Novel Protein Degraders for Treating RET Positive Cancer
Partner Awards
Grant title (if any)
RETpositive/LUNGevity Lung Cancer Research Award Program
Justin Drake, PhD
University of Minnesota
Minneapolis
MN
This project will investigate novel protein degraders (called PROTACs) as a treatment for RET-positive cancers, and will evaluate their efficacy in vitro and in vivo in prostate and lung cancer. PROTACs are highly specific molecules that degrade unwanted or harmful proteins in cells (in this case, RET tyrosine kinase). This research aims to provide a novel therapeutic approach targeting RET signaling, which could overcome resistance to existing RET inhibitors. If successful, it would be a first-in-class compound for further clinical development.
Research Summary
RET receptor tyrosine kinase is a proto-oncogene that requires a co-receptor and secreted ligand for activation. Activating RET mutations are oncogenic targets in non-small cell lung cancer, medullary thyroid cancer and neuroendocrine type cancers. Two RET-specific kinase inhibitors (BLU-667 and LOXO-292) have been FDA approved for treating RET fusion positive cancers. This has led to a tremendous advance in lung cancer therapy and objective response rates in patients naïve to RET inhibitors or who have received other RET inhibitors such as cabozantinib or vandetanib. It is also apparent that RET therapy-driven resistance is common and new alternatives are needed to drug this pathway. Our hypothesis is that targeting RET with novel, first-in-class RET degraders will result in cell death that is more durable than existing inhibitors of RET kinase activity. We will test these novel degraders on several models of prostate and lung cancer to assess on target RET degradation and efficacy in cell line and mouse models. Once novel RET protein degraders are developed and tested in prostate and lung cancer models in vitro and in vivo, we plan to perform pre-clinical optimization studies of compounds and work towards clinical implementation in late stage prostate, lung, and other cancers that rely on RET signaling for survival.
Technical Abstract
Two RET-specific kinase inhibitors (BLU-667 and LOXO-292) have been FDA approved for treating RET fusion positive cancers. This has led to a tremendous advance in lung cancer therapy and objective response rates in patients naïve to RET inhibitors or who have received other RET inhibitors such as cabozantinib or vandetanib. It is also apparent that RET therapy-driven resistance is common and new alternatives are needed to drug this pathway. Our hypothesis is that targeting RET with novel, first-in-class RET degraders will result in cell death that is more durable than existing inhibitors of RET kinase activity. We will test hypothesis via the following specific aims: Aim 1. Development and characterization of RET degraders for treating RET positive cancers and Aim 2. Evaluate efficacy of RET degraders in in vitro and in vivo NEPC models. In aim 1, we propose to develop RET degraders based on a new RET inhibitor, vepafestinib, and assess RET degrader specificity and activity using a panel of prostate and lung cancer cell line models that overexpress RET or contain RET fusions. We will then evaluate the efficacy of our RET degrader in in vitro and in vivo models of lung and prostate cancer. Once these novel RET protein degraders are developed and tested, we plan to perform pre-clinical optimization studies of compounds and work to identify a suitable pharma partner to develop for clinical implementation in late stage prostate, lung, and other cancers that rely on RET signaling for survival.
Key words
