1stOncology™: Cancer Intelligence Service – Page 17239 – 1stOncology is recognized as a Top 10 Global Pharma Analytic Provider

Drugging ATR: progress in the development of specific inhibitors for the treatment of cancer.

In this article, we review the ATR inhibitor field from initial pharmacological tools to first-generation clinical candidates with the potential to bring benefit to cancer patients. ATR is a critical part of the cell DNA-damage response. Over the past decade or more, compounds with weak ATR potency and low specificity have been used as tools in early studies to elucidate ATR pharmacology. More recently highly potent, selective and in vivo active ATR inhibitors have been developed enabling detailed preclinical in vitro and in vivo target assessment to be made. The published studies reveal the potential of ATR inhibitors for use as monotherapy or in combination with DNA-damaging agents. To date, VX-970 and AZD6738, have entered clinical assessment.

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Testing of evaluation bias for progression free survival endpoint in oncology clinical trials.

Progression-free survival is an increasingly popular end point in oncology clinical trials. A complete blinded independent central review (BICR) is often required by regulators in an attempt to reduce the bias in progression-free survival (PFS) assessment. In this paper, we propose a new methodology that uses a sample-based BICR as an audit tool to decide whether a complete BICR is needed. More specifically, we propose a new index, the differential risk, to measure the reading discordance pattern, and develop a corresponding hypothesis testing procedure to decide whether the bias in local evaluation is acceptable. Simulation results demonstrate that our new index is sensitive to the change of discordance pattern; type I error is well controlled in the hypothesis testing procedure, and the calculated sample size provides the desired power. Copyright © 2016 John Wiley &amp; Sons, Ltd.
Copyright © 2016 John Wiley &amp; Sons, Ltd.

Genomic Landscape Survey Identifies SRSF1 as a Key Oncodriver in Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is an aggressive disease with poor survival. A few sequencing studies performed on limited number of samples have revealed potential disease-driving genes in SCLC, however, much still remains unknown, particularly in the Asian patient population. Here we conducted whole exome sequencing (WES) and transcriptomic sequencing of primary tumors from 99 Chinese SCLC patients. Dysregulation of tumor suppressor genes TP53 and RB1 was observed in 82% and 62% of SCLC patients, respectively, and more than half of the SCLC patients (62%) harbored TP53 and RB1 mutation and/or copy number loss. Additionally, Serine/Arginine Splicing Factor 1 (SRSF1) DNA copy number gain and mRNA over-expression was strongly associated with poor survival using both discovery and validation patient cohorts. Functional studies in vitro and in vivo demonstrate that SRSF1 is important for tumorigenicity of SCLC and may play a key role in DNA repair and chemo-sensitivity. These results strongly support SRSF1 as a prognostic biomarker in SCLC and provide a rationale for personalized therapy in SCLC.

Targeting endoplasmic reticulum stress in liver disease.

The accumulation of unfolded protein in the endoplasmic reticulum (ER) initiates an unfolded protein response (UPR) via three signal transduction cascades, which involve protein kinase RNA-like ER kinase (PERK), inositol requiring enzyme-1α (IRE1α) and activating transcription factor-6α (ATF6α). An ER stress response is observed in nearly all physiologies related to acute and chronic liver disease and therapeutic targeting of the mechanisms implicated in UPR signaling have attracted considerable attention. This review focuses on the correlation between ER stress and liver disease and the possible targets which may drive the potential for novel therapeutic intervention. We describe pathways which are involved in UPR signaling and their potential correlation with various liver diseases and underlying mechanisms which may present opportunities for novel therapeutic strategies are discussed.

AbbVie, University of Chicago collaborate to advance cancer research

On April 20, 2016 The University of Chicago and AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported that they have entered into a five-year collaboration agreement designed to improve the pace of discovery and advance medical research in oncology at both organizations (Press release, AbbVie, APR 20, 2016, View Source [SID:1234511313]).

The joint strategic research agreement between AbbVie and the University of Chicago is designed to encourage and strengthen collaboration among researchers. Initially, both organizations will work together to advance research in several areas of oncology, which could include, among others, breast, lung, prostate, colorectal and hematological cancer. Research projects are chosen by a joint steering committee, comprised of representatives from each organization. AbbVie also gains an option for an exclusive license to certain University of Chicago discoveries made under the agreement.

"University of Chicago researchers and clinicians have worked closely with AbbVie scientists in areas such as immunology and oncology for some time," said Kenneth S. Polonsky, MD, executive vice president for medical affairs at the University of Chicago and dean of the Biological Sciences Division and Pritzker School of Medicine. "This agreement adds depth to that established and productive collaboration. The increased level of interaction should speed progress in medical care, beginning with cancer patients."

As part of the agreement, AbbVie will provide funding for the collaboration that may be used for purposes including preclinical research, clinical trials and possible future programs at the University resulting from this partnership. The overall collaborative efforts will provide University of Chicago physicians and scientists with the opportunity to participate in AbbVie-sponsored clinical trials, access to new therapies developed by AbbVie for use in preclinical research funded under the collaboration, as well as opportunities to work closely with AbbVie’s research and development teams to promote scientific knowledge exchange.

"Advancements in oncology – both at the basic science and clinical levels – are happening faster and more broadly every day," said Gary Gordon, M.D., Ph.D., vice president, oncology clinical development, AbbVie. "Collaborating closely with the scientists and clinicians at the University of Chicago allows us to expand our own research efforts even further to benefit patients."

As part of the collaborative agreement, researchers from the University of Chicago and AbbVie will participate in an annual symposium that brings together scientists from both institutions to discuss research and evaluate potential new projects.

"This is a wonderful opportunity for our investigators to join forces with a leader in oncology and new drug development, accelerate the pace of discovery and deliver clinical benefits to our patients," said cancer specialist Everett Vokes, MD, professor and chairman of medicine at the University of Chicago. "This will support pre-clinical research, give our physician-scientists earlier access to drugs in the AbbVie pipeline and lay the groundwork for further interaction and collaboration."

AbbVie also holds a membership to the Chicago Innovation Exchange, a hub for multidisciplinary collaborations and support for business startup activities and an observer seat at meetings of the University of Chicago Innovation Fund Advisory Committee, which provides guidance to the Innovation Fund, a $20 million investment fund focusing on commercializing early stage research and supporting emerging companies at the University. The Innovation Fund is managed by the Chicago Innovation Exchange in partnership with UChicagoTech and the Polsky Center for Entrepreneurship & Innovation.

Collaborative efforts also provide AbbVie researchers with access to data commons technology developed by the Center for Data Intensive Science at the University of Chicago and the core technical team that is developing the technology. This novel platform powers several large-scale resources for the research community, including the National Cancer Institute Genomic Data Commons – one of the world’s largest storage, analysis and distribution systems for cancer genomics data.