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Proceedings of the Strategy Meeting for the Development of an International Consortium for Chinese Medicine and Cancer

Proceedings of the Strategy Meeting for the Development of an International Consortium for... executive summary special article Proceedings of the Strategy Meeting for the Development of an International Consortium for Chinese Medicine and Cancer On November 3, 2014, in Bethesda, MD, the Office of Cancer Complementary and Alternative Medicine of the National Cancer Institute held a meeting to examine the potential utility and feasibility of establishing an international consortium for Chinese medicine and cancer. There is significant interest in the West in using components of Chinese medicine (CM) —such as botanicals and herbal medicines, acupuncture and acupressure, and qigong—in the field of oncology, as potential anticancer agents, for symptom management, and to improve quality of life. The proposal for a consortium on CM came from the Chinese Academy of Chinese Medical Sciences, with the aims of improving scientific communications and collaborations and modernizing the studies of CM for cancer. The US National Cancer Institute’s Office of Cancer Complementary and Alternative Medicine agreed to work with Chinese Academy of Chinese Medical Sciences to explore the feasibility of establishing an international consortium for Chinese medicine and cancer. At the meeting, participants from the United States, China, Canada, Australia, and Korea discussed issues in CM and cancer research, treatment, and management, including potential mechanisms of action, proof of efficacy, adverse effects, regulatory issues, and the need for improving the quality of randomized clinical trials of CM treatments and supportive care interventions. Presented in these Jeffrey D. White proceedings are some of the main issues and opportunities discussed by workshop participants. Hongsheng Lin Libin Jia INTRODUCTION an anticancer vaccine in women with metastatic Roy S. Wu breast cancer. Increasingly, patients and health care providers in Stephen Lam In April 2006, the US National Cancer Institute’s Western countries have begun using components Jie Li of Chinese medicine (CM) —such as botanicals Office of Cancer Complementary and Alternative and herbal medicines, acupuncture and acu- Medicine (OCCAM) hosted a conference titled Jinhui Dou “Traditional Chinese Medicine and Cancer Re- pressure, and qigong—to aid in managing various Nagi Kumar search: Fostering Collaborations; Advancing the medical conditions. Simultaneously, research on Lizhu Lin Science” at the National Institutes of Health (NIH), the effectiveness and mechanism of action of Lixing Lao which almost 200 scientists and physicians these approaches has also expanded. In the field attended, including more than 40 from China. of oncology, many of these treatment approaches This meeting served as an incubator for establish- Author affiliations and have been explored, both as potential anticancer support information (if ing new collaborative relationships between CM agents and symptom management methods. Be- applicable) appear at the and Western medicine practitioners and re- tween 2005 and 2012, the research portfolio of the end of this article. searchers for cancer prevention, treatment, and US National Cancer Institute (NCI) included more J.D.W. and H.L. palliation. Since then, many new collaborations contributed equally to this than 200 grants or other projects examining as- 3-16 have been established (Table 2). article. pects of CM (Table 1). The research focus of these Corresponding author: projects ranges across the broad spectrums of In 2011 and 2013, OCCAM and Cancer Institute, Libin Jia, MD, Office of cancer prevention, treatment, and symptom man- China Academy of Chinese Medical Sciences Cancer Complementary and Alternative Medicine, agement research. Some of these grants have (CACMS) cohosted two conferences in Beijing, Division of Cancer studied interventions that have advanced to clin- China, on CM and cancer research. These meet- Treatment and Diagnosis, ical trials in the United States, such as the oral National Cancer Institute, ings continued to explore the intersection of CM 5W134, 9609 Medical protein-bound polysaccharide mixture derived from and Western oncology and further established the Center Dr, Rockville, the mushroom Trametes versicolor, polysaccharide potential value of more dialogue between scien- Maryland 20850; e-mail: libinj@mail.nih.gov. K (PSK), which is being tested as an adjuvant to tists and health care practitioners from different 814 Volume 3, Issue 6, December 2017 jgo.org JGO – JournalofGlobal Oncology © 2016 by American Society of Clinical Oncology Licensed under the Creative Commons Attribution 4.0 License Table 1. CM and Cancer Research: National Cancer Institute Grant Portfolio 2005 to 2012 (N 5 206) CM Grants Study Areas Acupuncture/acupressure/acustimulation 15 Nausea and vomiting from chemotherapy; cancer-related fatigue; menopausal hot flashes; hot flashes in patients with prostate cancer; shoulder syndrome after cancer surgery; post-colectomy recovery; xerostomia Qigong 4 Biobehavioral effects; quality of life Tai chi 2 Chronic insomnia; effects on immune system Tibetan yoga 1 Fatigue and sleep in cancer Botanicals 18 Bitter melon, danshen, garlic, ginger, Effects on tumor vasculature; prostate/brain gingko, Oldenlandia diffusa, PHY906, cancer treatment; symptom pomegranate, withania, somnifera management; genetic instability; diet- endocrine interaction; cancer prevention Compounds from medicinal plants Curcumin and analogs 30 Chemotherapy sensitizer; radiotherapy sensitizer; cancer prevention; tumor growth inhibition; cancer stem cell inhibition EGCG and other tea polyphenols 70 Cancer prevention; tumor growth control; transcription regulation Genistein and soy protein/isoflavones 42 Cancer prevention; cancer therapy; gene methylation; radiotherapy sensitization; DNA damage; colorectal polyps; epigenetic regulation; nutrient-gene interaction; effects on estrogens; effects on mammographic density; adjuvant therapy; postthoracotomy pain Various compounds 23 Bowman-Birk inhibitor, bryonolic acid, Cancer prevention; anticancer activity; crocetin diallyl trisulfide, ginsenoside, mechanisms of immune modulation; b-glucans, kaempferol, lycopene, receptor antagonists; neoadjuvant mangostin, pachymic acid, therapy pentagalloyl-glucose, PSK, quercetin, resveratrol, salidroside, tanshinone IIA, triptolide, triterpenoids Others 1 International Center for the Evaluation of CM herb collection and evaluation East Asian Botanicals for Cancer Abbreviations: CM, Chinese medicine; EGCG, epigallocatechin gallate; PHY906, a four-herb Chinese medicine formula; PSK, polysaccharide K. countries and backgrounds, the potential syner- CM drugs, and modernizing the research of CM gies that can come from joining together com- for cancer. NCI’s OCCAM agreed to work with plementary resources, and the potential for CACMS to explore the feasibility of establishing international scientific communications and col- an international consortium for CM and cancer. laborations to aid in the modernization of CM for On November 3, 2014, NCI held a meeting at oncology applications. the US National Institutes of Health’s Bethesda, In February 2014, the Cancer Institute, CACMS, MD, campus to assess the feasibility of developing presented OCCAM with a proposal for an interna- an international consortium for Chinese medicine tional consortium with the aims of improving and cancer (ICCMC) and to discuss the potential scientific communications and collaborations, goals and structures for such an international improving the quality of research on CM for collaboration. Topics and questions proposed oncology applications, finding potential promising by the organizers included: What are the most 815 Volume 3, Issue 6, December 2017 jgo.org JGO – JournalofGlobal Oncology Table 2. Chinese Medicine and Cancer Research Collaborations After Office of Cancer Complementary and Alternative Medicine/National Cancer Institute 2006 Meeting Collaborating Institutions Projects LCP/NCI/US and CI/CACMS/China Berberine regulates AMP-activated protein kinase signaling pathways and inhibits colon tumorigenesis in mice LCP/NCI/US and CI/CACMS/China Resveratrol prevents tumorigenesis in mouse model of Kras-activated sporadic colorectal cancer by suppressing oncogenic Kras expression LCP/NCI/US and CI/CACMS/China Fei-Liu-Ping ointment inhibits lung cancer growth and invasion by suppressing tumor inflammatory microenvironment LMI/NCI/US and CI/CACMS/China Fufang Kushen injection inhibits sarcoma growth and tumor- induced hyperalgesia via TRPV1 signaling pathways LCP/NCI/US and CI/CACMS/China Targeting AMPK for cancer prevention and treatment 7a NPB/NCI/US and CAS, CAMS/China The anticancer compounds and natural products screening IDIS/ML/NIH/US and DP/Yale U/US Interaction of a traditional Chinese medicine (PHY906) and CPT-11 on the inflammatory process in the tumor microenvironment. DS/WUSM/US and CI/CAMS/China Chemoprevention of lung squamous cell carcinoma in mice by a mixture of Chinese herbs TC/UC/US and CPU/China American ginseng: potential structure-function relationship in cancer chemoprevention TC/UC/US and CPU/China Ginsenoside compound K, not Rb1, possesses potential chemopreventive activities in human colorectal cancer TC/UC/US and CPU/China Salvia miltiorrhiza (dan shen) significantly ameliorates colon inflammation in dextran sulfate sodium induced colitis TC/UC/US and CPU/China Identification of potential anticancer compounds from Oplopanax horridus TC/UC/US and CPU/China Chemopreventive effects of oplopantriol A, a novel compound isolated from Oplopanax horridus on colorectal cancer TC/UC/US and CPU/China Anticancer compound oplopantriol A kills cancer cells through inducing ER stress and BH3 proteins Bim and Noxa MSKCC/US and SUT/China Safety and pharmacokinetic trial of docetaxel plus an astragalus-based herbal formula for patients with non–small- cell lung cancer Abbreviations: AMP, 59 adenosine monophosphate-activated protein; AMPK, 59 adenosine monophosphate-activated protein kinase; CAS, CAMS/China: China Academy of Sciences, China Academy of Medical Sciences, China; CI/CACMS/China: Cancer Institute, China Academy of Chinese Medical Sciences, China; CI/CAMS/China: Cancer Institute, China Academy of Medical Sciences, China; CPU/China: China Pharmacology University, China; DP/Yale U/US: Department of Pharmacology, Yale University, United States; DS/WUSM/US: Department of Surgery, Washington University School of Medicine, United States; ER, endoplasmic reticulum; IDIS/ML/NIH/US: Infectious Disease and Immunogenetics Section, Clinical Center, National Institutes of Health, United States; LCP/NCI/US: Laboratory of Cancer Preventions, National Cancer Institute, United States; LMI/NCI/US: Laboratory of Molecular Immunoregulation, National Cancer Institute, United States; MSKCC/US: Memorial Sloan Kettering Cancer Center, United States; NPB/NCI/US: Natural Products Branch, National Cancer Institute, United States; SUT/China, Shanghai University of Traditional Chinese Medicine, China; TC/UC/US: Tang Center, University of Chicago, United States; TRPV1, transient receptor potential cation channel subfamily V member 1. promising therapies from CM for cancer treat- hospitals to work effectively with industry to ment and management? What are the mecha- carefully study the clinical utility of CM herbal nisms of action of these promising therapies? therapies in cancer management? How can this information help in optimally com- MEETING PROCEEDINGS bining these therapies with conventional Western Bridging CM and Modern Biomedicine biomedical approaches? How can these ap- proaches be standardized (eg, plant sourcing Jie Li, MD, PhD, and Hongsheng Lin, MD, from and content analysis) so that they provide con- Cancer Institute, CACMS, highlighted one of the sistent effects and are optimized (eg, dose and main differences between CM and Western on- schedule) to provide maximal benefit? What is cology: CM focuses on comprehensively adjusting necessary for academic centers and research the internal environment of the body, whereas the 816 Volume 3, Issue 6, December 2017 jgo.org JGO – JournalofGlobal Oncology general goal of Western cancer treatment is to treat decoction) for patients with stage II and III colon the tumor alone. CM uses a clinical assessment cancer, one arm of the study in China and one in process that differs greatly from modern Western Norway. The trial is testing if the use of a CM medicine. The CM diagnostic approach defines herbal formula after radical surgery and conven- specific body types or constitutions, such as Chi tional chemotherapy/radiotherapy could reduce (or Qi) deficient. What are the molecular pathways the rate of recurrence and metastasis and prolong associated with specific diagnosis patterns? With the overall survival time. modern technologies, there are opportunities to Dose finding may also be different for herbal examine the molecular biology underlying CM formulas than for other pharmaceuticals. For ex- diagnoses. Researchers could potentially explore ample, in one trial discussed by participants, the the genetic background for those types with suf- highest dose did not provide the best response. ficient sample sizes. Also, in CM, practitioners can use different herbs for the same goals—the concept of same disease, Recent Clinical Research of Chinese Botanical different medicine. One formula may not work Medicines for everyone with the same tumor type. CM is a Stephen Lam, MD, discussed a series of phase I complex intervention system, including herbs, and phase II cancer trials of botanical drugs, co- diet, exercise, and other components. Some par- ordinated by his group at the British Columbia ticipants expressed concern that when you re- Cancer Agency and performed in Canada and duce the system to its components to simplify the United States. The drugs his group has the research study design, you have the potential tested included the multi-herb agents ACAPHA to reduce efficacy. (also known as antitumor B or Zeng Sheng-ping 9,17,18 19 20,21 Pian), Aneustat, myoinositol, and Nagi Kumar, MD, of the Moffitt Cancer Center at the green tea extract Polyphenon E. All botanicals the University of South Florida overviewed the used in the presented trials were manufactured literature and her own research showing that under good manufacturing practices, with careful botanicals can influence multiple biochemical standardization. In general, although the safety cascades leading to inhibition of mutagenesis profile in these trials was good, as stand-alone and proliferation, induction of apoptosis, and sup- agents these botanical drugs to date have shown pression of formation and growth of human can- only modest effects for chemoprevention of cancer. cers, with a significantly superior safety profile compared with most agents evaluated to date. Jie Li, MD, PhD, and Hongsheng Lin, MD, pre- Kumar presented a systematic approach to accel- sented promising data on CM applications for can- 6,22-29 erate development of CM and discussed the cer treatment and symptom management. In ABCDEs (Agent, Biomarkers, Cohorts for testing, an ongoing randomized trial, an herbal medicinal Design, and End points) of evaluating compounds/ cream is being studied for the treatment of hand- herbal mixtures for cancer prevention and treat- foot syndrome among patients being treated with ment. Factors to consider when evaluating CM/ the chemotherapeutic agent capecitabine. Early herbal mixture include ADME (absorption, distri- results showed significant improvements in bution, metabolism, and excretion) properties and pain and restricted mobility caused by epider- profiles; toxicity; risk/benefit ratio; dose, route, mal growth factor receptor inhibitor–related schedule, and half-life; whole compounds or mix- skin toxicity. tures versus single agents; and standardization Issues of Trial Design and Monitoring With CM and quality control. Chemoprevention biomarkers for a trial should be identified early, clinically In China, CM practitioners see a large number of relevant, and modulated by a given therapy; they patients, but the treatment efficacy has not been should reliably estimate the end point of in- well documented in a standardized way. Meeting terest and have accuracy in predicting a spe- participants discussed a need among the CM 34-36 cific cancer. programs in China for research capacity building and for improving the quality of clinical trials. Lizhu Lin, MD, of the First Affiliated Hospital of Guangzhou University of Chinese Medicine, An outstanding question is whether using thera- highlighted current issues with published clin- pies selected based on a patient’s CM diagnosis 29 37-41 makes a difference in outcomes. A clinical trial is ical trials of CM for cancer. In a search of currently underway to examine the potential ben- ClinicalTrials.gov and Chinese Clinical Trial efit of adjuvant therapy with two herbal formulas Register, 42 registered trials with published (Si Jun Zi decoction and Liu Wei Di Huang results between 2008 and 2014 were identified. 817 Volume 3, Issue 6, December 2017 jgo.org JGO – JournalofGlobal Oncology Most of these reports failed to properly docu- from medicinal plants, purification of the mixture ment the CM diagnosis according to disease and into single molecules is not required (but partial syndrome differentiation. Only four (9.5%) of the purification is encouraged), and identification of study protocols mentioned syndrome classifica- active constituents is not essential. Experiences tion and a description of the CM diagnosis. Only from prior human use may substitute for some of two (4.8%) mentioned a blinded design, no the animal toxicology studies to support the safety study included sample size calculation, and of early-phase clinical trials. With extensive human no study performed an intention-to-treat analy- experience to be reviewed as adequate to support sis. Measures to ensure patient compliance and safety, nonclinical evaluations may be reduced or quality control of the study drug were inade- delayed until when the phase III trials are planned. quate. For clinical trials of CM on cancer in With a well-documented history of prior human China, Lin indicated that the following are use, most of the botanicals can advance directly to needed: integration of national resources of clin- single-dose or multiple-dose phase II trials. Ade- ical research centers to build the capacity of quate and well-controlled trials are necessary for multiagency cooperation and to use big data to marketing CM and other herbal products as bo- explore the efficacy of CM on cancer, identi- tanical drugs in the United States. When late- fication of the most important clinical opportu- phase clinical studies are being considered to nities for the use of CM for treatment of common demonstrate the clinical safety and efficacy of cancers, and selection of the most appropriate the botanical products for an NDA, the FDA re- therapeutic outcome measures. Measures of quires the same level of clinical efficacy/safety quality of life may be particularly important in requirements as nonbotanical drugs for new drug such trials. On the topic of improving the stan- market approvals. Because botanicals are com- dards of randomized controlled trials for CM, plex mixtures, multiple-dose and multiple-batch several participants stressed the importance of phase III clinical trials can be useful tools to extending the CONSORT statement to herbal demonstrate consistency of the botanical prod- medicine trials. ucts, when practical. Dou highlighted two case studies of botanical products that received FDA Quality Control and Standardization of Chinese approval as NDAs in the past decade. The first Botanical Medicines was the topical agent Veregen from MediGene (Planegg/Martinsried, Germany), for treating In a panel session, participants discussed how genital/perianal warts (investigational new drug ensuring the quality of CM products and the in 1996). The active ingredient is a partially puri- consistency between batches is a complex issue, fied green tea extract, mainly catechins. The NDA because of regional and seasonal variations in the for Veregen was approved in 2006. The second chemical composition of many herbs. Large com- example was the oral agent Fulyzaq (crofelemer) panies with steady cash flow are in a position to for HIV-related diarrhea. The botanical raw mate- develop high-quality study agents, and the ques- rial for producing the drug substance (crofelemer) tion was posed whether large Chinese companies is crude plant latex from a South American plant would want to partner with investigators in the species, Croton lechleri (commonly known as United States and elsewhere to research these dragon’s blood). The NDA sponsor of Fulyzaq products. Such companies have the financial re- was Salix Pharmaceuticals (Raleigh, NC), and it sources but may not be familiar with international was approved in 2012. Lessons learned from the regulatory requirements. A consortium could serve as a conduit for these types of research two botanical NDAs include that botanical raw collaborations to study herbal products from the material controls are required, with adoption of CM pharmacopeia. good agriculture and collection practices, and that specifications for drug substance/product are US Regulatory Issues for Botanical Medicines acceptable for chemical batch equivalence, but alone may be inadequate; non–Chemistry Jinhui Dou, MD, a pharmacologist from Botanical Manufacturing and Controls data (eg, bioassays) Review Team, Center for Drug Evaluation and may be needed to ensure therapeutic consistency. Research, of the US Food and Drug Administra- tion (FDA), presented on further development of Working With Other CM–Related Organizations herbal medicines as FDA-approved new botanical drug products through investigational new drug Lixing Lao, MD, PhD, Director of the School of application and new drug application (NDA) Chinese Medicine, University of Hong Kong, intro- 45,46 processes. For developing a botanical drug duced an existing consortium for which he serves 818 Volume 3, Issue 6, December 2017 jgo.org JGO – JournalofGlobal Oncology as the secretary general, which brings together similar to a grant mechanism, but it requires CM and Western medicine researchers and prac- participation by NIH staff. Additional outside fund- titioners: The Consortium for Globalization of Chi- ing is allowed, as long as there is no overlap in nese Medicine (CGCM), founded in 2003. It how the funding is used. A center of excellence currently has 144 institutional members and 18 was proposed as another potential organizational industrial affiliate members. The CGCM has also structure. At the NIH these centers are often spawned an offshoot, the Good Practice in CM supported by P50 grants. The potential also Research Association, launched in April 2012 in exists to organize a consortium with multiple net- the Netherlands. The meeting participants be- works of activities and different levels of funding or lieved that the CGCM has a good system for even involve some industry partners, so the con- recruiting academic institutions and industry sortium would not be defined or restricted by its and that lessons could be learned from the funding. Regarding the work of the consortium, CGCM in how to establish this new consortium participants suggested that a registry project may in a stable way. The CGCM focuses on all as- be a good start for establishing a structure for pects of CM; therefore, collaborations focused collaboration; this is how the Academic Consor- purely on CM and cancer treatment have the tium for Integrative Medicine and Health began. potential to add value to both CGCM and the Future Directions emergent ICCMC. The participants gave some possible early project Consortium Funding Mechanisms and Structures suggestions, including developing exemplary Roy Wu, PhD, Chief of the Clinical Grants and guidelines for CM oncology clinical trials, devel- Contracts Branch of NCI’s Division of Cancer oping standard treatment protocols and evalua- Treatment and Diagnosis, presented potential tion procedures (like National Comprehensive funding models for a consortium. He stressed that Cancer Network guidelines), and creating educa- the ideal consortium structure will depend on what tional exchanges to find common ground and participants want to accomplish, but a secondary develop research capacity. The sentiment that it issue will be the type of funding pursued, because is time to solidly act, not just talk, was expressed by certain types of government grants require certain many participants. Pick a smaller, straightforward organizational structures. Among the possible project and use that to establish collaborative funding mechanisms for a consortium is the working relationships and figure out what may NIH Cooperative Agreement program (U01). This and may not work for a consortium. Levels of mechanism has been used to support various complexity can be added as the collaborations types of clinical trials networks, as exemplified grow and mature. The first meeting of the consor- by the existing Cancer Immunotherapy Network, tium was planned and held on October 16 to 18, Blood and Marrow Transplant Clinical Trials 2015 in Dalian, China. Network, and Experimental Therapeutics Clini- DOI: https://doi.org/10.1200/JGO.2016.005710 cal Trial Network. The cooperative agreement is Published online on jgo.org on September 7, 2016. AUTHOR CONTRIBUTIONS Libin Jia No relationship to disclose Provision of study materials or patients: Hongsheng Lin, Jie Li Manuscript writing: All authors Roy S. Wu Final approval of manuscript: All authors No relationship to disclose Stephen Lam AUTHORS’ DISCLOSURES OF Honoraria: CSA Medical, Exact Sciences POTENTIAL CONFLICTS OF INTEREST Consulting or Advisory Role: CSA Medical, Exact Sciences The following represents disclosure information provided by Research Funding: Qu Biologics (Inst), AstraZeneca (Inst) authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I 5 Jie Li Immediate Family Member, Inst 5 My Institution. Relation- No relationship to disclose ships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, Jinhui Dou please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. No relationship to disclose Jeffrey D. White Nagi Kumar No relationship to disclose No relationship to disclose Hongsheng Lin Lizhu Lin No relationship to disclose No relationship to disclose 819 Volume 3, Issue 6, December 2017 jgo.org JGO – JournalofGlobal Oncology Lixing Lao Other meeting participants: Joost J. Oppenheim, De Yang, John A. Beutler (Center for Cancer Research, National No relationship to disclose Cancer Institute, MD), Paul M. Coates (Office of Dietary ACKNOWLEDGMENT Supplements, National Institutes of Health, MD), O.M. The authors thank the panelists and panel chairs who Zack Howard (Center for Scientific Review, National contributed to the meeting: Brian Berman (University of Institutes of Health, MD), Laura Lee Johnson, Sau Larry Maryland, MD), Ping Ping Li (Peking University Cancer Lee, Charles G. Wu (Center for Drug Evaluation and Hospital, People’s Republic of China), Yun Yen (Taipei Research,USFoodand Drug Administration,MD),David Medical University, Taiwan), Wei Hou (Cancer Institute, Newman, Michael Sachs (Division of Cancer Treatment China Academy of Chinese Medical Sciences, People’s and Diagnosis, National Cancer Institute, MD), Choi, Republic of China), Luming Liu (Fudan University Rak-Won (College of Oriental Medicine, Daejeon Shanghai Cancer Center, People’s Republic of China), University, Republic of Korea), Li Fu (Dalian Fusheng Shiuan Chen (City of Hope, CA), Peiying Yang (University Institute of Natural Medicine Development, Dalian, of Texas Anderson Cancer Center, TX), Yufei Yang People’s Republic of China), Jongmin Kim (East-West (Xiyan Hospital, China Academy of Chinese Medical Cancer Center, Dunsan Korean Medical Hospital of Sciences, People’s Republic of China), Yingjie Jia (First Daejeon University, Republic of Korea), Anping Li, Rongli Teaching Hospital of Tianjin University of TCM, People’s You (Shanxi Zhendong Pharmaceutical, Shanxi, People’s Republic of China), Guangru Xie (Tianjin Cancer Hospital, Republic of China), Huizheng Li (Unitech Medical, People’s Republic of China), Daniel Weber (Panaxea Minneapolis, MN), Jie Liu, Yong Li, Zhizheng Zhao (Cancer International, Australia), David Adelson (University of Institute of China Academy of Chinese Medical Sciences, Adelaide, Australia), Edward Chu (University of Pittsburgh, Beijing, People’s Republic of China), Ji-Wei Liu (1st PA), Gary Deng (Memorial Sloan Kettering Cancer Center, Affiliated Hospital of Dalian Medical University, Dalian, NY), Xiao-Ou Shu (Vanderbilt University, TN), Jianping People’s Republic of China), Xiaojiang Li (Tianjin Liu (Beijing University of Chinese Medicine, People’s University of Traditional Chinese Medicine, Tianjin, Republic of China), Dongfeng Yin (Affiliated Hospital of People’s Republic of China), Zongwei Wang (Massachusetts Liao Ning University of Traditional Chinese Medicine, General Hospital, Harvard Medical School, Boston, MA), and People’s Republic of China), Ling Xu (Shanghai Farah Zia, Oluwadamilola Olaku, Dan Xi, Avraham Rasooly, Longhua Hospital, People’s Republic of China), Hwaseung Christina Armstrong, and Manda Fordyce (Office of Cancer Yoo (East-West Cancer Center, Daejeon University, Complementary and Alternative Medicine, Division of Cancer Republic of Korea). Treatment and Diagnosis, National Cancer Institute, MD). Affiliations Jeffrey D. White, Libin Jia, and Roy S. Wu, National Cancer Institute, Rockville; Jinhui Dou, Food and Drug Administration, Silver Spring, MD; Hongsheng Lin and Jie Li, China Academy of Chinese Medical Sciences, Beijing; Lizhu Lin, First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou; Lixing Lao, The University of Hong Kong, Pokfulam, Hong Kong, Special Administrative Region, People’s Republic of China; Stephen Lam, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; and Nagi Kumar, Moffitt Cancer Center, University of South Florida, Tampa, FL. REFERENCES 1. Lu H, Yang Y, Gad E, et al: Polysaccharide krestin is a novel TLR2 agonist that mediates inhibition of tumor growth via stimulation of CD8 T cells and NK cells. Clin Cancer Res 17:67-76, 2011 2. 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Academic Consortium for Integrative Medicine and Health. http://www.imconsortium.org/ 822 Volume 3, Issue 6, December 2017 jgo.org JGO – JournalofGlobal Oncology http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Global Oncology Wolters Kluwer Health

Proceedings of the Strategy Meeting for the Development of an International Consortium for Chinese Medicine and Cancer

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Abstract

executive summary special article Proceedings of the Strategy Meeting for the Development of an International Consortium for Chinese Medicine and Cancer On November 3, 2014, in Bethesda, MD, the Office of Cancer Complementary and Alternative Medicine of the National Cancer Institute held a meeting to examine the potential utility and feasibility of establishing an international consortium for Chinese medicine and cancer. There is significant interest in the West in using components of Chinese medicine (CM) —such as botanicals and herbal medicines, acupuncture and acupressure, and qigong—in the field of oncology, as potential anticancer agents, for symptom management, and to improve quality of life. The proposal for a consortium on CM came from the Chinese Academy of Chinese Medical Sciences, with the aims of improving scientific communications and collaborations and modernizing the studies of CM for cancer. The US National Cancer Institute’s Office of Cancer Complementary and Alternative Medicine agreed to work with Chinese Academy of Chinese Medical Sciences to explore the feasibility of establishing an international consortium for Chinese medicine and cancer. At the meeting, participants from the United States, China, Canada, Australia, and Korea discussed issues in CM and cancer research, treatment, and management, including potential mechanisms of action, proof of efficacy, adverse effects, regulatory issues, and the need for improving the quality of randomized clinical trials of CM treatments and supportive care interventions. Presented in these Jeffrey D. White proceedings are some of the main issues and opportunities discussed by workshop participants. Hongsheng Lin Libin Jia INTRODUCTION an anticancer vaccine in women with metastatic Roy S. Wu breast cancer. Increasingly, patients and health care providers in Stephen Lam In April 2006, the US National Cancer Institute’s Western countries have begun using components Jie Li of Chinese medicine (CM) —such as botanicals Office of Cancer Complementary and Alternative and herbal medicines, acupuncture and acu- Medicine (OCCAM) hosted a conference titled Jinhui Dou “Traditional Chinese Medicine and Cancer Re- pressure, and qigong—to aid in managing various Nagi Kumar search: Fostering Collaborations; Advancing the medical conditions. Simultaneously, research on Lizhu Lin Science” at the National Institutes of Health (NIH), the effectiveness and mechanism of action of Lixing Lao which almost 200 scientists and physicians these approaches has also expanded. In the field attended, including more than 40 from China. of oncology, many of these treatment approaches This meeting served as an incubator for establish- Author affiliations and have been explored, both as potential anticancer support information (if ing new collaborative relationships between CM agents and symptom management methods. Be- applicable) appear at the and Western medicine practitioners and re- tween 2005 and 2012, the research portfolio of the end of this article. searchers for cancer prevention, treatment, and US National Cancer Institute (NCI) included more J.D.W. and H.L. palliation. Since then, many new collaborations contributed equally to this than 200 grants or other projects examining as- 3-16 have been established (Table 2). article. pects of CM (Table 1). The research focus of these Corresponding author: projects ranges across the broad spectrums of In 2011 and 2013, OCCAM and Cancer Institute, Libin Jia, MD, Office of cancer prevention, treatment, and symptom man- China Academy of Chinese Medical Sciences Cancer Complementary and Alternative Medicine, agement research. Some of these grants have (CACMS) cohosted two conferences in Beijing, Division of Cancer studied interventions that have advanced to clin- China, on CM and cancer research. These meet- Treatment and Diagnosis, ical trials in the United States, such as the oral National Cancer Institute, ings continued to explore the intersection of CM 5W134, 9609 Medical protein-bound polysaccharide mixture derived from and Western oncology and further established the Center Dr, Rockville, the mushroom Trametes versicolor, polysaccharide potential value of more dialogue between scien- Maryland 20850; e-mail: libinj@mail.nih.gov. K (PSK), which is being tested as an adjuvant to tists and health care practitioners from different 814 Volume 3, Issue 6, December 2017 jgo.org JGO – JournalofGlobal Oncology © 2016 by American Society of Clinical Oncology Licensed under the Creative Commons Attribution 4.0 License Table 1. CM and Cancer Research: National Cancer Institute Grant Portfolio 2005 to 2012 (N 5 206) CM Grants Study Areas Acupuncture/acupressure/acustimulation 15 Nausea and vomiting from chemotherapy; cancer-related fatigue; menopausal hot flashes; hot flashes in patients with prostate cancer; shoulder syndrome after cancer surgery; post-colectomy recovery; xerostomia Qigong 4 Biobehavioral effects; quality of life Tai chi 2 Chronic insomnia; effects on immune system Tibetan yoga 1 Fatigue and sleep in cancer Botanicals 18 Bitter melon, danshen, garlic, ginger, Effects on tumor vasculature; prostate/brain gingko, Oldenlandia diffusa, PHY906, cancer treatment; symptom pomegranate, withania, somnifera management; genetic instability; diet- endocrine interaction; cancer prevention Compounds from medicinal plants Curcumin and analogs 30 Chemotherapy sensitizer; radiotherapy sensitizer; cancer prevention; tumor growth inhibition; cancer stem cell inhibition EGCG and other tea polyphenols 70 Cancer prevention; tumor growth control; transcription regulation Genistein and soy protein/isoflavones 42 Cancer prevention; cancer therapy; gene methylation; radiotherapy sensitization; DNA damage; colorectal polyps; epigenetic regulation; nutrient-gene interaction; effects on estrogens; effects on mammographic density; adjuvant therapy; postthoracotomy pain Various compounds 23 Bowman-Birk inhibitor, bryonolic acid, Cancer prevention; anticancer activity; crocetin diallyl trisulfide, ginsenoside, mechanisms of immune modulation; b-glucans, kaempferol, lycopene, receptor antagonists; neoadjuvant mangostin, pachymic acid, therapy pentagalloyl-glucose, PSK, quercetin, resveratrol, salidroside, tanshinone IIA, triptolide, triterpenoids Others 1 International Center for the Evaluation of CM herb collection and evaluation East Asian Botanicals for Cancer Abbreviations: CM, Chinese medicine; EGCG, epigallocatechin gallate; PHY906, a four-herb Chinese medicine formula; PSK, polysaccharide K. countries and backgrounds, the potential syner- CM drugs, and modernizing the research of CM gies that can come from joining together com- for cancer. NCI’s OCCAM agreed to work with plementary resources, and the potential for CACMS to explore the feasibility of establishing international scientific communications and col- an international consortium for CM and cancer. laborations to aid in the modernization of CM for On November 3, 2014, NCI held a meeting at oncology applications. the US National Institutes of Health’s Bethesda, In February 2014, the Cancer Institute, CACMS, MD, campus to assess the feasibility of developing presented OCCAM with a proposal for an interna- an international consortium for Chinese medicine tional consortium with the aims of improving and cancer (ICCMC) and to discuss the potential scientific communications and collaborations, goals and structures for such an international improving the quality of research on CM for collaboration. Topics and questions proposed oncology applications, finding potential promising by the organizers included: What are the most 815 Volume 3, Issue 6, December 2017 jgo.org JGO – JournalofGlobal Oncology Table 2. Chinese Medicine and Cancer Research Collaborations After Office of Cancer Complementary and Alternative Medicine/National Cancer Institute 2006 Meeting Collaborating Institutions Projects LCP/NCI/US and CI/CACMS/China Berberine regulates AMP-activated protein kinase signaling pathways and inhibits colon tumorigenesis in mice LCP/NCI/US and CI/CACMS/China Resveratrol prevents tumorigenesis in mouse model of Kras-activated sporadic colorectal cancer by suppressing oncogenic Kras expression LCP/NCI/US and CI/CACMS/China Fei-Liu-Ping ointment inhibits lung cancer growth and invasion by suppressing tumor inflammatory microenvironment LMI/NCI/US and CI/CACMS/China Fufang Kushen injection inhibits sarcoma growth and tumor- induced hyperalgesia via TRPV1 signaling pathways LCP/NCI/US and CI/CACMS/China Targeting AMPK for cancer prevention and treatment 7a NPB/NCI/US and CAS, CAMS/China The anticancer compounds and natural products screening IDIS/ML/NIH/US and DP/Yale U/US Interaction of a traditional Chinese medicine (PHY906) and CPT-11 on the inflammatory process in the tumor microenvironment. DS/WUSM/US and CI/CAMS/China Chemoprevention of lung squamous cell carcinoma in mice by a mixture of Chinese herbs TC/UC/US and CPU/China American ginseng: potential structure-function relationship in cancer chemoprevention TC/UC/US and CPU/China Ginsenoside compound K, not Rb1, possesses potential chemopreventive activities in human colorectal cancer TC/UC/US and CPU/China Salvia miltiorrhiza (dan shen) significantly ameliorates colon inflammation in dextran sulfate sodium induced colitis TC/UC/US and CPU/China Identification of potential anticancer compounds from Oplopanax horridus TC/UC/US and CPU/China Chemopreventive effects of oplopantriol A, a novel compound isolated from Oplopanax horridus on colorectal cancer TC/UC/US and CPU/China Anticancer compound oplopantriol A kills cancer cells through inducing ER stress and BH3 proteins Bim and Noxa MSKCC/US and SUT/China Safety and pharmacokinetic trial of docetaxel plus an astragalus-based herbal formula for patients with non–small- cell lung cancer Abbreviations: AMP, 59 adenosine monophosphate-activated protein; AMPK, 59 adenosine monophosphate-activated protein kinase; CAS, CAMS/China: China Academy of Sciences, China Academy of Medical Sciences, China; CI/CACMS/China: Cancer Institute, China Academy of Chinese Medical Sciences, China; CI/CAMS/China: Cancer Institute, China Academy of Medical Sciences, China; CPU/China: China Pharmacology University, China; DP/Yale U/US: Department of Pharmacology, Yale University, United States; DS/WUSM/US: Department of Surgery, Washington University School of Medicine, United States; ER, endoplasmic reticulum; IDIS/ML/NIH/US: Infectious Disease and Immunogenetics Section, Clinical Center, National Institutes of Health, United States; LCP/NCI/US: Laboratory of Cancer Preventions, National Cancer Institute, United States; LMI/NCI/US: Laboratory of Molecular Immunoregulation, National Cancer Institute, United States; MSKCC/US: Memorial Sloan Kettering Cancer Center, United States; NPB/NCI/US: Natural Products Branch, National Cancer Institute, United States; SUT/China, Shanghai University of Traditional Chinese Medicine, China; TC/UC/US: Tang Center, University of Chicago, United States; TRPV1, transient receptor potential cation channel subfamily V member 1. promising therapies from CM for cancer treat- hospitals to work effectively with industry to ment and management? What are the mecha- carefully study the clinical utility of CM herbal nisms of action of these promising therapies? therapies in cancer management? How can this information help in optimally com- MEETING PROCEEDINGS bining these therapies with conventional Western Bridging CM and Modern Biomedicine biomedical approaches? How can these ap- proaches be standardized (eg, plant sourcing Jie Li, MD, PhD, and Hongsheng Lin, MD, from and content analysis) so that they provide con- Cancer Institute, CACMS, highlighted one of the sistent effects and are optimized (eg, dose and main differences between CM and Western on- schedule) to provide maximal benefit? What is cology: CM focuses on comprehensively adjusting necessary for academic centers and research the internal environment of the body, whereas the 816 Volume 3, Issue 6, December 2017 jgo.org JGO – JournalofGlobal Oncology general goal of Western cancer treatment is to treat decoction) for patients with stage II and III colon the tumor alone. CM uses a clinical assessment cancer, one arm of the study in China and one in process that differs greatly from modern Western Norway. The trial is testing if the use of a CM medicine. The CM diagnostic approach defines herbal formula after radical surgery and conven- specific body types or constitutions, such as Chi tional chemotherapy/radiotherapy could reduce (or Qi) deficient. What are the molecular pathways the rate of recurrence and metastasis and prolong associated with specific diagnosis patterns? With the overall survival time. modern technologies, there are opportunities to Dose finding may also be different for herbal examine the molecular biology underlying CM formulas than for other pharmaceuticals. For ex- diagnoses. Researchers could potentially explore ample, in one trial discussed by participants, the the genetic background for those types with suf- highest dose did not provide the best response. ficient sample sizes. Also, in CM, practitioners can use different herbs for the same goals—the concept of same disease, Recent Clinical Research of Chinese Botanical different medicine. One formula may not work Medicines for everyone with the same tumor type. CM is a Stephen Lam, MD, discussed a series of phase I complex intervention system, including herbs, and phase II cancer trials of botanical drugs, co- diet, exercise, and other components. Some par- ordinated by his group at the British Columbia ticipants expressed concern that when you re- Cancer Agency and performed in Canada and duce the system to its components to simplify the United States. The drugs his group has the research study design, you have the potential tested included the multi-herb agents ACAPHA to reduce efficacy. (also known as antitumor B or Zeng Sheng-ping 9,17,18 19 20,21 Pian), Aneustat, myoinositol, and Nagi Kumar, MD, of the Moffitt Cancer Center at the green tea extract Polyphenon E. All botanicals the University of South Florida overviewed the used in the presented trials were manufactured literature and her own research showing that under good manufacturing practices, with careful botanicals can influence multiple biochemical standardization. In general, although the safety cascades leading to inhibition of mutagenesis profile in these trials was good, as stand-alone and proliferation, induction of apoptosis, and sup- agents these botanical drugs to date have shown pression of formation and growth of human can- only modest effects for chemoprevention of cancer. cers, with a significantly superior safety profile compared with most agents evaluated to date. Jie Li, MD, PhD, and Hongsheng Lin, MD, pre- Kumar presented a systematic approach to accel- sented promising data on CM applications for can- 6,22-29 erate development of CM and discussed the cer treatment and symptom management. In ABCDEs (Agent, Biomarkers, Cohorts for testing, an ongoing randomized trial, an herbal medicinal Design, and End points) of evaluating compounds/ cream is being studied for the treatment of hand- herbal mixtures for cancer prevention and treat- foot syndrome among patients being treated with ment. Factors to consider when evaluating CM/ the chemotherapeutic agent capecitabine. Early herbal mixture include ADME (absorption, distri- results showed significant improvements in bution, metabolism, and excretion) properties and pain and restricted mobility caused by epider- profiles; toxicity; risk/benefit ratio; dose, route, mal growth factor receptor inhibitor–related schedule, and half-life; whole compounds or mix- skin toxicity. tures versus single agents; and standardization Issues of Trial Design and Monitoring With CM and quality control. Chemoprevention biomarkers for a trial should be identified early, clinically In China, CM practitioners see a large number of relevant, and modulated by a given therapy; they patients, but the treatment efficacy has not been should reliably estimate the end point of in- well documented in a standardized way. Meeting terest and have accuracy in predicting a spe- participants discussed a need among the CM 34-36 cific cancer. programs in China for research capacity building and for improving the quality of clinical trials. Lizhu Lin, MD, of the First Affiliated Hospital of Guangzhou University of Chinese Medicine, An outstanding question is whether using thera- highlighted current issues with published clin- pies selected based on a patient’s CM diagnosis 29 37-41 makes a difference in outcomes. A clinical trial is ical trials of CM for cancer. In a search of currently underway to examine the potential ben- ClinicalTrials.gov and Chinese Clinical Trial efit of adjuvant therapy with two herbal formulas Register, 42 registered trials with published (Si Jun Zi decoction and Liu Wei Di Huang results between 2008 and 2014 were identified. 817 Volume 3, Issue 6, December 2017 jgo.org JGO – JournalofGlobal Oncology Most of these reports failed to properly docu- from medicinal plants, purification of the mixture ment the CM diagnosis according to disease and into single molecules is not required (but partial syndrome differentiation. Only four (9.5%) of the purification is encouraged), and identification of study protocols mentioned syndrome classifica- active constituents is not essential. Experiences tion and a description of the CM diagnosis. Only from prior human use may substitute for some of two (4.8%) mentioned a blinded design, no the animal toxicology studies to support the safety study included sample size calculation, and of early-phase clinical trials. With extensive human no study performed an intention-to-treat analy- experience to be reviewed as adequate to support sis. Measures to ensure patient compliance and safety, nonclinical evaluations may be reduced or quality control of the study drug were inade- delayed until when the phase III trials are planned. quate. For clinical trials of CM on cancer in With a well-documented history of prior human China, Lin indicated that the following are use, most of the botanicals can advance directly to needed: integration of national resources of clin- single-dose or multiple-dose phase II trials. Ade- ical research centers to build the capacity of quate and well-controlled trials are necessary for multiagency cooperation and to use big data to marketing CM and other herbal products as bo- explore the efficacy of CM on cancer, identi- tanical drugs in the United States. When late- fication of the most important clinical opportu- phase clinical studies are being considered to nities for the use of CM for treatment of common demonstrate the clinical safety and efficacy of cancers, and selection of the most appropriate the botanical products for an NDA, the FDA re- therapeutic outcome measures. Measures of quires the same level of clinical efficacy/safety quality of life may be particularly important in requirements as nonbotanical drugs for new drug such trials. On the topic of improving the stan- market approvals. Because botanicals are com- dards of randomized controlled trials for CM, plex mixtures, multiple-dose and multiple-batch several participants stressed the importance of phase III clinical trials can be useful tools to extending the CONSORT statement to herbal demonstrate consistency of the botanical prod- medicine trials. ucts, when practical. Dou highlighted two case studies of botanical products that received FDA Quality Control and Standardization of Chinese approval as NDAs in the past decade. The first Botanical Medicines was the topical agent Veregen from MediGene (Planegg/Martinsried, Germany), for treating In a panel session, participants discussed how genital/perianal warts (investigational new drug ensuring the quality of CM products and the in 1996). The active ingredient is a partially puri- consistency between batches is a complex issue, fied green tea extract, mainly catechins. The NDA because of regional and seasonal variations in the for Veregen was approved in 2006. The second chemical composition of many herbs. Large com- example was the oral agent Fulyzaq (crofelemer) panies with steady cash flow are in a position to for HIV-related diarrhea. The botanical raw mate- develop high-quality study agents, and the ques- rial for producing the drug substance (crofelemer) tion was posed whether large Chinese companies is crude plant latex from a South American plant would want to partner with investigators in the species, Croton lechleri (commonly known as United States and elsewhere to research these dragon’s blood). The NDA sponsor of Fulyzaq products. Such companies have the financial re- was Salix Pharmaceuticals (Raleigh, NC), and it sources but may not be familiar with international was approved in 2012. Lessons learned from the regulatory requirements. A consortium could serve as a conduit for these types of research two botanical NDAs include that botanical raw collaborations to study herbal products from the material controls are required, with adoption of CM pharmacopeia. good agriculture and collection practices, and that specifications for drug substance/product are US Regulatory Issues for Botanical Medicines acceptable for chemical batch equivalence, but alone may be inadequate; non–Chemistry Jinhui Dou, MD, a pharmacologist from Botanical Manufacturing and Controls data (eg, bioassays) Review Team, Center for Drug Evaluation and may be needed to ensure therapeutic consistency. Research, of the US Food and Drug Administra- tion (FDA), presented on further development of Working With Other CM–Related Organizations herbal medicines as FDA-approved new botanical drug products through investigational new drug Lixing Lao, MD, PhD, Director of the School of application and new drug application (NDA) Chinese Medicine, University of Hong Kong, intro- 45,46 processes. For developing a botanical drug duced an existing consortium for which he serves 818 Volume 3, Issue 6, December 2017 jgo.org JGO – JournalofGlobal Oncology as the secretary general, which brings together similar to a grant mechanism, but it requires CM and Western medicine researchers and prac- participation by NIH staff. Additional outside fund- titioners: The Consortium for Globalization of Chi- ing is allowed, as long as there is no overlap in nese Medicine (CGCM), founded in 2003. It how the funding is used. A center of excellence currently has 144 institutional members and 18 was proposed as another potential organizational industrial affiliate members. The CGCM has also structure. At the NIH these centers are often spawned an offshoot, the Good Practice in CM supported by P50 grants. The potential also Research Association, launched in April 2012 in exists to organize a consortium with multiple net- the Netherlands. The meeting participants be- works of activities and different levels of funding or lieved that the CGCM has a good system for even involve some industry partners, so the con- recruiting academic institutions and industry sortium would not be defined or restricted by its and that lessons could be learned from the funding. Regarding the work of the consortium, CGCM in how to establish this new consortium participants suggested that a registry project may in a stable way. The CGCM focuses on all as- be a good start for establishing a structure for pects of CM; therefore, collaborations focused collaboration; this is how the Academic Consor- purely on CM and cancer treatment have the tium for Integrative Medicine and Health began. potential to add value to both CGCM and the Future Directions emergent ICCMC. The participants gave some possible early project Consortium Funding Mechanisms and Structures suggestions, including developing exemplary Roy Wu, PhD, Chief of the Clinical Grants and guidelines for CM oncology clinical trials, devel- Contracts Branch of NCI’s Division of Cancer oping standard treatment protocols and evalua- Treatment and Diagnosis, presented potential tion procedures (like National Comprehensive funding models for a consortium. He stressed that Cancer Network guidelines), and creating educa- the ideal consortium structure will depend on what tional exchanges to find common ground and participants want to accomplish, but a secondary develop research capacity. The sentiment that it issue will be the type of funding pursued, because is time to solidly act, not just talk, was expressed by certain types of government grants require certain many participants. Pick a smaller, straightforward organizational structures. Among the possible project and use that to establish collaborative funding mechanisms for a consortium is the working relationships and figure out what may NIH Cooperative Agreement program (U01). This and may not work for a consortium. Levels of mechanism has been used to support various complexity can be added as the collaborations types of clinical trials networks, as exemplified grow and mature. The first meeting of the consor- by the existing Cancer Immunotherapy Network, tium was planned and held on October 16 to 18, Blood and Marrow Transplant Clinical Trials 2015 in Dalian, China. Network, and Experimental Therapeutics Clini- DOI: https://doi.org/10.1200/JGO.2016.005710 cal Trial Network. The cooperative agreement is Published online on jgo.org on September 7, 2016. AUTHOR CONTRIBUTIONS Libin Jia No relationship to disclose Provision of study materials or patients: Hongsheng Lin, Jie Li Manuscript writing: All authors Roy S. Wu Final approval of manuscript: All authors No relationship to disclose Stephen Lam AUTHORS’ DISCLOSURES OF Honoraria: CSA Medical, Exact Sciences POTENTIAL CONFLICTS OF INTEREST Consulting or Advisory Role: CSA Medical, Exact Sciences The following represents disclosure information provided by Research Funding: Qu Biologics (Inst), AstraZeneca (Inst) authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I 5 Jie Li Immediate Family Member, Inst 5 My Institution. Relation- No relationship to disclose ships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, Jinhui Dou please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. No relationship to disclose Jeffrey D. White Nagi Kumar No relationship to disclose No relationship to disclose Hongsheng Lin Lizhu Lin No relationship to disclose No relationship to disclose 819 Volume 3, Issue 6, December 2017 jgo.org JGO – JournalofGlobal Oncology Lixing Lao Other meeting participants: Joost J. Oppenheim, De Yang, John A. Beutler (Center for Cancer Research, National No relationship to disclose Cancer Institute, MD), Paul M. Coates (Office of Dietary ACKNOWLEDGMENT Supplements, National Institutes of Health, MD), O.M. The authors thank the panelists and panel chairs who Zack Howard (Center for Scientific Review, National contributed to the meeting: Brian Berman (University of Institutes of Health, MD), Laura Lee Johnson, Sau Larry Maryland, MD), Ping Ping Li (Peking University Cancer Lee, Charles G. Wu (Center for Drug Evaluation and Hospital, People’s Republic of China), Yun Yen (Taipei Research,USFoodand Drug Administration,MD),David Medical University, Taiwan), Wei Hou (Cancer Institute, Newman, Michael Sachs (Division of Cancer Treatment China Academy of Chinese Medical Sciences, People’s and Diagnosis, National Cancer Institute, MD), Choi, Republic of China), Luming Liu (Fudan University Rak-Won (College of Oriental Medicine, Daejeon Shanghai Cancer Center, People’s Republic of China), University, Republic of Korea), Li Fu (Dalian Fusheng Shiuan Chen (City of Hope, CA), Peiying Yang (University Institute of Natural Medicine Development, Dalian, of Texas Anderson Cancer Center, TX), Yufei Yang People’s Republic of China), Jongmin Kim (East-West (Xiyan Hospital, China Academy of Chinese Medical Cancer Center, Dunsan Korean Medical Hospital of Sciences, People’s Republic of China), Yingjie Jia (First Daejeon University, Republic of Korea), Anping Li, Rongli Teaching Hospital of Tianjin University of TCM, People’s You (Shanxi Zhendong Pharmaceutical, Shanxi, People’s Republic of China), Guangru Xie (Tianjin Cancer Hospital, Republic of China), Huizheng Li (Unitech Medical, People’s Republic of China), Daniel Weber (Panaxea Minneapolis, MN), Jie Liu, Yong Li, Zhizheng Zhao (Cancer International, Australia), David Adelson (University of Institute of China Academy of Chinese Medical Sciences, Adelaide, Australia), Edward Chu (University of Pittsburgh, Beijing, People’s Republic of China), Ji-Wei Liu (1st PA), Gary Deng (Memorial Sloan Kettering Cancer Center, Affiliated Hospital of Dalian Medical University, Dalian, NY), Xiao-Ou Shu (Vanderbilt University, TN), Jianping People’s Republic of China), Xiaojiang Li (Tianjin Liu (Beijing University of Chinese Medicine, People’s University of Traditional Chinese Medicine, Tianjin, Republic of China), Dongfeng Yin (Affiliated Hospital of People’s Republic of China), Zongwei Wang (Massachusetts Liao Ning University of Traditional Chinese Medicine, General Hospital, Harvard Medical School, Boston, MA), and People’s Republic of China), Ling Xu (Shanghai Farah Zia, Oluwadamilola Olaku, Dan Xi, Avraham Rasooly, Longhua Hospital, People’s Republic of China), Hwaseung Christina Armstrong, and Manda Fordyce (Office of Cancer Yoo (East-West Cancer Center, Daejeon University, Complementary and Alternative Medicine, Division of Cancer Republic of Korea). Treatment and Diagnosis, National Cancer Institute, MD). Affiliations Jeffrey D. White, Libin Jia, and Roy S. Wu, National Cancer Institute, Rockville; Jinhui Dou, Food and Drug Administration, Silver Spring, MD; Hongsheng Lin and Jie Li, China Academy of Chinese Medical Sciences, Beijing; Lizhu Lin, First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou; Lixing Lao, The University of Hong Kong, Pokfulam, Hong Kong, Special Administrative Region, People’s Republic of China; Stephen Lam, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; and Nagi Kumar, Moffitt Cancer Center, University of South Florida, Tampa, FL. REFERENCES 1. Lu H, Yang Y, Gad E, et al: Polysaccharide krestin is a novel TLR2 agonist that mediates inhibition of tumor growth via stimulation of CD8 T cells and NK cells. Clin Cancer Res 17:67-76, 2011 2. 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Journal

Journal of Global OncologyWolters Kluwer Health

Published: Aug 31, 2016

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