Novel selective allosteric modulators of PTHrP/PTH receptor to inhibit prostate cancer metastases

About This Grant

The parathyroid hormone (PTH) receptor type 1 (PTH1R) is a G-protein coupled receptor (GPCR) and the only cell surface receptor for the PTH-related protein (PTHrP), which causes the “vicious” cycle of prostate cancer (PCa) bone metastases. Clinical trials to block PTHrP using neutralizing antibodies only showed palliative effects in cancer patients. We have identified a series of small molecules (referred to as Pitt molecules) that act as negative allosteric modulators of PTH1R signaling. We hypothesize that Pitt molecules have the potential to prevent PTH1R overactivity induced by PTHrP hypersecretion encountered in prostate cancer cells. As allosteric molecules, Pitt molecules have the key advantage over orthosteric antagonists to restore normal receptor activity when PTHrP is hypersecreted. Furthermore, PTH1R is recently identified as a target for enzalutamide resistance in PCa bone metastases. The goal of this project is to identify selective Pitt molecules targeting PTHrP- induced PTH1R overactivity as potential lead candidates for the development of drugs treating bone osteolysis induced by prostate cancer metastases. Specific Aim 1 will identify the most effective Pitt molecules for inhibition of PTH1R hyperactivation by PTHrP. We will use state-of- the-art optical analysis of receptor signaling in live cells expressing recombinant and native PTH1R. We will evaluate the toxicity and biostability of the Pitt molecules using assays in cell culture. Specific Aim 2 will determine the efficacy of selected Pitt molecules in prostate cancer metastases. We found that the selective deletion of PTH1R in mesenchymal lineage cells of a mouse model significantly inhibits prostate cancer metastases. We have successfully established cell culture and mouse models to longitudinally monitor prostate cancer tumor growth and metastases. We will use these models to test the efficacy of selected Pitt molecules, as a single agent or in combination with current clinical therapies such as enzalutamide, in inhibiting prostate cancer metastases. The significance of this research program lies in its premise to lay the groundwork for a future translational research program that will examine the development and therapeutic utility of Pitt molecules for treating prostate cancer bone metastases and overcoming enzalutamide resistance.