Small cell lung cancer (SCLC) leads to over 30,000 deaths each year in the United States (US) alone with a two-year survival rate of ~6%. Unlike the other major subtypes of lung cancer, there are currently no targeted therapies approved for SCLC. SCLC is initially highly responsive to chemotherapy, but rapidly develops resistance leading to mortality in an average of 10 months. Clearly, a major unmet need for the treatment of SCLC is the identification of new therapeutic targets and treatment strategies to combat this deadly disease. SCLC uniformly lacks activity of the RB1 and TP53 tumor suppressors. One of the most frequent oncogenic events in SCLC is mutually exclusive amplification of a MYC family member, including MYC, MYCL or MYCN. Kinases are not frequently altered in SCLC and until recently, there have been few genetically-engineered mouse models (GEMMs) of the disease. Previous GEMMs exhibit long latencies, variable histologies and reportedly fail to mimic the initial chemo-sensitivity found in human SCLC. To address these challenges, we developed a novel GEMM of SCLC driven by loss of Rb1, Trp53 and overexpression of c-Myc?three of the most common genetic alterations in human SCLC. Mice develop SCLC within five weeks that highly resembles the human disease at the level of histopathology, biomarker expression and chemo-sensitivity followed by relapse. Our in vitro studies identified exquisite sensitivity of mouse and human SCLC cell lines to mitotic checkpoint inhibitors, some of which are in clinical trials but on their own lead to modest effects in a fraction of patients. The objective of this study is to use this novel GEMM to test the efficacy of mitotic checkpoint inhibitors specifically in c-MYC-driven SCLC in vivo, both as monotherapies and in combination with the standard-of-care chemotherapy. Second, we will perform a novel anchor screen with mitotic checkpoint inhibitors to identify small molecules that synergize with mitotic checkpoint inhibition in c-MYC-driven SCLC. We hypothesize that mitotic checkpoint inhibitors will significantly improve chemotherapy response in vivo, and that inhibitors of DNA damage repair, apoptosis or other processes will cooperate to produce greater efficacy. To test these hypotheses, we will: 1) Determine whether AURKA, AURKB or PLK1 inhibitors block tumor growth and prolong survival of mice with c-MYC-driven SCLC, and 2) Identify small molecules that synergize with Aurora kinase inhibition in c-MYC-driven SCLC using an alisertib-based anchor screen. This approach is innovative because we will use a novel immune-competent GEMM of SCLC that recapitulates key features of the human disease. Anchor screens with mitotic checkpoint inhibitors have not been performed in SCLC. This research is significant because lung cancer is the leading cause of cancer death in the US and there are currently no targeted therapies approved for SCLC. A better understanding of the therapeutic vulnerabilities of c-MYC-driven SCLC will impact the treatment and survival of patients with this intractable disease.
Small cell lung cancer (SCLC) is a recalcitrant subtype of lung cancer for which there are limited treatment options. This study will employ a novel mouse model of the disease to test new therapeutic strategies in vivo and to identify new combinatorial approaches to reduce tumor burden and prolong survival. This work is relevant to public health and the NIH mission because it will impact the development of new therapies to improve the quality of life and survival of lung cancer patients.
|Wagner, Alex H; Devarakonda, Siddhartha; Skidmore, Zachary L et al. (2018) Recurrent WNT pathway alterations are frequent in relapsed small cell lung cancer. Nat Commun 9:3787|