On March 22, 2016 Verastem, Inc. (NASDAQ:VSTM), focused on discovering and developing drugs to treat cancer, reported the presentation of scientific data at the Society of Gynecologic Oncology’s 2016 Annual Meeting on Women’s Cancer being held March 19-22, 2016 in San Diego, CA (Press release, Verastem, MAR 22, 2016, View Source;p=RssLanding&cat=news&id=2150260 [SID:1234509826]).

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"The data presented today at SGO 2016 are important because they provide further scientific evidence that chemotherapy can lead to an increase in ovarian cancer stem cells (CSCs), making the tumor more aggressive and resistant to further treatment," said Dr. Jonathan Pachter, Verastem Head of Research. "At Verastem, we believe that our compounds in development may be especially beneficial as therapeutics when used in combination with other agents, including current and emerging standard of care treatments and immunotherapies, and have the potential to create a more durable clinical response. We look forward to the initiation of a Phase 1/1b clinical trial of the combination of VS-6063 and avelumab, in collaboration with Pfizer and Merck KGaA, for patients with ovarian cancer in the second half of this year."

Verastem, and its collaborators, are presenting these scientific data in support of Verastem’s development programs which utilize a multi-faceted approach to treat cancer by reducing cancer stem cells, enhancing anti-tumor immunity, and modulating the local tumor microenvironment. The Company’s most advanced clinical product candidates are the Focal Adhesion Kinase inhibitors, VS-6063 and VS-4718, and the dual PI3K/mTOR inhibitor, VS-5584. Research on the FAK and PI3K/mTOR signaling pathways has revealed critical roles for each in cancer stem cell survival and disease progression.

Details for the SGO presentation are as follows:

Oral Presentation

Title: Standard chemotherapy for ovarian cancer increases expression of cancer stem cell biomarkers which is predictive of survival

Session: Scientific Plenary IX: Ovary

Date and time: Tuesday, March 22, 2016 at 8:30 – 10:05 AM

Location: Hall A

Summary: In ovarian cancer, certain molecular mediators are thought to possess CSC characteristics and the presence of these mediators, which is linked to earlier recurrence and shorter survival, is possibly brought about by chemotherapy. The aim of this study was to explore the effect of chemotherapy on ovarian cancer stem-like mediators and to determine if there was a relationship to survival. Researchers obtained matched pre- and post-chemotherapy tumor specimens from stage IIIC/IV ovarian cancer patients (n=22) who all underwent neoadjuvant chemotherapy with interval debulking surgery. Samples were then analyzed for expression of 27 CSC markers. CSC markers were then validated in tumorsphere model and in vivo tumor initiating studies.

All 27 CSC markers demonstrated a mean increase in gene expression after exposure to chemotherapy. A 3-fold or greater increase in gene expression after exposure to chemotherapy was seen in 8 of 27 (30%) markers: ABCG2, ALDH1A1, CTGF, DPP4, MYC, CD133, SOX2, and POSTN. Three markers demonstrated a significant fold increase that correlated with platinum resistance: POSTN (4.1-fold), ALDH1A1 (5-fold), and SOX2 (14.5-fold). When implanted into immunocompromised mice, SOX2(hi) cells exhibited significantly higher levels of tumorsphere forming potential than SOX2(lo) cells and were more tumorigenic. High gene expression in these 3 markers demonstrated shorter progression free survival, compared to low expression. These results support the further investigation of directed agents to inhibit these CSC markers to potentially extend survival for patients with ovarian cancer.

A copy of the oral presentation will be available at http://bit.ly/R3M6wc

When cells are exposed to death ligands such as TRAIL, a fraction undergoes apoptosis and a fraction survives; if surviving cells are re-exposed to TRAIL, fractional killing is once again observed. Therapeutic antibodies directed against TRAIL receptors also cause fractional killing, even at saturating concentrations, limiting their effectiveness. Fractional killing arises from cell-to-cell fluctuations in protein levels (extrinsic noise), but how this results in a clean bifurcation between life and death remains unclear. In this paper, we identify a threshold in the rate and timing of initiator caspase activation that distinguishes cells that live from those that die; by mapping this threshold, we can predict fractional killing of cells exposed to natural and synthetic agonists alone or in combination with sensitizing drugs such as bortezomib. A phenomenological model of the threshold also quantifies the contributions of two resistance genes (c-FLIP and Bcl-2), providing new insight into the control of cell fate by opposing pro-death and pro-survival proteins and suggesting new criteria for evaluating the efficacy of therapeutic TRAIL receptor agonists.
© 2015 The Authors. Published under the terms of the CC BY 4.0 license.

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Lysine deacetylases inhibitors (KDACIs) are used in basic research, and many are being investigated in clinical trials for treatment of cancer and other diseases. However, their specificities in cells are incompletely characterized. Here we used quantitative mass spectrometry (MS) to obtain acetylation signatures for 19 different KDACIs, covering all 18 human lysine deacetylases. Most KDACIs increased acetylation of a small, specific subset of the acetylome, including sites on histones and other chromatin-associated proteins. Inhibitor treatment combined with genetic deletion showed that the effects of the pan-sirtuin inhibitor nicotinamide are primarily mediated by SIRT1 inhibition. Furthermore, we confirmed that the effects of tubacin and bufexamac on cytoplasmic proteins result from inhibition of HDAC6. Bufexamac also triggered an HDAC6-independent, hypoxia-like response by stabilizing HIF1-α, providing a possible mechanistic explanation of its adverse, pro-inflammatory effects. Our results offer a systems view of KDACI specificities, providing a framework for studying function of acetylation and deacetylases.

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We recently demonstrated that brain endothelial cells and astrocytes protect cancer cells from chemotherapy through an endothelin-dependent signaling mechanism. Here, we evaluated the efficacy of macitentan, a dual endothelin receptor (ETAR and ETBR) antagonist, in the treatment of experimental breast and lung cancer brain metastases.
The effect of macitentan on astrocyte- and brain endothelial cell-mediated chemoprotective properties was measured in cytotoxic assays. We compared survival of mice bearing established MDA-MB-231 breast cancer or PC-14 non-small cell lung cancer (NSCLC) brain metastases that were treated with vehicle, macitentan, paclitaxel, or macitentan plus paclitaxel. Cell division, apoptosis, tumor vasculature, and expression of survival-related proteins were assessed by immunofluorescent microscopy.
Cancer cells and tumor-associated endothelial cells expressed activated forms of AKT and MAPK in vehicle- and paclitaxel-treated groups in both metastasis models, but these proteins were downregulated in metastases of mice that received macitentan. The survival-related proteins Bcl2L1, Gsta5, and Twist1 that localized to cancer cells and tumor-associated endothelial cells in vehicle- and paclitaxel-treated tumors were suppressed by macitentan. Macitentan or paclitaxel alone had no effect on survival. However, when macitentan was combined with paclitaxel, we noted a significant reduction in cancer cell division and marked apoptosis of both cancer cells and tumor-associated endothelial cells. Moreover, macitentan plus paclitaxel therapy significantly increased overall survival by producing complete responses in 35 of 35 mice harboring brain metastases.
Dual antagonism of ETAR and ETBR signaling sensitizes experimental brain metastases to paclitaxel and may represent a new therapeutic option for patients with brain metastases.
© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

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Monoclonal antibodies (mAbs) have revolutionized the diagnosis and treatment of many human diseases and the application of combinations of mAbs has demonstrated improved therapeutic activity in both preclinical and clinical testing. Combinations of antibodies have several advantages such as the capacities to target multiple and mutating antigens in complex pathogens and to engage varied epitopes on multiple disease-related antigens (e.g. receptors) to overcome heterogeneity and plasticity. Oligoclonal antibodies are an emerging therapeutic format in which a novel antibody combination is developed as a single drug product. Here, we will provide historical context on the use of oligoclonal antibodies in oncology and infectious diseases and will highlight practical considerations related to their preclinical and clinical development programs.
Copyright © 2016 Elsevier Ltd. All rights reserved.

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