Andrew K Godwin, PhD

Research Interests

Our studies are directed at improving the understanding of the etiology of several types of cancer and assessing molecular-targeted therapies for the treatment of these diseases. Our studies primarily involve three different types of cancer, gastrointestinal stromal tumors (GISTs), ovarian, and breast. Our laboratory has taken several approaches to study these diseases.

1. We have identified several putative tumor suppressor genes, OVCA1 and OVCA2 on 17p13.3 through positional cloning approaches and are determining their function and role in the pathogenesis of breast and ovarian cancer. Recent studies have shown that in mouse models Ovca1 is required for postnatal survival and that Ovca1 heterozygous mutant mice are tumor-prone, developing epithelial tumors of the lung, liver, and ovary.
2. We have found that a member of the synuclein family, γ-synuclein, is abnormally expressed in a high percentage of both breast and ovarian tumors, and that this over-expression may directly increase the invasiveness of these cells and resistance to stress-induced apoptosis. We have shown that aberrant expression of γ-synuclein in cancer is associated with hypomethylation of its promoter and are currently screening for small molecules that will inhibit the function of γ-synuclein.
3. To identify genetic factors that predispose to cancer, we are following >3,000 breast and ovarian cancer-prone kindreds. We are evaluating cancer risks associated with inherited alterations in BRCA1, BRCA2, TP53, CHK2, ATM, and p16 and are searching for new breast cancer predisposing genes.
4. We have recently identified the human TREX complex, a multi-protein complex that links transcription elongation to messenger RNA transport, as the culprit of aggressive human breast cancers. hTREX84, a subunit of TREX, is over-expressed in cancerous tissues, as compared to normal mammary epithelium, and its aberrant expression correlates strongly with poor prognosis, including lymph node metastasis and tumor size. Reduction of hTREX84 levels in breast cancer cells by siRNA results in inhibition of cellular proliferation and abrogation of messenger RNA export. Our studies identified hTREX84 as a prognosticator of breast cancer and a target for therapeutic drugs against breast cancer.
5. We are studying the biochemical function of BRCA1 and establishing its role in the initiation of breast and ovarian cancer using in vitro tissue culture models. We have recently reported the identification and characterization of a novel BRCA1 interacting protein complex, BRCC. One protein in this multiprotein complex, referred to as BRCC36, was found to directly interact with BRCA1. We demonstrated that BRCC36 has an important role in regulating the ubiquitin E3 ligase activity of BRCC and that it is overexpressed in the majority of breast cancer cell lines and clinical breast tumors. We are currently elucidating the functional consequence of BRCC36 over-expression in breast cancer.
6. We are evaluating the molecular mechanisms of action of novel therapeutic agents used in the treatment of cancer by genomic and proteomic approaches. Through our Ovarian Cancer SPORE program we are evaluating EGFR- and mutant EGFR-targeted therapies (e.g., cetuximab, gefitinib, and a vaccine directed against EGFRvIII) in both pre-clinical and Phase I/II clinical trials. We are also evaluating the response of patients with metastatic/recurrent GIST to imatinib mesylate (Gleevec), a specific inhibitor with activity against KIT. Using biopsy specimens from patients with GIST before and after administration of imatinib on a multi-institutional clinical study, RTOG-0132, we are exploring the molecular genomic mechanisms of response/resistance. We have identified several important differentially regulated genes in GIST specimens, the expression of which appears to correspond to clinical outcome. Further elucidation may predict response patterns, a basis for resistance to this specifically targeted molecular drug, and may serve as a paradigm for investigations of other kinase inhibitors in the management of solid tumors.