Exploiting Lineage-Specific Dependencies in Solid Tumors: Using Transcription Factors to Drive Therapeutic Effect In Situ - Many cancers exhibit aberrant overexpression of developmental lineage-specific transcription factors. In this project we investigate the potential of exploiting oncogenic overexpressed transcription factors to force cancer cells to produce anti-cancer therapies using a gene therapy strategy. We will design synthetic promoters specifically responsive to transcription factors of interest in different cancers to use in therapeutic vectors as drivers of cancer therapies. As a proof-of-concept, the project will begin with the lineage-specific transcription factor ‘X’ in the context of lung cancer. In lung adenocarcinoma the highly expressed homeobox protein ‘X’ is regularly used as a clinical marker and has been shown to be an oncogenic driver and fundamental to carcinogenesis. The investigation will extend to other lineage-specific transcription factors in different types of cancer, including prostate, breast, melanoma, brain, liver, head and neck, gastric, ovarian, kidney, cervical, pancreas, and Ewing sarcoma. The goal of our proposed aims is to develop a novel science for controlling spatial precision of drug delivery by exploiting a cancer’s transcription factor lineage-addiction to drive production of therapeutics locally. Our preliminary results indicate cancer-specific transgene expression after systemic therapy administration. In our first aim, we propose to study the effect of our gene therapy on cancer growth in a humanized murine model with therapeutic payloads safely used systemically in the clinic. In our second aim, we propose to develop a pipeline for unbiased discovery and validation of synthetic promoters specifically responsive to transcription factors of interest; work that will move beyond proof-of-concept experiments to designing gene therapy strategies for the range of human cancers with transcription factor-mediated growth dependencies.
