RET Kinase Signaling as a Key Switch Toward the Neuroendocrine Phenotype
Abstract
Prostate cancer is the second most common male cancer in the United States and is responsible for 30,000 deaths in the United States each year. With a 5-year survival of greater than 95%, the prognosis for localized prostate cancer is excellent, but once metastatic prostate cancer develops, survival is poor. Since prostate cancer cells require androgens (testosterone, 5-HT) for growth, first-line treatments for metastatic disease block androgen synthesis or signaling through the androgen receptor (AR). However, prostate cancer inevitably becomes resistant to androgen blockade and develops castration-resistant prostate cancer (CRPC). An emerging subset of CRPC patients develop a highly aggressive tumor phenotype designated aggressive variant prostate cancer (AVPC). AVPC most commonly evolves from pre-existing prostate adenocarcinoma and may be present in up to 25% of patients with metastatic CRPC; treatment provides modest 1- to 2-year survival rates due to rapid therapy resistance and disease progression. One alternative is to investigate protein kinase signaling pathways that drive metastatic AVPC growth in the presence of AR inhibitors, and we have nominated RET tyrosine kinase as a strong candidate driving AVPC. RET is a novel tyrosine kinase target overexpressed and phosphorylated in clinical AVPC tissues and has been shown to promote various other small cell neuroendocrine cancers, including medullary thyroid carcinoma, papillary thyroid carcinoma, and subsets of small cell lung cancer. In this proposal, we plan to functionally assess the role of RET kinase in the transition to AVPC, determine whether RET kinase collaborates with EZH2 to drive AVPC, determine RET-dependent kinase signaling driving lineage plasticity, and conduct preclinical trials to evaluate co-inhibition of RET kinase and EZH2 for treatment of AVPC and re-sensitizing AVPC to enzalutamide. Applicability of the Research: Through collaborative basic and translational research, we must advance our understanding of the biological mechanisms that drive progression to CRPC in order to develop novel therapies. These all are important and unanswered questions involving the most lethal prostate cancer phenotype observed clinically, and the proposed study will provide a solid foundation for developing targeted and more rational combination therapy strategies for patients with AVPC. Our success will drive the prostate cancer field forward and significantly alter clinical management of patients with AVPC. With highly relevant preclinical models and drug targeting strategies proposed in this application, we anticipate the results of our work could lead to clinical trials in patients with AVPC within 5 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810541
Entities
People
- Leigh Ellis
Organizations
- Dana–Farber Cancer Institute
- United States Army