Sang J.,Synta Pharmaceuticals |
Acquaviva J.,Synta Pharmaceuticals |
Friedland J.C.,Synta Pharmaceuticals |
Smith D.L.,Synta Pharmaceuticals |
And 15 more authors.
EML4-ALK gene rearrangements define a unique subset of patients with non-small cell lung carcinoma (NSCLC), and the clinical success of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib in this population has become a paradigm for molecularly targeted therapy. Here, we show that the Hsp90 inhibitor ganetespib induced loss of EML4-ALK expression and depletion of multiple oncogenic signaling proteins in ALK-driven NSCLC cells, leading to greater in vitro potency, superior antitumor efficacy, and prolonged animal survival compared with results obtained with crizotinib. In addition, combinatorial benefit was seen when ganetespib was used with other targeted ALK agents both in vitro and in vivo. Importantly, ganetespib overcame multiple forms of crizotinib resistance, including secondary ALK mutations, consistent with activity seen in a patient with crizotinib-resistant NSCLC. Cancer cells driven by ALK amplification and oncogenic rearrangements of ROS1 and RET kinase genes were also sensitive to ganetespib exposure. Taken together, these results highlight the therapeutic potential of ganetespib for ALK-driven NSCLC. Significance: In addition to direct kinase inhibition, pharmacologic blockade of the molecular chaperone Hsp90 is emerging as a promising approach for treating tumors driven by oncogenic rearrangements of ALK. The bioactivity profile of ganetespib presented here underscores a new therapeutic opportunity to target ALK and overcome multiple mechanisms of resistance in patients with ALK-positive NSCLC. © 2013 American Association for Cancer Research. Source
Thomas L.R.,Vanderbilt University |
Thomas L.R.,Insight Genetics, Inc. |
Foshage A.M.,Vanderbilt University |
Weissmiller A.M.,Vanderbilt University |
Tansey W.P.,Vanderbilt University
The MYC oncogenes encode a family of transcription factors that feature prominently in cancer. MYC proteins are overexpressed or deregulated in a majority of malignancies and drive tumorigenesis by inducing widespread transcriptional reprogramming that promotes cell proliferation, metabolism, and genomic instability. The ability of MYC to regulate transcription depends on its dimerization with MAX, which creates a DNA-binding domain that recognizes specific sequences in the regulatory elements of MYC target genes. Recently, we discovered that recognition of target genes by MYC also depends on its interaction with WDR5, a WD40-repeat protein that exists as part of several chromatin-regulatory complexes. Here, we discuss how interaction of MYC with WDR5 could create an avidity-based chromatin recognition mechanism that allows MYC to select its target genes in response to both genetic and epigenetic determinants. We rationalize how the MYC-WDR5 interaction provides plasticity in target gene selection by MYC and speculate on the biochemical and genomic contexts in which this interaction occurs. Finally, we discuss how properties of the MYC-WDR5 interface make it an attractive point for discovery of small-molecule inhibitors of MYC function in cancer cells. © 2015 AACR. Source
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.50M | Year: 2012
Constitutively activated forms of ALK caused by genetic aberrations have been shown to cause an expanding variety of human cancers. The FDA recently approved the Pfizer drug Xalkori (crizotinib) to treat patients with non-small cell lung cancers (NSCLC) that express ALK. Numerous other pharmaceutical companies (ARIAD, Novartis, Synta, Xcovery, others) have ongoing ALK small-molecule inhibitor programs. The current diagnostic standard an ALK break-apart FISH assay has low sensitivity and is difficult tointerpret, creating a precarious situation for clinicians attempting to select the proper patients for ALK inhibitor treatment. Insight Genetics has therefore designed a qPCR platform, Insight ALK Screen , to provide highly sensitive and unambiguous identification of the complete spectrum of oncogenic ALK. During Phase I development, Insight ALK Screen was shown to be agnostic with regard to the 5 fusion partner of ALK, highly sensitive in cell line dilution studies, and highly specific in FFPE NSCLC patient specimens. Phase II will demonstrate clinical utility of the assay by testing a large cohort of clinical specimens to unequivocally demonstrate statistical significance in sound patient selection for ALK inhibitor therapy. The product will then enter co-development with IVD partner, QIAGEN, for commercialization of the assay as a FDA-approved companion diagnostic.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 200.00K | Year: 2010
Kinase inhibitors such as Gleevec and Tarceva have markedly improved cancer therapy. Essential to the use of such inhibitors are companion diagnostics enabling determination of the mutational status of th eir kinase targets in tumors. Anaplastic lymphoma kinase (ALK) fusion oncogenes have emerged as an important cause of lung cancer, and ALK inhibitor programs (by Pfizer, Lil ly, Ariad, Astell as, Zenobia, and others) are in progress, ALK inhibition causes marked anti-tumor responses, but only in patients whose tumors conta in mutant ALK. Both immunohistochemistry (IHe) and fluorescence in situ hybridization (FISH) can identify ALK mutations, but each has multiple limitations Herein, we propose development of a microarray¿based test to ident ify ALK fus ions (EML4¿ALK. NPM¿ALK, CL TC-ALK, and others) from FFPE tissues as a rapid, highly specific and sensit ive companion diagnostic. Insight Genetics has established collaborations with experts in the genetics of ALK and lung cancer, as well as collaborations with pharmaceutical companies developing ALK inhibitors. In the studies proposed, we wi ll establish and validate our ALK mutation detection platform using lung cancer specimens. many also characte rized by ALK FISH and/or IHC to benchmark our assay against these methodolog ies. The Insight Genetics ALK microarray will enable personalized therapy by caregive rs, tra ns lating to improved patient outcomes.
Insight Genetics, Inc. | Date: 2013-03-08
Disclosed are methods and compositions for detecting the presence of a cancer in a subject and assessing the efficacy of treatments for the same. The disclosed method use reverse transcription polymerase chain reaction (RT-PCR), real time polymerase chain reaction, and multiplex polymerase chain reaction techniques to detect fusions, over-expression, truncation, and nucleic acid variation of RET and DEPDC1 in cancers.