Interview with Jan Brábek about his article in Trends in Cancer
Cell biologists from BIOCEV and King´s College declared an entirely new category of anti-cancer drugs. In a Cell Press Journal Trends in Cancer was just released a Perspective published by an international team under the guidance of Prof. Brabek (corresponding author), Prof. Rosel from the Department of Cell Biology, Charles University in Prague and BIOCEV and Prof. Sanz-Moreno from King´s College, London: MIGRASTATICS – anti-metastatic and anti-invasion drugs: promises and challenges (http://www.sciencedirect.com/science/article/pii/S2405803317300857)
In solid cancers, invasion and metastasis account for greater than 90% of mortality. However, in the current armory of anti-cancer therapies, a specific category of anti-invasion and anti-metastatic drugs is missing. The authors of the Perspective coin the term “migrastatics” for drugs interfering with all modes of cancer cell invasion and metastasis, to distinguish this class from conventional cytostatic drugs, mainly directed against cell proliferation. They define actin polymerization and contractility as target mechanisms for migrastatics, and review candidate migrastatic drugs. Critical assessment of these anti-metastatic agents is warranted, as they may define new options for the treatment of solid cancers.
Petr Solil, Head of Communications, BIOCEV: Why a novel category of anti-cancer drugs is needed?
Jan Brábek, Head of Group – Molecular and Cellular Mechanisms of Invasiveness of Tumour Cells: In solid cancers, invasion and metastasis account for greater than 90% of mortality. However, in the current armory of anti-cancer therapies, a specific category of anti-invasion and anti-metastatic drugs is missing. In our Perspective, we coin the term “migrastatics” for drugs interfering with all modes of cancer cell invasion and metastasis, to distinguish this class from conventional cytostatic drugs, mainly directed against cell proliferation. We define actin polymerization and contractility as target mechanisms for migrastatics, and review tractable drug candidates suitable for R&D. Critical assessment of these anti-metastatic agents is warranted, as they may define new options for the treatment of solid cancers.
Here we would like to give credit to all biomedical scientists, working in fields of cancer cell migration, invasiveness and metastasis, medicinal chemists, translational scientists and all people the work of which enabled us to bring up the new concept of therapy of solid cancer!
PS: Do you suggest to replace current therapy in solid cancer with migrastatic drugs?
JB: It should be emphasized that the goal here is not to replace anti-proliferative therapy, but rather complement it. In fact, synergy of migrastatics with anti-proliferative cancer drugs appears to be a promising approach for treatment of metastasis.
The interactions of migrastatics with other groups of anti-cancer drugs may offer chances for synergistic impairment of tumor cells. Migrastatics targeting actin polymerization or dynamics could be used to enhance the efficacy of physicochemical therapeutic approaches resulting in cytoskeletal perturbations such as X-radiation or sonodynamic therapy. Combination of migrastatics with other cytoskeleton targeting agents could also result in effective chemotherapeutic protocols. Since many migrastatics target cytokinesis, the combination with microtubule-directing agents interfering with mitosis would results in much more efficient inhibition of tumor cell proliferation. Cells exposed to actin dynamics targeting migrastatics exhibit significantly increased mitochondrial activity, which make them potentially more vulnerable to mitochondrial metabolism directed agents. Since tumor cells exposed to migrastatics inhibiting cytokinesis have a highly perturbed cytoskeleton due to the disruption of actin polymerization and multiple nuclei because of high proliferation rates, they could be potentially much more sensitive to DNA-directed agents. Intriguingly, the migrastatics targeting ROCK kinases could themselves possess anti-proliferative characteristics. It was shown that inhibition of both ROCK isoforms causes severe proliferation defects and blocks tumor formation in mice. Based on the evidences mentioned above, we are convinced that migrastatics could complement the current armory of clinicians, providing more comprehensive, and therefore more effective therapeutic protocols.
PS: Why you think it is better to target the downstream effector mechanisms of cancer cell invasiveness rather than upstream regulatory signaling? How about the resistance to migrastatics (vs. standard cytostatic therapy)?
JB: Signaling pathways regulating cell migration are highly redundant and inhibition of single pathways leads almost inevitably to resistance. In fact, resistance itself may explain failures in targeting key, genetically stable mechanisms, since many intracellular signaling processes are redundant or bypassable. Thus, while precise targeting of suspect pathways is possible, it is unlikely to be successful. Accordingly, we propose that migrastatics should rather target the ultimate downstream effector mechanisms of cell migration such actin polymerization and contractility, which are extremely hard to bypass. There is virtually no possibility for cancer cells to substitute actin polymerization or develop an alternative contractile apparatus. Actin polymerization and contractility satisfy the requirement for ideal migrastatics targets because these processes are required by all invasion/3D migration mechanisms irrespective of their protease-dependence. Moreover, in striking contrast to cytostatics, resistance to migrastatics even if acquired, will not give resistant cancer cell the proliferative advantage!
PS: What would you predict as the single most likely obstacle in furthering this concept to the clinic?
JB: Every silver lining has a cloud! Actually, there are three clouds here: regulatory endpoints for clinical trials in solid cancer, issues related to intellectual property, and research funding.
- Regulatory endpoints. Tumor shrinkage is the key regulatory endpoint in clinical trials in solid cancer. Even if migrastatics perform in the clinic as designed, tumor shrinkage is unlikely and they will fail to gain approval. One must keep in mind that biology is not subject to regulations; it is the other way around. We now know that tumor shrinkage does not reflect inhibition of the metastatic process or interruption of the natural history of solid cancer. In the presence of “successful” conventional therapy, progression of the disease (metastatic activity) occurs despite tumor shrinkage. Here we look to advanced imaging to devise coherent criteria efficacy that can be correctly interpreted as interruption of the natural course of the disease – antimetastasis.
- Intellectual property. In addition to the drug candidates we have reviewed, there are surely others that are available, especially in the archives of Ayurveda and Traditional Chinese Medicine. Here, intellectual property issues will be a concern, since the chemistry and pharmacological properties are in the public domain. But open competition, if successful, may likely result in lower prices and a novel pharma strategy – nonpatented new drug discovery. This strategy, though novel, is not new and characterized drug discovery for ages up to the development of penicillin and streptomycin. In the past, drug discovery was a science, not a business. Patenting constrains the use of medicinally-validated resources – natural products, and is expensive to obtain and defend.
- Research funding to universities. Pharma funds R&D on patentable drug candidates via profits from commercialization. There is minimal, if any, funding for R&D on promising but nonpatentable drug candidates. In view of the dismal record of funding towards anticancer research (especially metastasis), it may be time for a serious rethink on priorities – is the objective high prices and high profits, or improvements in patients and society’s welfare? Universities are best positioned to explore an alternative and validated approaches to drug development – why not back to the future with new and improved understanding and technology?
We propose that medicinal products derived from public domain sources and developed by nonprofit entities should not be contested. Since public domain knowledge cannot be patented, the current legal environment precludes conventional R&D studies on drug substances derived from natural products.
Fragment-based ligand and drug discovery coupled with 3D invasion models presents a huge and novel opportunity for university-based translational programs (Tashiro E, Imoto M. Chemistry and biology of the compounds that modulate cell migration. J Ind Microbiol Biotechnol 2016; 43:213–219; Erlanson DA, Fesik SW, Hubbard RE, Jahnke W, Jhoti H. Twenty years on: the impact of fragments on drug discovery. Nat Rev Drug Discovery 2016; 15: 605-619; Rodrigues T, Reker D, Schneider P, Schneider G. Counting on natural products for drug design. Nat Chem 2016; 8: 531-541; Keserű GM, Erlanson DA, Ferenczy GG, Hann MM, Murray CW, Pickett SD. Design Principles for Fragment Libraries: maximizing the value of learnings from pharma fragment-based drug discovery (FBDD) programs for use in academia. J Med Chem 2016; 59: 8189-8206; Over B, Wetzel S, Grütter C, Nakai Y, Renner S, Rauh D, Waldmann H. Natural-product-derived fragments for fragment-based ligand discovery. Nat Chem. 2013; 5: 21-28.)
Most important is the intent, and here, we find the recent report by Aggarwal and colleagues to be both relevant and timely (Do patient access schemes for high-cost cancer drugs deliver value to society? —lessons from the NHS Cancer Drugs Fund. Ann Oncol. May 2017. (doi:10.1093/annonc/mdx110)
PS: Thank you and good luck!