Project Details
Description
The incredibly short survival of patients diagnosed with pancreatic cancer underscores one of the greatest failures of the medical community: the inability to identify effective treatments for pancreatic ductal adenocarcinoma. Most new compounds in clinical trials fail because of highly toxic side effects in normal tissues and limited efficacy in tumor response. An ideal drug would kill only tumor cells and spare the normal cells. In this regard, poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated a promising therapeutic potential, particularly in patients with BRCA-deficient tumors. BRCA-deficient cells have an impaired homology-directed repair (HDR) pathway, a mechanism critical for resolving DNA double strand breaks. PARP1 is a protein necessary for the repair of DNA single strand breaks. When PARP1 is inhibited, SSBs are not repaired and they mature to double strand breaks, which are very toxic for the cell. Hence, inhibition of PARP1 is selectively toxic to cells with an impaired HDR pathway, but not to normal cells. Because up to 10% of pancreatic cancer patients carry mutations in either BRCA2 or other proteins involved in the HDR pathway, PARP inhibitors may also prove effective in this setting. However, a number of subtleties remain that call this conclusion into question. We propose to perform a preclinical study to evaluate the efficacy of MK-4827 (a potent PARP inhibitor) in a well-validated, clinically predictive mouse model of pancreatic cancer (KPC mice). We will address some of the important questions surrounding the use of PARP inhibitors in pancreatic cancer, including poor drug delivery, BRCA2 loss of heterozygosity, and BRCA2-independent alterations of the HDR pathway. We will also work to identify predictive biomarkers that distinguish PARP inhibitor resistant and sensitive tumors.The proposal will use three different genetically engineered models (KPC, KPCB2+/- and KPCB2f/f mice) representing different patients populations. Our in vitro and in vivo preliminary data show that BRCA2-deficient KPC tumor cells strongly respond to treatment with MK-4827. We will test the response of pancreatic tumors to MK-4827 alone and in combination with other chemotherapeutic agents in order to identify the most effective therapy. In addition, we will use pre- and post-treatment tumor biopsies to determine the molecular mechanisms of response to PARP inhibition and to identify genetic determinants of PARP sensitivity. Thanks to the close collaboration with clinicians from the Pancreas Center at Columbia University and New York Presbyterian Hospital, we have access to a large bank of tissues from pancreatic cancer patients that will allow us to validate our results in a clinical setting. Identification of a biomarker would be an extremely valuable clinical tool to classify pancreatic cancer patients that could respond to the treatment with PARP inhibitors, a tool that is currently not available.
Status | Finished |
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Effective start/end date | 10/1/12 → 9/30/13 |
Funding
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
ASJC Scopus Subject Areas
- Cancer Research
- Oncology