Targeting acetylcholine signaling in chemotherapy-resistant prostate cancer
Abstract
Scientific Objective: Prostate cancer (PCa) is a current epidemic in the United States, with roughly one in nine men developing this disease during their lifetime and an expected 174,600 new cases in 2019. While initial treatments are very effective, many patients inevitably enter into a terminal stage of the disease that is extremely aggressive and leads to the death of over 30,000 men every year in the United States. Chemotherapy is one of the limited treatment options, yet eventually the disease becomes resistant to these agents, leaving patients with few to no options for further treatment. The development of drug resistance in PCa can lead to the emergence of “neuromimicry” by tumor cells expressing neuronal genes and signaling with neurotransmitters to change into a more neuron-like form. We are specifically interested in the role that neuromimicry plays in the ability of chemoresistant PCa to signal with the neurotransmitter acetylcholine (ACh) and its activation of the muscarinic ACh receptor 1 (CHRM1). In this proposal we will address the emergence of neuromimicry in chemoresistant PCa and define tumor-initiated ACh signaling. In addition, we will determine the role of CHRM1 in the development and maintenance of chemoresistance and test the ability of combination therapies to inhibit CHRM1 activation and re-sensitize tumors to chemotherapy agents. Research Applicability: The proposed project addresses several of the overarching challenges of the DoD Prostate Cancer Research Program. We aim to define the biology of lethal PCa while also developing treatments for men who suffer from this terminal disease. This study will validate the involvement of Ach signaling in chemoresistant PCa and provide insights into a better understanding of the biology of neuromimicry in PCa with the discovery of novel biomarkers. This research will help men who have not yet received chemotherapy treatment as well as men who have already developed resistance to chemotherapy agents. Building on the current knowledge that PCa exhibits altered muscarinic signaling during disease progression to an end stage provides a strong rationale to repurpose antimuscarinics already in use in other areas of the clinic, such as irritable bowel syndrome and overactive bladder, to treat lethal late-stage PCa. The proposed project repurposes a clinically available CHRM1 inhibitor already in use to treat irritable bowel syndrome, and the drug repositioning nature of this project gives it high translational impact for bringing new therapies for a deadly type of PCa. The combination treatment of a CHRM1 inhibitor and chemotherapy is anticipated to greatly impact the field of PCa research, as it currently remains unclear how PCa becomes resistant to chemotherapy agents, resulting in ineffective therapies for this type of PCa. Our new therapy has the unique advantage over alternate approaches in that our therapy aims to save chemotherapy-eligible PCa patients at multiple levels (1) to synergize with chemotherapy for improved efficacy, (2) to re-sensitize PCa that has already become resistant to chemotherapy, and (3) to potentially prevent the development of chemoresistance. This novel combination therapy has the potential to reach the market very quickly, as we are repurposing clinically available drugs for a new indication in terminal stage disease that lacks current therapies. We expect a quick transition from our preclinical study to application in the clinic because we expect to move the combination treatment forward to a Phase II clinical trial for proved clinical benefit within the next 2 to 3 years and to clinical use for men suffering from this disease within the next 5 to 7 years. Career Goals: I want to leverage my neuroscience expertise and pursue a career in academia by establishing a laboratory focused on translational research studying the biology of neuromimicry in PCa and using this knowledge to develop novel therapies for this
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010115
Entities
People
- Jing Wei
Organizations
- United States Army
- Washington State University