Cancer Biomarkers for Integrative Oncology
- 122 Downloads
Purpose of Review
There has been an increasing interest in using complementary and alternative medicine (CAM) approaches to treat cancer. It is therefore relevant and timely to determine if CAM biomarkers can be identified and developed to guide cancer diagnosis and treatment. Herein, we review the status of cancer biomarkers in CAM research and treatment to stimulate further research in this area.
Studies on promising anti-cancer natural products, such as PHY906, honokiol, bryostatin-1, and sulforaphane have demonstrated the existence of potential cancer biomarker(s). Additional studies are required to further develop and ultimately validate these biomarkers that can predict clinical activity of the anti-cancer natural products used alone or in combination with chemotherapeutic agents.
A systematic approach is needed to identify and develop CAM treatment associated biomarkers and to define their role in facilitating clinical decision-making. The expectation is to use these biomarkers in determining potential options for CAM treatment, examining treatment effects and toxicity and/or clinical efficacy in patients with cancer.
KeywordsBiomarker Cancer complementary and alternative medicine (CAM) Integrative oncology Cancer diagnostics Anti-cancer natural product Anti-cancer herbal medicine
The authors thank the past and present members of Dr. Y-C. Cheng’s laboratory group who were involved in the pre-clinical and translational studies on PHY906 and to all the clinical investigators, patients, and their families involved in the PHY906 clinical trials. The authors also thank Dr. Lyndsay Harris for the support and valuable comments, and to Dr. Laura K. Fogli for formatting this manuscript.
This research on PHY906 was supported in part by grants from the National Cancer Institute (grant nos. P01CA154295-01 and P30CA147904), the National Center for Complementary and Alternative Medicine, and a grant from the National Foundation for Cancer. Dr. David Frank was supported by NIH grant R01-CA160979.
Compliance with Ethical Standards
Conflict of Interest
Aniruddha Ganguly declares that he has no conflict of interest.
David Frank has received research funding from Gilead and Cstem; has received compensation from Kymera for service as a consultant; has a patent issued, licensed, and receives royalties for STAT Modulators; and has a patent pending for targeting the transcription factor NF-kB with harmine.
Nagi Kumar declares that she has no conflict of interest.
Yung-Chi Cheng is a fellow of the National Foundation for Cancer that partially supported PHY906 studies. He is a co-founder of Yiviva with the Yale University to further develop PHY906 (now known as Yiviva 906) for the treatment of various human cancers and other GI disorders.
Edward Chu is a member of the scientific advisory board of Yiviva.
Human and Animal Rights and Informed Consent
All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).
Papers of particular interest, published recently, have been highlighted as: • Of importance
- 4.Samanta SK, Sehrawat A, Kim SH, Hahm ER, Shuai Y, Roy R, et al. Disease subtype-independent biomarkers of breast cancer chemoprevention by the ayurvedic medicine phytochemical withaferin A. J Natl Cancer Inst. 2017;109(6).Google Scholar
- 5.• Battle TE, Arbiser J, Frank DA. The natural product honokiol induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells. Blood. 2005;106(2):690–7 This study defined the molecular mechanism by which a natural product displays a therapeutic index in killing malignant B lymphocytes versus normal lymphocytes. It also showed how honokiol can overcome biologically important resistance mechanisms and synergize with conventional anti-cancer agents, all critical aspects for a novel therapeutic. PubMedCrossRefGoogle Scholar
- 6.Hsu HYH, C.S. Commonly used Chinese herb formulas with illustrations. Oriental Healing Art Institute: Long Beach; 1980.Google Scholar
- 7.Li S. The Ben Cao Gang Mu: Chinese dition Univ. California Press; 2016.Google Scholar
- 10.Zhang W, Saif MW, Dutschman GE, Li X, Lam W, Bussom S, et al. Identification of chemicals and their metabolites from PHY906, a Chinese medicine formulation, in the plasma of a patient treated with irinotecan and PHY906 using liquid chromatography/tandem mass spectrometry (LC/MS/MS). J Chromatogr A. 2010;1217(37):5785–93.PubMedPubMedCentralCrossRefGoogle Scholar
- 11.Lam W, Jiang Z, Guan F, Hu R, Liu SH, Chu E, et al. The number of intestinal bacteria is not critical for the enhancement of antitumor activity and reduction of intestinal toxicity of irinotecan by the Chinese herbal medicine PHY906 (KD018). BMC Complement Altern Med. 2014;14:490.PubMedPubMedCentralCrossRefGoogle Scholar
- 15.• Kummar S, Copur MS, Rose M, Wadler S, Stephenson J, O’Rourke M, et al. A phase I study of the chinese herbal medicine PHY906 as a modulator of irinotecan-based chemotherapy in patients with advanced colorectal cancer. Clin Colorectal Cancer. 2011;10(2):85–96 This was the first randomized, placebo-controlled clinical study to show that the Chinese herbal medicine PHY906 was able to significantly reduce the diarrhea, nausea/vomiting, and fatigue of irinotecan-based chemotherapy in patients with metastatic colorectal cancer. This study also showed that PHY906 did not alter the pharmacokinetic profile of the chemotherapy agents 5-fluorouracil and irinotecan. PubMedCrossRefGoogle Scholar
- 21.• Wang X, Beitler JJ, Huang W, Chen G, Qian G, Magliocca KR, et al. Honokiol radiosensitizes squamous cell carcinoma of the head and neck by downregulation of survivin. Clin Cancer Res. 2017; This study demonstrated that increased expression of the pro-survival protein survivin is a negative prognostic indicator in squamous cell carcinoma of the head and neck, and may mediate resistance to radiation therapy. Downregulation of survivin in response to the natural product honokiol sensitizes these cells to radiation, suggesting an innovative, rational way to therapeutically exploit the activity of this drug. Google Scholar
- 23.Pearson HE, Iida M, Orbuch RA, McDaniel NK, Nickel KP, Kimple RJ, et al. Overcoming resistance to cetuximab with honokiol, a small-molecule polyphenol. Mol Cancer Ther. 2017.Google Scholar
- 25.Pan J, Lee Y, Zhang Q, Xiong D, Wan TC, Wang Y, et al. Honokiol decreases lung cancer metastasis through inhibition of the STAT3 signaling pathway. Cancer Prev Res. 2016.Google Scholar
- 26.Krige D. Traditional medicine and healers in South Africa. J Eur Med Writers Assoc. 2009.Google Scholar
- 28.Matias D, Bessa C, Fátima Simões M, Reis CP, Saraiva L, Rijo P. Chapter 2 - Natural products as lead protein kinase c modulators for cancer therapy. In: Atta ur R, editor. Studies in natural products chemistry. 50: Elsevier; 2016. p. 45–79.Google Scholar
- 32.• Battle TE, Frank DA. STAT1 mediates differentiation of chronic lymphocytic leukemia cells in response to bryostatin 1. Blood. 2003;102:3016–24 This study demonstrated that a natural product from a marine organism can have a unique mechanism as an anti-cancer therapeutic, by inducing the terminal differentiation of malignant cells. This approach holds the potential to be more effective and less toxic than standard cytotoxic therapies. This study also delineated the novel molecular pathway by which bryostatin 1 mediates this biological effect. PubMedCrossRefGoogle Scholar
- 36.Shapiro TA, Fahey JW, Wade KL, Stephenson KK, Talalay P. Human metabolism and excretion of cancer chemoprotective glucosinolates and isothiocyanates of cruciferous vegetables. Cancer Epidemiol Biomark Prev. 1998;7(12):1091–100.Google Scholar
- 53.Jo GH, Kim GY, Kim WJ, Park KY, Choi YH. Sulforaphane induces apoptosis in T24 human urinary bladder cancer cells through a reactive oxygen species-mediated mitochondrial pathway: the involvement of endoplasmic reticulum stress and the Nrf2 signaling pathway. Int J Oncol. 2014;45(4):1497–506.PubMedCrossRefGoogle Scholar
- 65.Bricker GV, Riedl KM, Ralston RA, Tober KL, Oberyszyn TM, Schwartz SJ. Isothiocyanate metabolism, distribution, and interconversion in mice following consumption of thermally processed broccoli sprouts or purified sulforaphane. Mol Nutr Food Res. 2014;58(10):1991–2000.PubMedPubMedCentralCrossRefGoogle Scholar
- 67.• Alumkal JJ, Slottke R, Schwartzman J, Cherala G, Munar M, Graff JN, et al. A phase II study of sulforaphane-rich broccoli sprout extracts in men with recurrent prostate cancer. Invest New Drugs. 2015;33(2):480–9 Based on results of their work demonstrating that sulforaphane inhibits AR signaling in prostate cancer cells, the current study reports results from the first clinical trial of sulforaphane-rich extracts in men with prostate cancer. The study was the first to report the safety of treatment and the effects of sulforaphane extract on PSA doubling time modulation. These are critical data of safety that inform future development of early-phase clinical trials in humans. PubMedCrossRefGoogle Scholar
- 68.• Atwell LL, Hsu A, Wong CP, Stevens JF, Bella D, Yu TW, et al. Absorption and chemopreventive targets of sulforaphane in humans following consumption of broccoli sprouts or a myrosinase-treated broccoli sprout extract. Mol Nutr Food Res. 2015;59(3):424–33 These are critical data of bioavailability that inform future development of early-phase clinical trials in humans. PubMedPubMedCentralCrossRefGoogle Scholar
- 69.• Cipolla BG, Mandron E, Lefort JM, Coadou Y, Della Negra E, Corbel L, et al. Effect of sulforaphane in men with biochemical recurrence after radical prostatectomy. Cancer Prev Res (Phila). 2015;8(8):712–9 The current study was the first randomized clinical trials to report that daily administration of free sulforaphane shows promise in managing biochemical recurrences in prostate cancer after radical prostatectomy. These are critical data of safety and efficacy that inform future development of early-phase clinical trials in humans. CrossRefGoogle Scholar
- 77.Islam SS, Mokhtari RB, Akbari P, Hatina J, Yeger H, Farhat WA. Simultaneous targeting of bladder tumor growth, survival, and epithelial-to-mesenchymal transition with a novel therapeutic combination of acetazolamide (AZ) and sulforaphane (SFN). Target Oncol. 2016;11(2):209–27.PubMedCrossRefGoogle Scholar