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Heyer J.,AVEO Pharmaceuticals | Kwong L.N.,Belfer Institute for Applied Cancer Science | Lowe S.W.,Howard Hughes Medical Institute | Chin L.,Belfer Institute for Applied Cancer Science | Chin L.,Harvard University
Nature Reviews Cancer

Genetically engineered mouse models (GEMMs) of cancer have affected virtually all areas of cancer research. However, the accelerated discovery of new cancer genes emerging from large-scale cancer genomics and new chemical entities pouring from the drug discovery pipeline have strained the capacity of traditional germline mouse models to provide crucial insights. This Review introduces new approaches to modelling cancer, with emphasis on a growing collection of non-germline GEMMs (nGEMMs). These offer flexibility, speed and uniformity at reduced costs, thus paving the way for much needed throughput and practical preclinical therapeutic testing models. © 2010 Macmillan Publishers Limited. All rights reserved. Source

Haque A.,Cold Spring Harbor Laboratory | Haque A.,State University of New York at Stony Brook | Andersen J.N.,Cold Spring Harbor Laboratory | Andersen J.N.,Belfer Institute for Applied Cancer Science | And 4 more authors.

Protein tyrosine phosphatase 1B (PTP1B) plays important roles in downregulation of insulin and leptin signaling and is an established therapeutic target for diabetes and obesity. PTP1B is regulated by reactive oxygen species (ROS) produced in response to various stimuli, including insulin. The reversibly oxidized form of the enzyme (PTP1B-OX) is inactive and undergoes profound conformational changes at the active site. We generated conformation-sensor antibodies, in the form of single-chain variable fragments (scFvs), that stabilize PTP1B-OX and thereby inhibit its phosphatase function. Expression of conformation-sensor scFvs as intracellular antibodies (intrabodies) enhanced insulin-induced tyrosyl phosphorylation of the β subunit of the insulin receptor and its substrate IRS-1 and increased insulin-induced phosphorylation of PKB/AKT. Our data suggest that stabilization of the oxidized, inactive form of PTP1B with appropriate therapeutic molecules may offer a paradigm for phosphatase drug development. © 2011 Elsevier Inc. Source

Chong C.R.,Dana-Farber Cancer Institute | Chong C.R.,Brigham and Womens Hospital | Janne P.A.,Dana-Farber Cancer Institute | Janne P.A.,Brigham and Womens Hospital | Janne P.A.,Belfer Institute for Applied Cancer Science
Nature Medicine

All patients with metastatic lung, colorectal, pancreatic or head and neck cancers who initially benefit from epidermal growth factor receptor (EGFR)-targeted therapies eventually develop resistance. An increasing understanding of the number and complexity of resistance mechanisms highlights the Herculean challenge of killing tumors that are resistant to EGFR inhibitors. Our growing knowledge of resistance pathways provides an opportunity to develop new mechanism-based inhibitors and combination therapies to prevent or overcome therapeutic resistance in tumors. We present a comprehensive review of resistance pathways to EGFR-targeted therapies in lung, colorectal and head and neck cancers and discuss therapeutic strategies that are designed to circumvent resistance. © 2013 Nature America, Inc. Source

Gandhi L.,Dana-Farber Cancer Institute | Gandhi L.,Brigham and Womens Hospital | Janne P.A.,Dana-Farber Cancer Institute | Janne P.A.,Belfer Institute for Applied Cancer Science | Janne P.A.,Brigham and Womens Hospital
Clinical Cancer Research

Crizotinib (PF02341066, Xalkori; Pfizer) was recently approved by the U.S. Food and Drug Administration for treatment of ALK-positive non-small cell lung cancer (NSCLC) as defined by a jointly approved diagnostic test using a break-apart fluorescence in situ hybridization assay. The approval was based on dramatic response rates in ALK-positive NSCLC patients of 54% to 61% in phase I and II trials. To date, the overall disease control rates in these trials are close to 90%. Progression-free survival approaches 10 months. This review focuses on the ALK-inhibitory activity of crizotinib in preclinical and clinical trials that led to approval, as well as the diagnostic methods to classify patients with ALK-positive NSCLC. Although these patients represent a small subset of all patients with NSCLC, the rapid time course from identification of this unique target to an approved targeted therapy with striking benefit serves as a paradigm for the development of targeted therapeutics in an era of personalized medicine. ©2012 AACR. Source

Garraway L.A.,Dana-Farber Cancer Institute | Garraway L.A.,Brigham and Womens Hospital | Garraway L.A.,The Broad Institute of MIT and Harvard | Janne P.A.,Dana-Farber Cancer Institute | And 2 more authors.
Cancer Discovery

All successful cancer therapies are limited by the development of drug resistance. The increase in the understanding of the molecular and biochemical bases of drug efficacy has also facilitated studies elucidating the mechanism(s) of drug resistance. Experimental approaches that can help predict the eventual clinical drug resistance, coupled with the evolution of systematic genomic and proteomic technologies, are rapidly identifying novel resistance mechanisms. In this review, we provide a historical background on drug resistance and a framework for understanding the common ways by which cancers develop resistance to targeted therapies. We further discuss advantages and disadvantages of experimental strategies that can be used to identify drug resistance mechanism(s). Significance: Increased knowledge of drug resistance mechanisms will aid in the development of effective therapies for patients with cancer. We provide a summary of current knowledge on drug resistance mechanisms and experimental strategies to identify and study additional drug resistance pathways. © 2012 American Association for Cancer Research. Source

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