Therapeutic evaluation in ovarian and breast cancer GEM-GDA models

Division Of Basic Sciences - Nci

Investigators

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Abstract

Exploring the previously established multiple GEM and GDA models of serous ovarian cancer (SEOC) and more recently developed GE model for breast cancer in which tumors are driven by Rb/p105/p130 and p53 deficiency and are either wild type or lacking BRCA1 or BRCA2 expression, the ongoing studies in both SEOC and breast cancer models have the following objectives: 1). Develop histopathologic tumor assessment scale and determine patho-histologic and metabolite plus protein biomarkers in serum and tumors during SEOC cancer progression compared with those present in clinical samples before and after SEOC development. This objective involves both internal and collaborative studies. 2). Validate clinical relevance of genomic aberrations in tumors by molecular profiling and systems studies compared to published patient data (e.g. TCGA study of human SEOC) or other clinically obtained information. 3). Determine changes in molecular signatures in response to therapeutic intervention in GEM and GDA models. 4). Determine the similarity of GDA tumor responses with that of patients after treatment with standard of care cisplatin, experimental olaparib and combination treatments. 5) Develop and characterize molecularly cisplatin-resistant SEOC GDA models. 6) Evaluate the efficacy of novel therapeutics in SEOC GDA models, such as PARP and VEGF inhibitors, alone or in combination with immune system checkpoint inhibitors, such as those targeting CTLA-4 and PD-1/PD-L1. This objective involves both internal and collaborative studies, including large-scale funded study with a Pharma company. 7) In collaboration with both intramural and extramural academic organizations, develop SEOC GEM and GDA models in which ovarian malignancies originate through oncogenic transformation processes impacting fallopian epithelial cells to reflect the presently dominant hypothesis of serous ovarian cancer cell of origin located in epithelial lining of fallopian tubes. 8) Via intramural CCR collaborative efforts, evaluate potential preventive and anti-cancer vaccination therapies in existing SEOC GEM models. 9). Explore comparable strategies for inducing genetic deficiencies in pRb, Trp53, and BRCA1/2 oncoproteins and tumor suppressors in a tissue-specific manner, via regio-selective administration of Cre-expressing recombinant adenoviral and lentiviral vectors, engineer and characterize novel models for breast/mammary cancer.