Mechanisms of sensitivity and resistance to DNA damaging drugs in patient-derived xenograft (PDX) models of small cell lung cancer.

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Small cell lung cancer (SCLC) is an aggressive and highly metastatic type of cancer, which affects an estimated 270,000 individuals per year worldwide. SCLC accounts for about 10-20% of all lung cancer cases, only 7% survive for five years after diagnosis, and the median survival for patients with metastatic disease is less than one year. All therapies for SCLC involve DNA damaging agents and the standard first-line treatment used today is very similar to the treatment given thirty years ago. Despite SCLC is highly responsive to this initial treatment, almost all patients will experience relapse and more become relatively resistant to therapy. Most chemotherapy regimens show poor efficacy for relapsed SCLC and the progression of SCLC is characterized by a shift between an initial chemoresponsive state and a subsequent chemoresistant state. The major challenges for SCLC research are to understand the molecular mechanisms that underlie the acquisition of chemotherapeutic resistance, to find ways to suppress this, and to identify better treatment options for second line therapy. Despite the critical need, the development of new therapies for SCLC has suffered from a scarcity of cutting-edge laboratory models for research and absence of promising targets. Exciting new progress in the establishment of patient-derived xenograft (PDX) mouse models of SCLC can support a detailed analysis of genetic and molecular alterations that take place within the tumor cells during resistance acquisition. PDX models generated via direct implantation of tumor material into mice (with no intermediate in vitro culture) closely maintain the gene expression signatures and key characteristics of the primary tumor. The Dyson laboratory has generated an extensive panel of PDX models of SCLC from patients. This unique resource includes PDX models of treatment-naive tumors and tumors that have developed resistance to chemotherapy. Importantly, PDX models have a spectrum of sensitivity and resistance to treatment that directly parallel the clinical response. This resource provides new opportunities for detailed mechanistic investigation of tumor sensitivity/resistance in SCLC. The proposed project aims to investigate the molecular determinants of sensitivity and resistance to DNA damaging agents, and to search for improved therapeutic approaches. We propose to dissect the response of PDX models to DNA damaging drugs, by analyzing and comparing successive PDX models generated from SCLC patients, before and after their treatments. The insights gained from this research project can foster the progress of novel clinical trials and the future development of effective therapeutic programs for SCLC patients.