Development of a RET activity gene signature and a RET antibody-drug conjugate

Abstract

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer with limited treatment options and poor prognosis. The REarranged during Transfection (RET) receptor tyrosine kinase has emerged as a critical oncogenic driver in NEPC, with increased expression correlating with treatment resistance and disease progression. While RET-targeted therapies have shown to target RET fusions and RET kinase inhibitors have proven efficient in other cancer types such as medullary thyroid cancers, there is an urgent need for biomarker-specific approaches. To address this gap, we propose two strategies: (1) defining a RET activity signature to stratify NEPC patients most likely to benefit from RET inhibition therapies, and (2) developing a RET-targeted antibody-drug conjugate (ADC).To define a RET activity signature, we characterize transcriptional changes driven by RET expression. RNA sequencing of RET knockdown and overexpression models will identify key gene networks associated with RET expressions. Integration of this data will generate a functional RET signature, which will be evaluated as a potential biomarker for NEPC. In parallel, we are working on a novel RET ADC, in which a RET-targeting single-chain fragment variable (scFv) is conjugated to the topoisomerase-1 inhibitor SN-38 via optimized cleavable linkers. This approach leverages the selective overexpression of RET in NEPC to deliver cytotoxic payloads directly to tumor cells, thereby minimizing off-target toxicity. Together, these studies aim to establish RET as both a predictive biomarker as well as a therapeutic target in NEPC that improves patient outcomes in this cancer.