An interesting hypothesis in the evolutionary genetics of treating infections and cancers is that if the therapeutic agent does not directly target the pathogen or tumor, then the pathogen or tumor will be less likely to evolve resistance to that agent. While early work on inhibitors of angiogenesis as potential cancer therapeutics suggested that such treatment did not elicit resistance by the tumor cells (Boehm et al., 1997), a recent study by Conley et al. (2012) raises doubts about the reliability of this notion in the context of antiangiogenic therapy for human breast cancer.
Conley and colleagues established tumors in mice using human breast cancer cell lines by implanting the cells in the mammary fat pads of their experimental subjects. They then treated the mice with either a vehicle control or sunitinib malate, a tyrosine kinase inhibitor that targets among other molecules the receptor for vascular endothelial growth factor (VEGF). VEGF plays a role in new blood vessel formation. The sunitinib was administered either one day after tumor cell injection or when the tumor reached 4 mm in diameter.
As might have been expected on the basis of prior work, treatment at the early time point delayed tumor formation and reduced tumor growth at 70-plus days post-implantation and also inhibited development of new blood vessels. Treatment of the tumor-bearing mice at the later time point, when the tumors had reached 4 mm in diameter, also suppressed tumor growth. Treatment of tumor-bearing mice with the VEGF-inhibiting antibody, bevcizumab, elicited similar effects with respect to both inhibition of tumor growth and blood vessel development.
However, treatment of tumor-bearing mice with sunitinib or with bevacizumab also resulted in increased numbers (relatively and absolutely) of tumor cells expressing aldehyde dehydrogenase, expression of which has been associated with cells that behave like tumor stem cells. Furthermore, consistent with the preceding finding, the tumors treated with sunitinib were able to more rapidly form secondary tumors when transplanted to immunodeficient NOD/SCID mice. Sunitinib-treated tumors were also more hypoxic in comparison to tumors only exposed to vehicle and this relative hypoxia was correlated with a greater percentage of cells expressing aldehyde dehydrogenase, i.e. a greater percentage of cancer cells with stem cell-like properties.
Additional studies suggested that the effects of anti-angiogenic treatment were mediated by increased expression of hypoxia-inducible factor 1α (HIF-1α), one representative of a family of transcription factors known to mediate the effects of hypoxia. The authors also offered indirect evidence that signaling through the Akt/Wnt/β-catenin pathway was critically involved in the elicitation of the response to hypoxia in human breast cancer stem cells and following anti-angiogenic therapy of these cells.
Summarizing, while anti-angiogenic therapy initially limits tumor growth in this murine model of human breast cancer, it also has the effect of eliciting a cellular phenotype, i.e. increased numbers of tumor cells with stem cell-like properties, that can make the tumor cells grow more rapidly later if they survive the first therapeutic onslaught. The tumor cells do not become resistant to the treatment in the typical manner through mutation such that the therapeutic agent no longer affects the cells; instead they adopt a new and arguably a more aggressive phenotype that ultimately increases the threat to the host’s survival. So far as we now know, this new and more threatening phenotype arises primarily via epigenetic, not genetic, mechanisms.
Thus, contrary to the early and hopeful studies of Folkman and colleagues, even though anti-angiogenic molecules do not directly target breast cancer cells, the malignant cells can evade the desired outcome of the therapy. Conley et al. conclude that to minimize the clinical consequences of such tumor cell adaptation, therapeutic agents targeting cancer stem cells may need to be used in parallel with angiogenesis inhibitors.
In the near future, it will be interesting to watch for similar phenomena in the context of new therapeutic approaches for viruses, where it may make sense to explore inhibiting host pathways that are co-opted for virus replication. It may be overly anthropomorphic to say so, but intense selection pressure appears to bring out the creativity, or what looks like creativity, in entities capable of evolution.
References
Boehm T, Folkman J, Browder T, O’Reilly MS. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature. 1997 Nov 27;390(6658):404-7. PubMed PMID: 9389480.
Conley SJ, Gheordunescu E, Kakarala P, Newman B, Korkaya H, Heath AN, Clouthier SG, Wicha MS. Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2784-9. Epub 2012 Jan 23. PubMed PMID: 22308314; PubMed Central PMCID: PMC3286974.
Discover more from The Evolution and Medicine Review
Subscribe to get the latest posts sent to your email.
As a medical oncologist and student of evolutionary medicine, I would suggest that the premise that therapies which do not target the cancer cell directly would be less likely to induce resistance is deeply flawed from the outset, as the results of the described study illustrate. Adaptation develops, and evolution occurs, in response to changes in the environment, and anti-angiogeneic therapy, while targeting the non-malignant vascular system, is radically changing the microenvironment of the cancer cell population by inducing hypoxic stress. Therefore, not only is it not surprising that a more aggressive, hypoxia-tolerant cancer population developed, but one could argue that such therapies which exert a broad environmental change may actually be more likely to induce resistance, acting on the entire cancer cell population, as compared to therapies directed at cellular targets which may be presest in only a fraction of the cancer cell population. The more appropriate strategy, in light of the enormous adaptive potential of the cancer cell population, is to manipulate this tendency by “steering” adaptation and evolution of the population into a genetic corner, if possible, through a rationale sequencing of therapies, which may produce a bottleneck of diminished cellular diversity, more susceptible to extiniction by a final therapeutic intervention.
Dr. Audeh may be correct about the a priori case against the hypothesis put forward fifteen years ago by Boehm et al. [Nature. 1997 Nov 27;390(6658):404-7] and suggesting that angiogenesis inhibitors would not elicit cancer cell resistance, but in this instance the notion at issue was tested by experiments that, however flawed or unrepresentative in their outcomes, were published in a highly visible and highly cited research journal. Therefore, I think it was reasonable both to test cancer therapy with inhibitors of angiogenesis and to subject the hypothesis in question to further study.
The proposal to force tumor cells into a “genetic corner” is difficult to evaluate without considerably more detail, but there is good reason to doubt that any “sequence of therapies” would be the rational way to achieve the desired degree of genetic constraint on the part of the tumor cells. Typically, sequential therapies favor cancer cell or pathogen evolution in specific genetic directions that fail to provide clinical relief. The more rational and successful strategy is simultaneous treatment with multiple mechanistically-independent therapeutic agents that render the probability of resistant mutants extremely low due to the requirement for the simultaneous or nearly-simultaneous occurrence of several mutations at distinct genetic loci.
The goal of calling into question the notion of differential resistance of cancer cells versus host vascular cells was to argue for the most biologically complete application of Evolutionary Medicine to Cancer. To do so suggests that any cancer is best viewed as a population of organisms, in this case cells, seeking to survive within, and adapt to, its environment. Approached in this way, any selective pressure applied to this population, whether through direct targeting of the members of the population, or through changes in the microenvironment, such as host angiogenesis, must be expected to result in an adaptive response within the cancer cell population, otherwise known as “resistance”. One can argue as to the best method by which to subvert the adaptive response of a population of cancer cells, and taking the example of prokaryotic infectious organisms, the use of combined agents to exert selective pressure was aptly suggested by Dr Greenspan as the rational approach. This may indeed be appropriate for subverting the promethean adaptive potential of a cancer cell population as well, but the complexity of eukaryotic mammalian cell physiology, the genetic diversity within cancers, and the many possible adaptive pathways available to any cancer cell would make the construction of a comprehensively targeted therapeutic “cocktail” quite daunting, if not toxic. It may require, rather, that compatible combinations of a few targeted agents may be devised, which if not outright lethal to 100% of the cell population, will result in a population bottleneck with diminished diversity, amenable to the sequential addition of further agents targeted to the specific adaptive pathway taken. Recent reports at the America Society of Clinical Oncology in Chicago, June 1st -4, suggested in many instances that 1) combinations of two to three targeted therapies are active but not curative and 2)the genetic diversity in cancer cell populations is enormous, but finite. Both promise progress, with the appropriate application of Evolutionary Medicine to the problem of cancer.