1.
A randomized, phase 1, placebo-controlled trial of APG-157 in oral cancer demonstrates systemic absorption and an inhibitory effect on cytokines and tumor-associated microbes.
Basak, SK, Bera, A, Yoon, AJ, Morselli, M, Jeong, C, Tosevska, A, Dong, TS, Eklund, M, Russ, E, Nasser, H, et al
Cancer. 2020;126(8):1668-1682
-
-
-
Free full text
-
Plain language summary
APG-157 is a botanical drug containing multiple polyphenols that delivers the active components to oromucosal tissues near the tumour target. APG-157 slowly disintegrates in the oral cavity over 15 to 20 minutes to release the drug substance. The drug substance is a precise, rational combination of multiple molecules derived from Curcuma longa wherein curcumin is the principal component. The main aim of this study was to determine the pharmacokinetics and safety of the orally delivered pastille (APG-157) when used by normal subjects and patients with cancer. This study is a randomised, double-blind, placebo-controlled trial. A total of 32 subjects were enrolled, and 25 completed the study (13 normal individuals and 12 patients with oral cancer). Results demonstrated that transoral APG-157 treatment leads to systemic absorption of curcumin and its analogs. There was a statistically significant concentration reduction in inflammatory cytokines and Bacteroides species noted in the salivary cells. Pre-treatment and post-treatment tumour samples from patients with cancer demonstrated T-cell recruitment to the tumour microenvironment. Authors conclude that APG-157 is absorbed well, reduces inflammation, and attracts T-cells to the tumour thus, it can be potentially used in combination with immunotherapy drugs. Furthermore, a long-term evaluation of immune checkpoint blockade with and without APG-157 could provide a clear understanding of the usefulness of APG-157 as either an adjuvant or neoadjuvant therapeutic agent for patients with advanced or recurrent head and neck cancer.
Abstract
BACKGROUND Although curcumin's effect on head and neck cancer has been studied in vitro and in vivo, to the authors' knowledge its efficacy is limited by poor systemic absorption from oral administration. APG-157 is a botanical drug containing multiple polyphenols, including curcumin, developed under the US Food and Drug Administration's Botanical Drug Development, that delivers the active components to oromucosal tissues near the tumor target. METHODS A double-blind, randomized, placebo-controlled, phase 1 clinical trial was conducted with APG-157 in 13 normal subjects and 12 patients with oral cancer. Two doses, 100 mg or 200 mg, were delivered transorally every hour for 3 hours. Blood and saliva were collected before and 1 hour, 2 hours, 3 hours, and 24 hours after treatment. Electrocardiograms and blood tests did not demonstrate any toxicity. RESULTS Treatment with APG-157 resulted in circulating concentrations of curcumin and analogs peaking at 3 hours with reduced IL-1β, IL-6, and IL-8 concentrations in the salivary supernatant fluid of patients with cancer. Salivary microbial flora analysis showed a reduction in Bacteroidetes species in cancer subjects. RNA and immunofluorescence analyses of tumor tissues of a subject demonstrated increased expression of genes associated with differentiation and T-cell recruitment to the tumor microenvironment. CONCLUSIONS The results of the current study suggested that APG-157 could serve as a therapeutic drug in combination with immunotherapy. LAY SUMMARY Curcumin has been shown to suppress tumor cells because of its antioxidant and anti-inflammatory properties. However, its effectiveness has been limited by poor absorption when delivered orally. Subjects with oral cancer were given oral APG-157, a botanical drug containing multiple polyphenols, including curcumin. Curcumin was found in the blood and in tumor tissues. Inflammatory markers and Bacteroides species were found to be decreased in the saliva, and immune T cells were increased in the tumor tissue. APG-157 is absorbed well, reduces inflammation, and attracts T cells to the tumor, suggesting its potential use in combination with immunotherapy drugs.
2.
A phase I trial of mushroom powder in patients with biochemically recurrent prostate cancer: Roles of cytokines and myeloid-derived suppressor cells for Agaricus bisporus-induced prostate-specific antigen responses.
Twardowski, P, Kanaya, N, Frankel, P, Synold, T, Ruel, C, Pal, SK, Junqueira, M, Prajapati, M, Moore, T, Tryon, P, et al
Cancer. 2015;121(17):2942-50
-
-
-
Free full text
-
Plain language summary
Prostate specific antigen (PSA) is a protein produced both by normal cells in the prostate and by prostate cancer cells. For men who have had prostate cancer, monitoring PSA levels can provide an early indication of recurrence of the disease. Naturally-occurring plant compounds, known as phytochemicals, may play a role in prostate cancer prevention, risk of recurrence, and therapy. This phase 1 trial evaluated the effects of white button mushroom (WBM) powder on PSA levels and determined the tolerability and biological activity of WBM. The 36 patients enrolled in this trial had previously undergone surgery and/or radiation treatment for prostate cancer and subsequently were found to have a continuously rising PSA level. Patients were given tablets containing WBM powder at doses from 4g to 14g (equivalent to 40g to 140g of fresh WBM). The mean reduction in PSA levels was 11%. Two patients receiving 8 and 14 g/d demonstrated complete response: their PSA declined to undetectable levels that continued for 49 and 30 months. Two patients who received 8 and 12 g/d experienced partial response: a decline of at least 50% in PSA levels. After 3 months of therapy, 13 (36%) patients experienced some PSA decrease below baseline. PSA levels remained stable in 5 patients. Patients who responded had higher levels of a cytokine called interleukin-15 (IL-15) at the beginning of this study, and experienced a decline in immuno-suppressive myeloid-derived suppressor cells (MDSCs) during the study. When comparing responders to non-responders, the following factors did not seem to affect the response: the daily mushroom dose, grade of cancer, baseline PSA level, weight, age, baseline testosterone levels and type of prior therapy. WBM powder therapy did not influence the levels of circulating androgen hormones: testosterone, dihydrotestosterone (DHT) and dehydroepiandrosterone (DHEA). The authors concluded that therapy with WBM appears to impact PSA levels and decrease immunosuppressive factors. Future trials should contain a placebo group and more research is needed to isolate the compound(s) from the WBM with anti-prostate cancer activity.
Abstract
BACKGROUND Each year in the United States, nearly 50,000 prostate cancer patients exhibit a rise in prostate-specific antigen (PSA) levels, which can indicate disease recurrence. For patients with biochemically recurrent prostate cancer, we evaluated the effects of white button mushroom (WBM) powder on serum PSA levels and determined the tolerability and biological activity of WBM. METHODS Patients with continuously rising PSA levels were enrolled in the study. Dose escalation was conducted in cohorts of 6; this ensured that no more than 1 patient per cohort experienced dose-limiting toxicity (DLT). The primary objective was to evaluate treatment feasibility and associated toxicity. The secondary objectives were to determine WBM's effect on serum PSA/androgen levels; myeloid-derived suppressor cells (MDSCs); and cytokine levels. RESULTS Thirty-six patients were treated; no DLTs were encountered. The overall PSA response rate was 11%. Two patients receiving 8 and 14 g/d demonstrated complete response (CR): their PSA declined to undetectable levels that continued for 49 and 30 months. Two patients who received 8 and 12 g/d experienced partial response (PR). After 3 months of therapy, 13 (36%) patients experienced some PSA decrease below baseline. Patients with CR and PR demonstrated higher levels of baseline interleukin-15 than nonresponders; for this group, we observed therapy-associated declines in MDSCs. CONCLUSIONS Therapy with WBM appears to both impact PSA levels and modulate the biology of biochemically recurrent prostate cancer by decreasing immunosuppressive factors.