Transmembrane Prostatic Acid Phosphatase is a Marker, Driver, and Therapeutic Target for Lethal Prostate Cancer
Abstract
Background/Rationale: Metastatic castrate-resistant prostate cancer (mCRPC) is an incurable disease. There is an urgent need to identify specific drivers of lethal tumors that can serve as targets for new drug therapies. The ideal target for advanced disease would persist even after male hormones are removed, be expressed in cancer cells in metastatic disease, and represent a treatment-resistant cancer cell population. Our team has identified Prostatic Acid Phosphatase (PAP), a protein that removes phosphate groups from proteins but also from nucleotides (building blocks of DNA). The removal of phosphates from nucleotides produces high levels of adenosine, a substance that has been shown to stimulate its receptors in a variety of cancers, including prostate, to promote cancer cell growth and metastases. When PAP is attached to the surface of prostate cancer cells, it is called transmembrane-PAP (TMPAP). TMPAP protein levels are high in prostate tumors that have spread to bone and are resistant to standard treatments. Thus, in this proposal, we plan to block TMPAP using existing drugs (inhibitors) that target its activity in prostate cells that are about to become metastatic. Plan: We hypothesize that TMPAP is a marker of a more resistant, aggressive type of prostate cancer cells, that it promotes cancer growth and metastases by creating a lot of adenosine, and that both TMPAP and adenosine receptors can be targeted to develop effective therapies to eradicate lethal disease. In Aim 1, we will utilize samples of RNA from patient tumors (from their prostate tumors and metastatic lesions) to determine whether TMPAP RNA and protein levels are higher in aggressive tumors. In Aim 2, we will use human prostate cancer cell lines, grow them in low oxygen conditions (such as exist in bone metastases), and determine whether those conditions increase TMPAP, adenosine, and adenosine receptor protein levels. We will also determine the effects of adenosine receptor inhibitors on the prostate cancer cells grown in low oxygen. In Aim 3, we will test the effects of TMPAP antibodies and adenosine receptor inhibitors growth of human prostate cancer preclinical models in mice. Impact: The above experiments will lay the groundwork for clinical trials in men with hormone-resistant, metastatic prostate cancer. Our unique approach to block TMPAP activity pharmacologically will lead to novel treatment modalities to treat patients with recurrent, resistant, lethal disease and increase their survival.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110330
Entities
People
- Alice Levine
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army