Targeting the Dysregulation of Adiponectin as a Novel Prostate Cancer Therapy
Abstract
Each year ~200,000 U.S. men are diagnosed with prostate cancer (PC), the second most prevalent cancer in American males. The prostate gland is located under the bladder in men, playing a role in reproductive and sexual function. Male sex hormones, androgens, control the normal function of the prostate. But they are also important in prostate cancer, where they drive tumor growth and spread. This feature is exploited by therapies for advanced PC. These therapies prevent androgens from being made (androgen deprivation therapy [ADT]) or from working correctly (androgen targeted therapy [ATT]), and stop PC growth. However, ATTs only offer short-lived remission from cancer, as the cancer employs numerous escape strategies to progress to castrate-resistant PC (CRPC). Abiraterone, enzalutamide, and apalutamide, strong ATT drugs, are used in advanced metastatic CRPC and extend survival but fail to cure patients. New treatments with prolonged effectiveness are vital, as once PC spreads to a distant site, men face a ~30% chance of surviving past 5-years. A side effect of anti-androgens is that while they starve tumors of growth-promoting androgens, they also lower androgens throughout the entire body, which has deleterious effects on men’s metabolic health. Symptoms resemble obesity, impacting the patient through reduced muscle mass and strength, as well as increased body fat and raised blood glucose, lipids, and insulin. A further metabolic comorbidity observed in PC progression is that blood levels of hormones secreted from fat-tissue that vitally control whole body metabolism are altered. One such altered hormone is adiponectin, whose fundamental role is to ensure our body appropriately uses fuel sources to produce the energy it needs to function. Circulating adiponectin levels are decreased in men with PC and continue to decrease in men with advanced disease. Our work at a leading Australian prostate cancer research center has uncovered that the receptors, through which adiponectin communicates to cancer and other organs, are also lower in prostate tumor tissue, and are further decreased in metastatic PC. In patients with low adiponectin receptors in their tumors, the likelihood of cancer recurrence was higher than men with normal receptor expression. This led us to test whether correcting the lowered adiponectin action in patients could be exploited as a novel target to stop cancer progression. Adiponectin acts on multiple pathways that are important to cancer growth including energy pathways, inflammation, and blood vessel growth. We therefore hypothesized that activating adiponectin, using highly potent new drug, ADP-355 (ADP) that binds to and promotes activity through adiponectin’s receptors, would prevent PC growth and progression to advanced CRPC. Using our drug to restore adiponectin activity, we could block multiple processes contributing to PC progression and spread. ADP treatment inhibited tumor growth and slowed progression to CRPC, extending mouse survival. In this proposal, we aim to test our novel drug ADP in further preclinical studies to assess its best dosage, formulation and disease stage to position the therapy for best impact to test in clinical trials. Efficacy of ADP in blocking tumor growth will be assessed in mice through advanced live imaging throughout the study. Tumors will also be assessed by state-of-the-art technologies to chart global changes to gene, protein, and metabolite abundance. Our proposal addresses two PCRP Overarching Challenges: (1) to develop treatments to improve outcomes for lethal PC and (2) through the direct action of ADP in restoring the adiponectin signaling in patients with low adiponectin to improve quality of life for PC sufferers. ADP is a specific potent new drug with clear anti-tumor efficacy, outstanding drug properties, and no evidence of toxicity (tested to 50 mg/kg). Through focused development of this novel therapy, driven by PC researc
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010331
Entities
People
- Jennifer H. Gunter
Organizations
- Queensland University of Technology
- United States Army