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

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NCI - National Cancer Institute

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.

Up to $419K
2028-04-30
health research

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NSF Scholarships in Science, Technology, Engineering, and Mathematics Program

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U.S. National Science Foundation

The main goal of the S-STEM program is to enable academically talented, low-income students to pursue successful careers in promising STEM fields. Ultimately, the S-STEM program seeks to increase the number of academically promising low-income students who graduate with an S-STEM eligible degree and contribute to the American innovation economy with their STEM knowledge. Recognizing that financial aid alone cannot increase retention and graduation in STEM, the program provides awards to institutions of higher education (IHEs) not only to fund scholarships, but also to adapt, implement, and study evidence-based curricular and co-curricular[a] activities that have been shown to be effective in supporting recruitment, retention, transfer (if appropriate), student success, academic/career pathways, and graduation in STEM. To be eligible, scholars must be domestic low-income students with academic ability, talent, or potential and demonstrated unmet financial need who are enrolled in an associate, baccalaureate, or graduate degree program in an S-STEM eligible discipline. Proposers must provide an analysis that articulates the characteristics and academic needs of the population of students they are trying to serve. NSF is particularly interested in supporting the attainment of degrees in fields identified as critical needs for the Nation. It is up to the proposer to make a compelling case that such a field serves a critical need in the United States. [a] an activity at a school or college pursued in addition to the normal course of study. S-STEM Eligible Degree Programs Associate of Arts, Associate of Science, Associate of Engineering, and Associate of Applied Science Bachelor of Arts, Bachelor of Science, Bachelor of Engineering and Bachelor of Applied Science Master of Arts, Master of Science, and Master of Engineering Doctoral (Ph.D. or other comparable doctoral degree) S-STEM Eligible Disciplines Disciplinary fields in which research is funded by NSF, including technology fields associated with the S-STEM-eligible disciplines (e.g., biotechnology, chemical technology, engineering technology, information technology, etc.). The following degrees and disciplines areexcluded: Clinical degree programs, including medical degrees, nursing, veterinary medicine, pharmacy, physical therapy, and others not funded by NSF, are ineligible degrees. Programs for STEM teacher certification or licensure currently covered by the Robert Noyce Teacher Scholarship program (NOYCE) are ineligible for S-STEM funding. Business school programs that lead to Bachelor of Arts or Science in Business Administration degrees (BABA/BSBA/BBA) are not eligible for S-STEM funding. Masters and Doctoral degrees in Business Administration are also excluded. Proposers are strongly encouraged to contact Program Officers before submitting a proposal if they have questions concerning degree or disciplinary eligibility. The S-STEM program particularly encourages proposals from 2-year institutions, predominately undergraduate institutions, and urban, suburban, and rural public institutions.

$1M – $5M
2027-03-02
sciencetechnology

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Octet-RH16 System

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NIGMS - National Institute of General Medical Sciences

Project Summary/Abstract The Center for Structural Biology, located in the Life Sciences Institute, is a comprehensive structural biology resource for researchers at University of Michigan (U-M) whose mission is to provide access to state-of-the-art facilities as well as expertise and training on all aspects of protein production and characterization through structure determination and analysis. We are requesting funds to purchase an Octet-RH16 system employing bio-layer interferometry (BLI) technology to calculate the rate of association (ka), rate of dissociation (kd) and affinity constants (KD) for biomolecular interactions in real-time. To run a successful drug development program, of which U-M is a leader having contributed to the most FDA approved drugs of any University in the US (Patridge et al., Drug Discovery Today 20, 1182-1187, 2015), access to technology that measures the kinetics of biomolecular interactions of drug-like molecules and biologics to their targets to prove target engagement and rank order the compounds/biologics is essential to the optimization of leads for clinical trials. This system will replace our current failing Octet-Red system, which is a high-demand instrument and whose end of service life was July 2019. Currently there are no other BLI instruments on campus available to our center users. Our current users are developing therapeutics to treat or prevent a broad range of diseases. They are developing new vaccines, new antibiotics, new therapies to combat neurodevelopmental disorders such as autism, new therapeutics against blood cancers such as myeloproliferative neoplasm and acute myeloid leukemia, new therapeutics against castration-resistant prostate cancer, and systemic and ocular toxoplasmosis in vulnerable populations. They are also engineering biosynthetic pathways to develop new drugs or improve existing ones. The new Octet-RH16 will double the number of samples that we can measure in parallel (16) and increase the number of samples we can measure in a single experiment by 8-fold, thus increasing our throughput by 700%. In addition, the required sample volumes will decrease by 5-fold. The new regeneration and re-racking standard feature will be cost saving as it allows the reuse of biosensors. This increase in productivity and reliability along with the decrease in operating cost will open new avenues of research for the U-M research community. It will provide an opportunity to directly screen targets against small drug-like chemical libraries housed at the U-M Center for Chemical Genomics, for example the Prestwick Library, where 95% of the compounds are drugs approved by the FDA-, EMA-, or other agencies.

Up to $430K
2027-06-14
health research

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