SBIR FY25 CONCEPT AWARD: DEVELOPMENT OF ENGINEERED TRNA THERAPEUTICS FOR CLEAR CELL RENAL CELL CARCINOMA

Kidney cancer is a growing public health concern, with new cases expected to rise by over 20% by 2030. Clear cell renal cell carcinoma (ccRCC) accounts for over 75% of all kidney cancer cases. Current therapeutics for advanced ccRCC are inadequate: the 5-year survival rate for patients ineligible for surgical resection is below 12%. This Concept Award proposal will to advance development of a new approach to treat ccRCC: we have uncovered a new and targetable vulnerability of ccRCC: they are dependent on high expression of multiple tRNA modifying enzymes to support their rapid proliferation. Cloverleaf Bio has developed a novel therapeutic approach to irreversibly inhibit these enzymes, halting disease progression. Using engineered tRNAs containing 5-fluorouracil (5FU), we can inhibit multiple tRNA modifying enzymes from a single tRNA. This multi-target activity dramatically increases therapeutic efficacy. Our lead candidate inhibitory tRNA, CLB-001, exhibits a nanomolar IC50 in multiple cancer models—an over 7,000-fold increase in potency over free 5FU—with minimal toxicity to non-transformed cells. This proposal builds off of our preliminary data to (1) develop optimal tRNA sequences for ccRCC (2) evaluate them in a panel of ccRCC cell lines (3) demonstrate anti-tumor activity in a mouse model of ccRCC.