PROJECT SUMMARY The slow growing nature of most prostate cancers (PCa) provides multiple windows of opportunity to block or delay disease progression to significantly reduce patient suffering and mortality. This is especially true following the failure of radical prostatectomy (RP) and radiation therapy (RT) of PCa prior to androgen deprivation therapy (ADT; i.e., medical or surgical castration). Biochemical recurrent PCa is sensitively indicated by rising blood prostate specific antigen (PSA). ADT is not curative and causes many serious adverse effects. Our goal is to develop Angelica gigas Nakai (AGN, Korean Angelica) root ethanolic extract or its constituent(s) as a safer and practical modality for PCa interception akin to secondary prevention to delay ADT or avoid it entirely. We hypothesize that (1) the PCa interception efficacy of AGN and its pyranocoumarins in animal models is extendable into human PCa patients, given sufficient AGN dosage and exposure duration; (2) multiple mechanisms including immune surveillance and suppression of inflammation contribute to the clinical cancer interception activity. The scientific premise is based on the presence of novel active pyranocoumarin compounds distinct from those in soy, tea, fish oil, raspberries, mushrooms, and cannabis and reported broad spectrum anti- cancer efficacy in animal cancer models. Moreover, we have demonstrated a) Oral bioavailability and favorable pharmacokinetic (PK) metrics in rodents and in humans; b) Cytochrome P450 (CYP) 2C19 and 3A4 first-pass conversion of pyranocoumarins decursin (D) and decursinol angelate (DA) to their metabolite decursinol (DOH); c) Proficient tissue retention of decursinol in mouse target prostate; d) Animal modeling of AGN and decursinol showing independence of the androgen receptor axis, avoiding side effects of ADT drugs and making blood PSA a reliable readout for cancer burden; e) AGN enhanced immune and decreased inflammatory gene signatures in an animal PCa model; and f) A single AGN dose in human subjects increased natural killer [NK] mRNA signature and decreased IL-8 chemokine mRNA in their peripheral blood mononuclear cells. We propose 3 specific aims in post-RP and post-RT patients with rising plasma PSA that is “clean” (due to prostate already removed) and indicative of the biochemical recurrent PCa burden. Aim 1. Characterize pyranocoumarin PK dose response proportionality to AGN supplement and food effects in 12 patients to probe any metabolic ceiling and minimize food-herbal interaction. Aim 2. Evaluate safety and recurrent PCa (PSA)-interception efficacy of twice daily AGN supplement in a Phase I/II trial with 36 patients. Aim 3. Measure acute- and repeated-dose PK metrics, CYP 2C19 and 3A4 metabolizer status and changes of immune and inflammation biomarkers to correlate to PSA outcomes. Impacts: The safety information and a favorable PSA response will guide future randomized control trials to prevent or treat PCa and other cancers. The novel knowledge on PK dose response, repeated dose PK behavior, CYP pharmacogenetics and the immune biomarkers not only fills in critical gaps for AGN supplements in cancer patients, but also is exportable to disease prevention and therapy beyond oncology.
|Effective start/end date||9/1/22 → 8/31/24|
- National Cancer Institute: $575,924.00
- National Cancer Institute: $623,285.00
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.