Rewiring fusion oncogenes to activate apoptosis

ABSTRACT The proliferation, survival, invasion, and metastasis of human cancers are driven by oncogenic gene expression networks specific to a malignant cell. Exploiting cancer-specific vulnerabilities in gene expression offers an attractive opportunity for precision medicine. I propose to develop novel pharmacological approaches to rewire oncogenic gene expression and kill a cancer cell, that could yield unprecedented precision and potency and offer a new paradigm for precision cancer therapy. In past work, I have shown that small molecule chemical inducers of proximity (CIPs) can rewire transcription factors to potently activate the expression of pro-apoptotic genes, apoptosis, and killing of a cancer cell. My overall objective is to systematically explore the potential of CIP to rewire fusion transcriptional regulators and produce cancer cell death. Fusion oncogenes are highly relevant target for precision cancer therapies because of their specific expression in tumor tissue and driving role in the progression of the malignancy. Aim 1 will develop CIPs that kill aggressive leukemias driven by translocations of the mixed- lineage-leukemia (MLL) gene. Methods used to achieve this goal will include organic synthesis, pharmacological assays, measurements of chromatin mechanisms, functional studies in cellular models of leukemia, and assessments of effects on primary human hematopoiesis. Aim 2 will discover the core molecular principles that underlie how CIPs can rewire transcription factors, using structural biology, biophysical measurements, protein biochemistry, and computational modeling. The expected outcomes include (Aim 1) a new class of molecules that target the MLL fusion oncoprotein for treatment of MLL-r leukemias and (Aim 2) a comprehensive structural and biophysical analysis of activating pro-apoptotic genes using CIP. Combined, the proposed research will develop novel pharmacology to target a cancer-driving fusion oncogenes. It also will develop important structural insights to inform the rational design of small molecules to rewire oncogenic gene expression. Each of the proposed directions has the potential to yield fundamentally new approaches to targeting gene expression in cancer. The Aims proposed will take place under the mentorship of world-recognized experts in medicinal chemistry, cancer pharmacology, hematologic malignancies, and structural biology who will provide the mentorship needed to acquire skills enabling success. The proposed research will allow me to apply my background in chromatin and chemical biology to make an impact on malignancies with high unmet need, while receiving additional training in synthesis and structural biology. It will prepare me for a successful independent career developing novel pharmacology to target dysregulated transcription in cancer.