The overarching goal of the Simpkins lab is to identify novel targets and strategies to overcome drug resistance in ovarian cancer and bring these new findings to the clinic. The laboratory has four areas of focus: (i) optimizing synthetic lethal approaches by exploiting genetic vulnerabilities in gynecological cancers with an emphasis on ovarian cancer, (ii) investigating biomarkers of response and resistance to targeted therapies by clinical trial tumor and blood studies (iii) investigating strategies to target “cancer-stem cells” in ovarian cancer, (iv) “humanizing” PDX models to evaluate the effects of targeted DNA damage agents on the human immune system.
The lab has developed a platform for preclinical drug development which includes novel experimental models such as primary tumor cell cultures and over 60 patient-derived xenografts (PDX). PDXs are derived from human ovarian tumors, which are characterized genomically, and proteomically. More importantly, the PDX platform depends on a unique orthotopic transplant technique which leads to the formation of a primary tumor which metastasizes to abdominal viscera. This approach results in a model which emulates the natural progression of ovarian cancer. The team has shown that their model maintains the characteristics of the patient’s original tumor, including mutation status, gene expression, and clinical response. The lab has developed and characterized relevant homologous recombination deficient (HR; i.e., BRCA1/2 mutant), CCNE1 amplified/over-expressing, PARP inhibitor-resistant, and platinum-resistant PDXs which represent >70% of ovarian cancers. The ultimate goal of the lab is to bring therapies with strong preclinical evidence learned in the laboratory to the clinic via phase I/II clinical trials.