Reversing platinum resistance
The development of resistance to chemotherapy is the single-greatest reason for our failure to cure patients with cancer. Platinum drugs are among the most effective and most widely used of the chemotherapeutic drugs, but platinum resistance develops commonly.The identification of an effective strategy to reverse platinum resistance would have wide-spread impact on patient outcomes. Christine Walsh, MD, MS is investigating ERCC5 (XPG) as a target to reverse platinum resistance. XPG is a member of the nucleotide excision repair pathway, a DNA repair pathway that excises bulky DNA damaging adducts from DNA, such as those caused by platinum drugs. In prior work, Walsh identified decreased expression of XPG in ovarian tumors to correlate with improved response to platinum-based chemotherapy. This led to the hypothesis that inhibition of XPG would lead to decreased DNA repair of platinum damage in cancer cells and improved response to platinum chemotherapy. The Walsh Laboratory is working to identify small molecule compounds inhibitors of XPG that could be developed further into novel drugs to test in clinical trials.
Modeling the genetic heterogeneity of ovarian cancer
Epithelial ovarian cancers (EOC) represent the gynecologic malignancy with the highest mortality rate. The Cancer Genome Atlas (TCGA) demonstrated a high degree of genetic heterogeneity among the papillary serous (PS) tumors, the most lethal of the EOC subtypes. Aside from almost universal mutation in TP53, there was a low prevalence of recurrent mutations in other genes, presenting a challenge to the development of targeted therapeutics against this aggressive tumor type. We are developing a mouse model of EOC by introducing defined genetic alterations to mouse ovarian surface epithelial (MOSE) cells. We had a particular interest in developing a cyclin E amplified tumor model, as CCNE1 amplification is found in 20% of human EOC tumors, making this one of the most prevalent PS EOC subtypes. Our data demonstrate a reproducible mouse model for the development of high-grade epithelial ovarian carcinomas with defined genetic alterations that are capable of study in both immunodeficient and immunocompetent mice. Tumor phenotypes vary based upon the combination of activated oncogenes used to induce malignant transformation.
Clinical questions in gynecologic oncology
Walsh is a physician-scientist, and has the privilege of caring for women affected by gynecologic malignancies. She serves as the fellowship director for the UCLA/Cedars-Sinai Gynecologic Oncology Fellowship Program. She actively mentors fellows and residents in research projects, many of which are sparked by a clinical question that arises during the course of patient care. Some areas of past investigation include adenocarcinoma in situ of the cervix, coexisting endometrial and ovarian malignancies, Lynch syndrome, endometrial cancer in premenopausal women, endometrial cancer in the elderly population, genetic modifiers of penetrance in BRCA1 - associated ovarian cancers, the BRCAness phenotype in serous ovarian cancers and thromboembolic disease in women with clear cell carcinoma of the ovary.