in 90% of CC-RCC driving the disease. This effect has been confirmed in three different CC-RCC cell lines with three different lipophilic statins...
May 2, 2018: Molecular Cancer Therapeutics
Monique J Kauke, Alison W Tisdale, Ryan L Kelly, Christian J Braun, Michael T Hemann, K Dane Wittrup
Mutated in approximately 30% of human cancers, Ras GTPases are the most common drivers of oncogenesis and render tumors unresponsive to many standard therapies. Despite decades of research, no drugs directly targeting Ras are currently available. We have previously characterized a small protein antagonist of K-Ras, R11.1.6, and demonstrated its direct competition with Raf for Ras binding. Here we evaluate the effects of R11.1.6 on Ras signaling and cellular proliferation in a panel of human cancer cell lines...
May 2, 2018: Molecular Cancer Therapeutics
Fengyi Mao, Jie Li, Qian Luo, Ruixin Wang, Yifan Kong, Colin Carlock, Zian Liu, Bennett D Elzey, Xiaoqi Liu
Polo-like kinase 1 (Plk1), a crucial regulator of cell cycle progression, is overexpressed in multiple types of cancers, and has been proven to be a potent and promising target for cancer treatment. In case of prostate cancer, we once showed that anti-neoplastic activity of Plk1 inhibitor is largely due to inhibition of androgen receptor (AR) signaling. However, we also discovered that Plk1 inhibition causes activation of the β-catenin pathway and increased ex-pression of c-Myc, eventually resulting in resistance to Plk1 inhibition...
May 1, 2018: Molecular Cancer Therapeutics
Marina Koutsioumpa, Hsiao-Wang Chen, Neil O'Brien, Filippos Koinis, Swapna Mahurkar-Joshi, Christina Vorvis, Artin Soroosh, Tong Luo, Shawnt Issakhanian, Allan J Pantuck, Vasilis Georgoulias, Dimitrios Iliopoulos, Dennis J Slamon, Alexandra Drakaki
Bladder cancer (BC) represents a disease associated with significant morbidity and mortality. MicroRNA-21 (MiR-21) has been found to have oncogenic activity in multiple cancers, including BC, while inhibition of its expression suppresses tumor growth. Here, we examine the molecular network regulated by miR-21 in BC and evaluate the effects of intravenous (I.V.) and intraperitoneal (I.P.) administration of a novel miR-21 chemical inhibitor in vivo. LNA miR-21 reduced the oncogenic potential of BC cells, while the MKAD-21 chemically-modified antisense oligo against miR-21, dose-dependently blocked xenograft growth...
April 27, 2018: Molecular Cancer Therapeutics
Robin Didier, Aude Mallavialle, Rania Ben Jouira, Marie Angela Domdom, Mélanie Tichet, Patrick Auberger, Frédéric Luciano, Mickael Ohanna, Sophie Tartare-Deckert, Marcel Deckert
Advanced cutaneous melanoma is one of the most challenging cancers to treat because of its high plasticity, metastatic potential and resistance to treatment. New targeted therapies and immunotherapies have shown remarkable clinical efficacy. However, such treatments are limited to a subset of patients and relapses often occur, warranting validation of novel targeted therapies. Post-translational modification of proteins by ubiquitin coordinates essential cellular functions, including ubiquitin-proteasome system (UPS) function and protein homeostasis...
April 27, 2018: Molecular Cancer Therapeutics
Tomomi Nakayama Iwata, Chiaki Ishii, Saori Ishida, Yusuke Ogitani, Teiji Wada, Toshinori Agatsuma
Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate with a topoisomerase I inhibitor exatecan derivative (DX-8951 derivative, DXd), has been reported to exert potent antitumor effects in xenograft mouse models and clinical trials. In this study, the immune system-activating ability of DS-8201a was assessed. DS-8201a significantly suppressed tumor growth in an immunocompetent mouse model with human HER2-expressing CT26.WT (CT26.WT-hHER2) cells. Cured immunocompetent mice rejected not only re-challenged CT26...
April 27, 2018: Molecular Cancer Therapeutics
Hui Chen, Rajyalakshmi Luthra, Mark J Routbort, Keyur P Patel, Maria E Cabanillas, Russell R Broaddus, Michelle D Williams
Next generation sequencing (NGS) for molecular diagnostics allows simultaneous testing of activating oncogenes and tumor suppressor mutations in multiple signal pathways. Extended mutational profiling of advanced thyroid cancers may enhance considerations for targeted therapies. We analyzed clinically derived molecular profiling of 216 patients with advanced thyroid carcinoma using NGS (Ion Torrent Personal Genome Machine) from 4/2012-2/2014. We examined substitutions and small indels in 46/50 cancer-related genes using Ampliseq Cancer Hotspot panel in respect to tumor diagnosis and clinical correlations...
April 25, 2018: Molecular Cancer Therapeutics
Viktoryia Sidarovich, Marilena De Mariano, Sanja Aveic, Michael Pancher, Valentina Adami, Pamela Gatto, Silvia Pizzini, Luigi Pasini, Michela Croce, Federica Parodi, Flora Cimmino, Marianna Avitabile, Laura Emionite, Michele Cilli, Silvano Ferrini, Aldo Pagano, Mario Capasso, Alessandro Quattrone, Gian Paolo Tonini, Luca Longo
Novel druggable targets have been discovered in neuroblastoma (NB), paving the way for more effective treatments. However, children with high-risk NB still show high mortality rates prompting for a search of novel therapeutic options. Here, we aimed at repurposing FDA-approved drugs for NB treatment by performing a high-content screening of a 349 anti-cancer compounds library. In the primary screening we employed three NB cell lines, grown as 3D multicellular spheroids, which were treated with 10 μM of the library compounds for 72 hours...
April 25, 2018: Molecular Cancer Therapeutics
Mengqiu Song, Xuejiao Liu, Kangdong Liu, Ran Zhao, Hai Huang, Yuanyuan Shi, Man Zhang, Silei Zhou, Hua Xie, Hanyong Chen, Yin Li, Yan Zheng, Qiong Wu, Fangfang Liu, Enmin Li, Ann M Bode, Zigang Dong, Mee-Hyun Lee
Overexpression or activation of AKT is very well known to control cell growth, survival and gene expression in solid tumors. Oridonin, an inflammatory medical and diterpenoid compound isolated from Rabdosia rubescens, has exhibited various pharmacological and physiological properties, including anti-tumor, anti-bacterial and anti-inflammatory effects. In this study, we demonstrated that oridonin is an inhibitor of AKT and suppresses proliferation of esophageal squamous cell carcinoma (ESCC) in vitro and in vivo...
April 25, 2018: Molecular Cancer Therapeutics
Guangmin Li, Jun Guo, Ben-Quan Shen, Daniela Bumbaca Yadav, Mark X Sliwkowski, Lisa M Crocker, Jennifer A Lacap, Gail D Lewis Phillips
The receptor tyrosine kinase HER2 is overexpressed in approximately 20% of breast cancer, and its amplification is associated with reduced survival. Trastuzumab emtansine (Kadcyla®, T-DM1), an antibody-drug conjugate that is comprised of trastuzumab covalently linked to the anti-mitotic agent DM1 through a stable linker, was designed to selectively deliver DM1 to HER2-overexpressing tumor cells. T-DM1 is approved for the treatment of patients with HER2-positive metastatic breast cancer following progression on trastuzumab and a taxane...
April 25, 2018: Molecular Cancer Therapeutics
Michalis Mastri, Christina R Lee, Amanda Tracz, Robert S Kerbel, Melissa Dolan, Yuhao Shi, John M L Ebos
The levels of various circulating blood proteins can change in response to cancer therapy. Monitoring therapy-induced secretomes (TIS) may have use as biomarkers for establishing optimal biological effect (such as dosing) or identifying sources of toxicity and drug resistance. While TIS can derive from tumor cells directly, non-tumor 'host' treatment responses can also impact systemic secretory programs. For targeted inhibitors of the tumor microenvironment, including antiangiogenic and immune-checkpoint therapies, host TIS could explain unexpected collateral 'side-effects' of treatment...
April 25, 2018: Molecular Cancer Therapeutics
George A Ward, Edward J Lewis, Jong Sook Ahn, Christopher N Johnson, John F Lyons, Vanessa Martins, Joanne M Munck, Sharna J Rich, Tomoko Smyth, Neil T Thompson, Pamela A Williams, Nicola E Wilsher, Nicola G Wallis, Gianni Chessari
Due to their roles in the evasion of apoptosis, Inhibitor of Apoptosis Proteins (IAPs) are considered attractive targets for anti-cancer therapy. Antagonists of these proteins have the potential to switch pro-survival signaling pathways in cancer cells towards cell death. Various SMAC-peptidomimetics with inherent cIAP selectivity have been tested clinically and demonstrated minimal single agent efficacy. ASTX660 is a potent, non-peptidomimetic, antagonist of cIAP1/2 and XIAP, discovered using fragment-based drug design...
April 25, 2018: Molecular Cancer Therapeutics
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