As it stands, there is at least one promising model of combination therapy for an advanced cancer that makes use of repurposed pharmaceuticals aimed at several molecular targets1. CUSP9 is a treatment protocol for recurrent glioblastoma that uses several repurposed pharmaceuticals (all widely approved by regulatory authorities and marketed for non-cancer indications). Each drug is known to inhibit one or more important growth-enhancing pathways used by glioblastoma, so the combination is intended to complement temozolomide (the cytotoxic drug used in primary glioblastoma treatment) and make treatment more effective.
Natural health products (NHPs) are also being used to support cancer therapy but not with the same sort of sophistication. Many of the drugs approved for cancer therapy by the US Food and Drug Administration (FDA) have been derived from plants, including taxanes (e.g., paclitaxel) and vinca alkaloids (e.g., vinblastine). In fact, of the 98 new small-molecule anticancer drugs that were approved by the FDA between 1981 and 2010, only 20 were synthetic; the remaining 78 were either natural products (11/78) or derived from natural products (67/78)2. However, the lack of patentability of many natural products makes funding for clinical trials particularly challenging.
Without the monopoly protection of a patent, most manufacturers don’t have enough margin and sales volume to warrant the support for clinical trials. Historically some funding for trials of individual natural products has come from the National Center for Complementary and Integrative Health (NCCIH), the American Society of Clinical Oncology (ASCO), and from individual cancer foundations3. Trials using single-agent interventions with common dietary supplements have failed to produce the kinds of outcomes needed, but evidence continues to accumulate that supports the mechanistic potential of many NHPs and their potential relevance for cancer, so combinations of NHPs are still a promising way forward4-6. There are many instances of promising phase 2 trials, but these trials are often not followed up by phase 3 trials, which is likely because the manufacturers see positive phase 2 trial outcomes as being sufficient for product promotion (without having to fund a randomized, placebo-controlled phase 3 trial)3. As a result the FDA has not yet approved any dietary supplement or food to prevent cancer, halt the growth of cancer, or prevent cancer recurrence3.
The formal use of NHPs in conjunction with conventional treatment is referred to as integrative oncology7 and there are many practitioners that fall into this category. In general, the most common integrative oncology modality of interest to cancer patients relates to NHPs as complementary therapeutics to arrest their cancer7. However, the evidence base is much stronger for the treatment of cancer-related symptoms (e.g., acupuncture for nausea, exercise for sleep, anxiety etc.), so in many clinics the patient’s interests are often not aligned with the complementary support that is available7. Also, even though integrative oncology programs in many clinics now offer nutritional counseling, meditation, lifestyle alterations, reflexology, acupuncture, homeopathy, etc. (to support cancer patients and improve outcomes), the scientific evidence supporting these complementary practices is not always strong, so even these practices have had considerable critique8-10.
Nonetheless, a recent survey of clinics in Washington State used data provided by oncology board certified Fellows of the American Board of Naturopathic Oncology to show that more than 72 oral or topical, nutritional, botanical, fungal and bacterial-based medicines had been used during the first year of care of the female breast cancer patients studied (n=324)11. This gives a sense of the number of NHPs used in the clinic to complement conventional treatment, but how these supplements are selected and combined varies considerably by practitioner. While physicians engaged in Integrative Medicine and Functional Medicine are accustomed to treating patients diagnosed with cancer utilizing multiple NHP supplements and (some) pharmaceutical medications, most physicians remain largely unfamiliar with cancer molecular signaling pathways and networks (c.f Gray et al.12), so their choices are not being guided by the best science available.
Consequently, genomic and proteomic assessments are currently not being used to greatest anti-cancer clinical potential, because typically only one high priority target is used and that is only when FDA approved therapies exist for that particular target and that particular cancer type. This is not antagonistic criticism of the way in which we approve individual cancer therapies. Rather it simply shows how our reliance on individual therapies for specific cancer types is now out of step with our understanding of what we know is needed to tackle the complexity of the disease biology found in many advanced cancers.
Despite these limitations, the use of NHPs among cancer patients is widespread, with 20-90% of them using supplements – yet roughly half of them do not share this detail with their treating physician (because they feel their physicians are not knowledgeable, or will be indifferent or negative toward their use)13,14. Recognizing that the majority of patients undergoing cancer therapy now use NHPs (many without consulting their physician), the Clinical Practice Committee of The Society of Integrative Oncology, which consists of leading researchers and clinicians who have experience in using supplements, recently developed a list of useful supplements for physicians. They provided basic information, such as evidence on effectiveness, clinical trials, adverse effects, and interactions with medications to give physicians and other health care providers up-to-date information so they could discuss realistic expectations, potential benefits and risks associated with these supplements. The list included curcumin, glutamine, vitamin D, maitake mushrooms, fish oil, green tea, milk thistle, astragalus, melatonin, and probiotics15. However, while this is certainly important information to share, given that most patients and most physicians don’t have a detailed understanding of cancer biology, it just doesn’t move us far enough in the right direction to capitalize on the therapeutic potential that a broad-spectrum methodology should be able to deliver.
In some ways, it is ironic that we are at a juncture where our rigorous approach to developing the very best individual therapies, is constraining our ability to approach treatment in the manner that is needed. Cancer chemotherapy began with crude cytotoxic therapies and has evolved to targeted therapies (once we began to understand the biology of the disease) and now the push is towards precision medicine, which uses more advanced diagnostics (e.g., next-generation sequencing technologies) to look for changes in tumor DNA, RNA and proteins. This precision gives the clinician the ability to improve the selection of therapies which target particular molecular abnormalities16, which is an appealing concept in principal but it is particularly difficult to implement in advanced cancer.
For example, in metastatic breast cancer, the identification of driver mutational events is a major clinical challenge. The field remains largely focused on single targets and once the canonical targets for a given cancer (e.g. in this case ER, HER2, PIK3CA and AKT1) are exhausted, finding additional oncogenic “drivers” is difficult17. This is a profound challenge that we face in most advanced cancers. The Halifax Project taskforce that focused on this problem envisioned that we could solve this issue by using a wide range of targets that are key to disabling the mechanisms of the hallmarks of cancer. This takes the emphasis away from finding oncogenic drivers and instead focuses on key events that could disrupt the many inter-related networks and signaling pathways that enable all aspects of cellular immortalization. So we have a conceptual approach to solve the problem, but how do we now reach many targets simultaneously (when we have a limited set of individual therapies approved for cancer treatment in any given cancer type)?
The solution that was articulated in the Halifax Project suggests a focus on NHPs, repurposed pharmaceuticals, and other chemicals that are readily available, well tolerated and known to have the sort of mechanistic anti-cancer potential that is needed for the targets which are relevant in any given cancer type. This sort of a broad-spectrum methodology would better exploit genomic and proteomic assessments because clinicians could aim to reach a much greater number of relevant targets simultaneously. On an individual case-by-case basis, this will involve the identification and selection of relevant therapeutic targets and options (i.e., relevant re-purposed pharmaceuticals and NHPs that have potential to reach the targets which are relevant for a given cancer) and it would be constrained by the practical availability of the various pharmaceuticals and NHPs of interest.
The heterogeneity that exists in most advanced cancers outstrips the capabilities of many approved therapies, so it demands a much more robust therapeutic solution and this is a problem of significant proportions. Yet the development of this sort of a protocol is simply not going to be possible in most clinics without expert support because most physicians don’t have the training to understand how NHPs and repurposed pharmaceuticals might be combined for greatest effect. Some oncologists might have the requisite knowledge but most won’t be willing and/or able (due to medical-legal restrictions) to implement therapeutic options beyond the existing standard-of-care. By contrast, there are functional and integrative medicine physicians who would be willing and able to implement multi-agent therapeutics aimed at a broad-spectrum of targets (i.e., in support of, and in addition to, conventional FDA-approved cancer treatments), but most won’t have the knowledge to develop such a protocol.
For this reason the Broadspec project has been initiated. Our goal is to demonstrate that the use of a broad-spectrum method will produce unique protocols for each cancer patient that will improve their overall chance of achieving cancer control and remission, significantly improve their quality of life and significantly extend their duration of survival compared to similar patients undergoing only conventional therapy and not supported by this method. This possibility is well-supported conceptually but it has not yet been demonstrated in systematic clinical research.
To that end, we intend to organize and assist functional integrative medicine physicians who are willing and able to implement multi-agent therapeutics in addition to, conventional FDA-approved cancer treatments administered by patients’ medical oncologists and radiation oncologists. This will bring rigor to the manner in which repurposed pharmaceuticals and NHP supplements are administered to cancer patients in their practice, because we will help these physicians develop safe, personalized, broad-spectrum precision medicine protocols optimally designed for their individual patients. Initially, this assistance will be offered to a very small number of physicians who are treating or supporting cancer patients across several cancer types. As positive outcomes in these individual case-studies are demonstrated, a greater number of cases will be considered.
- Kast RE, Karpel-Massler G, Halatsch ME. CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide. Oncotarget. 2014;5(18):8052-8082.
- Newman DJ, Cragg GM. Natural products as sources of new drugs over the 30 years from 1981 to 2010. Journal of natural products. 2012;75(3):311-335.
- Paller CJ, Denmeade SR, Carducci MA. Challenges of conducting clinical trials of natural products to combat cancer. Clinical advances in hematology & oncology : H&O. 2016;14(6):447-455.
- Shukla Y, George J. Combinatorial strategies employing nutraceuticals for cancer development. Annals of the New York Academy of Sciences. 2011;1229:162-175.
- Safe S, Kasiappan R. Natural Products as Mechanism-based Anticancer Agents: Sp Transcription Factors as Targets. Phytotherapy research : PTR. 2016;30(11):1723-1732.
- Shanmugam MK, Lee JH, Chai EZ, et al. Cancer prevention and therapy through the modulation of transcription factors by bioactive natural compounds. Semin Cancer Biol. 2016;40-41:35-47.
- Lopez G, McQuade J, Cohen L, et al. Integrative Oncology Physician Consultations at a Comprehensive Cancer Center: Analysis of Demographic, Clinical and Patient Reported Outcomes. Journal of Cancer. 2017;8(3):395-402.
- Gorski DH. Integrative oncology: really the best of both worlds? Nat Rev Cancer. 2014;14(10).
- Greenlee H, Zick SM, Rosenthal D, Cohen L, Cassileth B, Tripathy D. Integrative oncology – strong science is needed for better patient care. Nat Rev Cancer. 2015;15(3):165.
- Gorski DH. Integrative oncology – strong science is needed for better patient care. Nat Rev Cancer. 2015;15(3):165.
- Standish LJ, Dowd F, Sweet E, et al. Breast Cancer Integrative Oncology Care and Its Costs. Integrative cancer therapies. 2016.
- Gray SW, Hicks-Courant K, Cronin A, Rollins BJ, Weeks JC. Physicians’ attitudes about multiplex tumor genomic testing. J Clin Oncol. 2014;32(13):1317-1323.
- Frenkel M, Sierpina V. The use of dietary supplements in oncology. Curr Oncol Rep. 2014;16(11):411.
- Le TQ, Smith L, Harnett J. A systematic review – Biologically-based complementary medicine use by people living with cancer – is a more clearly defined role for the pharmacist required? Res Social Adm Pharm. 2016.
- Frenkel M, Abrams DI, Ladas EJ, et al. Integrating dietary supplements into cancer care. Integrative cancer therapies. 2013;12(5):369-384.
- Abrams J, Conley B, Mooney M, et al. National Cancer Institute’s Precision Medicine Initiatives for the new National Clinical Trials Network. American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting. 2014:71-76.
- Arnedos M, Vicier C, Loi S, et al. Precision medicine for metastatic breast cancer–limitations and solutions. Nature reviews. Clinical oncology. 2015;12(12):693-704.