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Verastem Announces Oral Presentation of Data Supporting the Preferential Targeting of Ovarian Cancer Stem Cells at the Society of Gynecologic Oncology’s 2016 Annual Meeting on Women’s Cancer

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

Pharmacokinetics and safety of subcutaneous pasireotide and intramuscular pasireotide long-acting release in Chinese male healthy volunteers: a phase I, single-center, open-label, randomized study.

The purpose of this study was to assess the pharmacokinetic (PK) properties and safety of single and multiple doses of subcutaneous (SC) pasireotide and a single-dose intramuscular (IM) long-acting release (LAR) formulation of pasireotide in Chinese healthy volunteers (HVs) versus the PK properties in Western HVs (pooled from previous PK studies).
In this phase I, single-center, open-label study, 45 Chinese male HVs were evenly randomized to 1 to 9 treatment sequences: each volunteer received a single dose of 300, 600, or 900 μg of pasireotide SC on day 1, followed by administration of the same dose BID from day 15 to the morning of day 19, and then a single IM dose of 20, 40, or 60 mg of pasireotide LAR on day 33. The PK parameters were assessed with noncompartmental analysis. Statistical comparison of PK parameters, including AUC, Cmax, and CL/F from both formulations, was made for Chinese versus Western male HVs. The safety profile was also assessed. Metabolic parameters, including blood glucose, insulin, and glucagon, and measures that reflect the effects of pasireotide LAR on relatively long-term glucose control, lipid metabolism, and systemic concentrations of pancreatic enzymes and thyrotropin were evaluated.
Of the 45 randomized HVs, 42 completed the study per protocol, 1 withdrew his informed consent for personal reasons, and 2 prematurely discontinued the study because of adverse events (AEs). Concentration-time and safety profiles of both formulations were similar to those reported in Western HVs. Mean geometric mean ratios (GMRs) of Chinese versus Western HVs ranged from 0.79 to 1.42. For most primary PK parameters, 90% CIs for GMRs were within a predefined ethnic insensitivity interval (90% CI, 0.70-1.43). After considering age and weight as covariates in the statistical model, the GMRs and 90% CIs for other PK parameters were within the predefined interval (Cmax in single-dose SC administration) or significantly decreased (Cmin,ss in multiple BID SC doses and first peak Cmax in the single-dose LAR formulation). No serious AEs were reported. Both formulations were well tolerated; pasireotide SC caused transient changes in glucose metabolism. Owing to the differential binding affinity to the somatostatin receptor subtypes, pasireotide LAR elicited a concentration-dependent increase of fasting blood glucose, substantial reduction in triglyceride, and a mild decrease in cholesterol. The most frequently reported AEs after single-dose and multiple-dose pasireotide SC were injection site reaction, nausea, dizziness, and diarrhea; most HVs developed diarrhea with single-dose pasireotide LAR.
The pasireotide formulations had similar PK and safety profiles between Chinese and Western male HVs. Thus, no ethnic sensitivity was found for pasireotide SC or LAR.
Copyright © 2014 The Authors. Published by EM Inc USA.. All rights reserved.

A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis.

Ruxolitinib, a potent Janus kinase 1/2 inhibitor, resulted in rapid and durable improvements in splenomegaly and disease-related symptoms in the 2 phase III COMFORT studies. In addition, ruxolitinib was associated with prolonged survival compared with placebo (COMFORT-I) and best available therapy (COMFORT-II). We present a pooled analysis of overall survival in the COMFORT studies using an intent-to-treat analysis and an analysis correcting for crossover in the control arms. Overall, 301 patients received ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 patients received placebo (n=154) or best available therapy (n=73). After a median three years of follow up, intent-to-treat analysis showed that patients who received ruxolitinib had prolonged survival compared with patients who received placebo or best available therapy [hazard ratio=0.65; 95% confidence interval (95%CI): 0.46-0.90; P=0.01]; the crossover-corrected hazard ratio was 0.29 (95%CI: 0.13-0.63). Both patients with intermediate-2- or high-risk disease showed prolonged survival, and patients with high-risk disease in the ruxolitinib group had survival similar to that of patients with intermediate-2-risk disease in the control group. The Kaplan-Meier estimate of overall survival at week 144 was 78% in the ruxolitinib arm, 61% in the intent-to-treat control arm, and 31% in the crossover-adjusted control arm. While larger spleen size at baseline was prognostic for shortened survival, reductions in spleen size with ruxolitinib treatment correlated with longer survival. These findings are consistent with previous reports and support that ruxolitinib offers a survival benefit for patients with myelofibrosis compared with conventional therapies. (clinicaltrials.gov identifiers: COMFORT-I, NCT00952289; COMFORT-II, NCT00934544).
Copyright© Ferrata Storti Foundation.

Varian Launches New Smaller Calypso Beacon Transponder To Guide Radiation Therapy In Soft Tissue Tumors

On March 22, 2016 Varian Medical Systems (NYSE: VAR) reported a new Calypso 17G soft tissue Beacon transponder that is 50 percent smaller than the previous version (Press release, Varian Medical Systems, MAR 22, 2016, View Source [SID:1234509820]). The 17G device can help enhance the precision of radiotherapy and radiosurgery treatments for cancer by providing real-time, continuous tumor position information, based on the implanted transponders, and has received FDA 510(k) clearance and CE mark.

The size of a grain of rice, the new Varian Calypso 17G soft tissue Beacon transponder, can help enhance the precision of radiotherapy and radiosurgery treatments for cancer by providing real-time, continuous tumor position information, based on the implanted transponders, and has received FDA 510(k) clearance and CE mark.
The size of a grain of rice, each Beacon transponder emits a non-ionizing electromagnetic signal that is tracked in real-time by the Calypso system, guiding treatment beams to precisely target tumors during treatment with medical linear accelerators, such as the Varian’s Edge radiosurgery system. The 17G Beacon transponders are commercially available, and for more information, visit View Source

The smaller Calypso technology benefits a broader range of patients during the implantation of the transponders, which is typically an outpatient procedure. "The new 17G implantation device has half the cross-sectional area as the prior 14G technology, increasing patient comfort and improving access to tumors," said Zachary S. Collins, M.D., section head of interventional radiology, Kansas University Medical Center. "The smaller technology may make the use of Calypso viable in a broader population of liver patients and may make it possible for interventional radiologists to implant Beacon transponders in the pancreas without an open surgical procedure."

The new transponders can be implanted within the soft tissue throughout the body, with the exception of the lung. Based on the transponder signals, the Calypso System uses "GPS for the body" technology to track even the slightest movement of the tumor without using ionizing radiation. Even tumors exhibiting respiratory motion can be precisely targeted through Calypso’s innovative technology, which allows the beam to be gated on only when the tumor is in the planned position.

The Calypso System is the only device on the market that delivers real-time, continuous (25 Hz update rate), 3D tumor position information, improving confidence that the prescribed dose has been delivered to the tumor. This increased precision can enable treatment margin reduction, which can protect healthy tissue and reduce certain side effects1. The Calypso system, when used with the new 17G transponders, delivers equivalent accuracy and precision as compared to the established 14G devices.

"With the precise targeting provided by Calypso technology, we are able to reduce treatment margins and liver toxicity compared to conventional radiotherapy without Calypso beacons," remarked Neal Dunlap, MD, Radiation Oncologist, University of Louisville, Kentucky.

Binding Mode and Selectivity of Steroids towards Glucose-6-phosphate Dehydrogenase from the Pathogen Trypanosoma cruzi.

Glucose-6-phosphate dehydrogenase (G6PDH) plays a housekeeping role in cell metabolism by generating reducing power (NADPH) and fueling the production of nucleotide precursors (ribose-5-phosphate). Based on its indispensability for pathogenic parasites from the genus Trypanosoma, G6PDH is considered a drug target candidate. Several steroid-like scaffolds were previously reported to target the activity of G6PDH. Epiandrosterone (EA) is an uncompetitive inhibitor of trypanosomal G6PDH for which its binding site to the enzyme remains unknown. Molecular simulation studies with the structure of Trypanosoma cruzi G6PDH revealed that EA binds in a pocket close to the G6P binding-site and protrudes into the active site blocking the interaction between substrates and hence catalysis. Site directed mutagenesis revealed the important steroid-stabilizing effect of residues (L80, K83 and K84) located on helix α-1 of T. cruzi G6PDH. The higher affinity and potency of 16α-Br EA by T. cruzi G6PDH is explained by the formation of a halogen bond with the hydrogen from the terminal amide of the NADP+-nicotinamide. At variance with the human enzyme, the inclusion of a 21-hydroxypregnane-20-one moiety to a 3β-substituted steroid is detrimental for T. cruzi G6PDH inhibition. The species-specificity of certain steroid derivatives towards the parasite G6PDH and the corresponding biochemically validated binding models disclosed in this work may prove valuable for the development of selective inhibitors against the pathogen’s enzyme.