43-56 Pros and Cons of the Cocktail Strategy

p. 45  Many herbal treatments naturally exhibit the principle of synergy: not only are TCM herbal formulae consisting of multiple herbs synergistic among the herbs, but individual herbs contain multiple molecular components synergistic amongst themselves.  Dr. Debu Tripathy, a respected researcher in the integrative oncology field, noted that “in our experience in the laboratory … when you begin to fractionate different compounds from the herbal extract whether by size or charge, you begin to lose the [anticancer] activity. However, when you reconstitute the fractions, you regain the activity – suggesting several active compounds working in synergy” (ASCO Post Sep 15 ’11, p.28). This is a well known phenomena and is common knowledge in pharmacognosy. I recall that we had the same problem when attempting to isolate the specific anti-viral molecular components from an Indian plant to treat hepatitis B when I collaborated with Dr. Blumberg in the 1990’s, the more pure the extract became, the less biological activity remained.

p.47  Cancer cocktail to deal with treatment resistance: In Nature 449,993-996, Oct 25 2007, researcher Charles l. Sawyers from Memorial Sloan Kettering Cancer Center in New York addresses the use of cocktails against cancer resistance in a News and Views article aptly titled Cancer: Mixing cocktails. In brief, some cancers are related to primary mutations in specific protein regulatory enzyme pathways (e.g. kinases), consequently single agent kinase inhibitors (e.g. erlotinib or Tarceva for lung cancers which have a mutated kinase known as EGFR) have been used for treatment.  The tumors then “fight back” by further mutation of the targeted kinase and/or recruiting other kinases to substitute for the targeted kinases to restore function and cancer growth.  The biology of cancers and their related pathways are clever and flexible enough to rewire themselves via switching under treatment. The analogy Sawyers put forth is that an orchestra of target enzymes (in any specific pathway) contributes to disease progression, with each player making contribution, but players can also pick up slack when other enzymes are disabled by single agent therapies.  Thus a picture of multiple-target-dependent cancers arises. Because of the multilevel receptor cross-stimulation and redundant signaling pathways, and blocking one could result in others acting as salvage or escape mechanisms, the idea of blocking multiple signaling pathways with a combination of targeted agents to achieve synergistic antitumor effect is appealing. Currently, techniques for profiling tumor cell to identify these multi-target dependent cancers exists and the implication for the future is that rationally chosen target inhibitors chosen by genotype and molecular guidance applied in cocktail fashion can achieve cancer containment.

For related references on possible synergies achievable from multi-targeting, also see:

Ciardiello F, Troiani T, Bianco R, et al. Interaction between the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) pathways: a rational approach for multi-target anticancer therapy. Annals of Oncology. 2006;17(7):vii109–vii114.
Tortora G, Caputo R, Damiano V, et al. Combination of a selective cyclooxygenase-2 inhibitor with epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 and protein kinase A antisense causes cooperative antitumor and antiangiogenic effect. Clinical Cancer Research. 2003;9(4):1566–1572.
Ganslmayer M, Ocker M, Kraemer G, et al. The combination of tamoxifen and 9cis retinoic acid exerts overadditive anti-tumoral efficacy in rat hepatocellular carcinoma. Journal of Hepatology. 2004;40(6):952–956.
Ganslmayer M, Ocker M, Zopf S, et al. A quadruple therapy synergistically blocks proliferation and promotes apoptosis of hepatoma cells. Oncology reports. 2004;11(5):943–950.
Herold C, Ganslmayer M, Ocker M, et al. Overadditive anti-proliferative and pro-apoptotic effects of a combination therapy on colorectal carcinoma cells. International Journal of Oncology. 2003;23:751–756.

p. 52  Dr. Debu Tripathy, Professor of Medicine at the University of Southern California Norris Comprehensive Cancer Center, is engaged in research and trials on Chinese herbs (e.g. Ban Zhi Lian or BZL 101) against cancer, recently commented on the difficulties of obtaining proper funding for trials for botanical and other natural agents: “There are two reasons funding is difficult to obtain. First government grants are subject to peer review from scientists who come from a strictly traditional view, and they tend to be skeptical about non-standard approaches. And second, because you cannot patent these compounds, funding from the private sector is equally difficult to obtain. Consequently, most of the research in this area has been limited to very small pilot studies , which may indicate safety but are just too small to prove efficacy.” (See Piana, R. Integrative Oncology Modalities Supported by Varying Levels of Evidence, but More Research Needed Overall”, ASCO Post Sep 15 ’11,  p.28)

p. 52  Besides “Cons” which are arguments against a cocktailed approach, there are actual barriers of implementation even if one is for the approach.  Some of these were raised at the Institute of Medicine’s National Cancer Policy Forum workshop on “Facilitating Collaborations to Develop Combination Investigational Cancer Therapies” last summer ( A summary in pdf format downloadable here).  Although the workshop focused mainly on combinations of targeted therapies, the issues raised are valid for combinations of cancer drugs in general:

a) Business obstacles: Pharmaceutical companies have an ingrained competitive mindset as businesses generally and naturally do, and each single company usually has a single or at most a handful of potential drugs on hand: can they change from a competitive mindset to a collaborative one?

b) Regulatory obstacles: There has been increasing concern of how the US FDA would regulate testing and approvals of combinations. In response to such concerns, the FDA has developed a draft guideline for development of such combinations where base requirements of safety and efficacy applies, in addition to some unique issues; this is the FDA’s position:

* Cocktail approaches (“codevelopment”) usually provides less information about safety and efficacy, and increased risk. Therefore, should be undertaken only for difficult-to-treat diseases.

* The need to demonstrate that each component of a combination contributes to treatment effect would require large phase II and III clinical trials with multi-arm designs.

* Assurance that drugs in a combination be used only together if approved together.

c) Legal obstacles: interesting antitrust concerns were raised by Robert Leibenluft from a DC law firm “It is possible that if pharmaceutical companies, who are otherwise competitors, coordinate their activities to develop drugs, the results will be higher prices, lower quality, and reduced innovation, which could in turn have an effect on the future market for products, services, technology and innovation” (ASCO Post Sep 15 2011, p.15)

These are all interesting points that were not discussed in the book and worthy of pointing out. All in all though, the raising of issues regarding a cocktail approach is in itself a positive development, despite some practical challenges such as costs of trials, company attitudes etc not something that can be resolved overnight.

All in

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