Our laboratory at the Fred Hutchinson Cancer Research Center is focused on understanding the mechanisms through which cancer-mutated genes drive tumorigenesis. We study two tumor types, small cell lung carcinoma (SCLC) and retinoblastoma. Genomic analyses of human tumors allow us to identify gene mutations that may contribute to tumor initiation, progression and metastasis. It is a challenge to determine which cancer-mutated genes function as oncogenes or tumor suppressor genes. We turn to genetically engineered mouse models to probe the activity of genes implicated in SCLC or retinoblastoma.
Children who inherit a mutant copy of the RB gene develop retinoblastoma with extremely high frequency. We have generated some of the first RB-knockout mouse models of retinoblastoma. We recently used these models to identify a microRNA cluster, miR-17~92 that synergizes with RB loss to drive uncontrolled proliferation. Retinoblastoma is an ideal tumor type to probe genes that collaborate with RB mutation broadly in cancer, as there are few genetic alterations beyond RB mutation in this tumor type.
RB is also frequently mutated in SCLC, the most aggressive form of lung cancer. SCLC is tumor with neuroendocrine characteristics and an extremely complex pattern of genetic alterations. Typically, SCLC has metastasized by the time it is diagnosed and survival rates for metastatic SCLC are dismal. Unlike other forms of lung cancer there are no targeted therapies for SCLC. We have recently undertaken efforts to identify the major driver genes mutated in human SCLC using next-generation sequencing approaches. A number of projects in the lab are now aimed at exploring the functions of new SCLC-mutated genes using mouse genetics. Our ultimate aim is to translate increased understanding of the basic biology of SCLC driver genes to the development of novel therapies for human SCLC. We aim to test the effectiveness of new therapeutic strategies for SCLC using improved mouse models.