Adaptive Therapy As Novel Treatment Strategy in Medical Oncology

adaptive therapy: adaptive therapyResistance to therapy is a major impediment in treating cancer. Resistance is generally held to arise primarily through random genetic mutations and the subsequent expansion of mutant clones via Darwinian selection. Further, current treatment protocols call for prescribing the same drugs and doses through multiple cycles. This therapeutic strategy, referred to as continuous therapy, is based on the presumption that a tumor must be eradicated quickly to thwart the evolution of resistance, and the dissemination of the evolved clones to distant locations. Ironically, however, this rationale appears an oversimplification and counterintuitive; continuous treatment at maximum dose promotes the growth of resistant populations because it both strongly selects for adapted phenotypes and eliminates all potentially competing populations. In contrast to the prevailing wisdom, recent evidence strongly suggests that non-genetic mechanisms also play an important role underscoring the genetic/non-genetic duality of drug resistance in cancer.1 Further, new developments in the field have also provided compelling evidence that drug sensitivity and resistance are not merely binary states of a cancer cell. In fact, cancer cells are highly plastic and can exhibit a continuum of multiple phenotypes including hybrid states.2 Phenotypic plasticity refers to the cancer cell's capacity to exhibit different characteristics under varied environmental conditions without involving genetic mutations. It is an adaptive strategy that requires that the population be heterogeneous despite being isogenic. Phenotypic plasticity represents an example of bet hedging, an evolutionary strategy in which an isogenic population randomly diversifies into coexisting subgroups with different phenotypes.3,4 In other words, it is able to create phenotypic heterogeneity. This not only helps improve fitness in varying environments, but also ensures that individuals primed to evade drug toxicity are present before therapy. By virtue of phenotypic plasticity, cancer cells, like bacteria, can switch on cell autonomous traits such as persistence and quorum sensing in response to stress. Persisters are slow-growing tolerant cells that can arise stochastically or in response to a trigger, and thereby give rise to tolerant cells that play a dominant role in the emergence of drug resistance. However, while persistence usually refers to a subpopulation of cells, tolerance is the general ability of the population to survive longer treatments by phenotypic rewiring. More importantly, both these states are reversible, implying a causative role for non-genetic mechanisms.5 Therefore, true resistance involves irreversible genetic alterations that enable the emergence of the resistant cells via an intermediate state of tolerant cells in the population. Thus, there appears a window of opportunity whereby a truly irreversible resistant state could be delayed, perhaps even precluded, if tumor cells are cajoled to remain in a drug-tolerant state by manipulating treatment time and dose. Indeed, new therapeutic strategies that can prolong tumor drug sensitivity appear promising, at least in some cancers such as prostate and breast cancer, are currently being evaluated in the clinic with striking success.6 In some other cancers such as lung cancer, preclinical studies also indicate that such strategies may prove successful as well.7 If so, they could have a significant impact on the recently approved KRAS-mutant inhibitors for lung cancer that are promising, but appear to encounter emergence of drug resistance.8 The underlying logic stems from the principles of ecology and evolution and is fairly simple. In the tumor microenvironment where cancer cells reside, there are many other cell types that cohabit this space. Together, these supporting cells create an ecosystem that enables the malignant cell population to grow and flourish by producing growth factors and proinflammatory cytokines to promote angiogenesis. Besides, the collective response of cancer cells in the group—group behavior—plays in an important role. Group behavior is defined as the collective actions performed by a group of individuals as a whole or by each individual when the individual is part of a group. In the latter case, group behavior refers to those actions of the individuals that are influenced by the group. They are actions that the same individuals would not perform on their own. Such processes impose costs and benefits to the participating cells that may be conveniently recast in the form of a game payoff matrix. Thus, tumor progression and dynamics can be described in terms of evolutionary game theory, which provides an elegant conceptual framework to capture the frequency-dependent nature of ecosystem dynamics. It also serves to discern the games cancer cells play by either cooperating or competing in the absence or presence of stress (selective pressure). Therefore, treatment strategies that take into account the tactics cancer cells adopt to deal with drug effects have been developed and are referred to as intermittent or adaptive therapy.9 Examples of such new treatment strategies include protocols that strategically use initial therapies to induce adaptive changes in the tumor environment in such a way that the growth of resistant clones can be markedly suppressed for prolonged periods. In this paradigm, therapy is administered in small doses to impede tumor growth just enough to improve symptoms. In other words, treatment is administered at a minimal dose necessary and not at the maximum tolerated. Furthermore, treatment is then withheld briefly (administered in alternate cycles rather than at every scheduled time and hence referred to as intermittent treatment) so that drug-sensitive cells will proliferate at the expense of the resistant ones. Although the tumor likely progresses between treatments, the extant tumor cells will continue to be sensitive to therapy and thus delay, perhaps even preclude, the onset of drug-resistant disease (Figure 1).Figure 1.: Continuous monotherapy versus intermittent combination therapy. (A) In continuous monotherapy, the idea is to eradicate the tumor as quickly as possible. However, this strategy can give rise to resistance and resistant cells are expected to propagate over time (top). By contrast, combination therapy applied intermittently (bottom) could induce “adaptive strategies” to change the tumor environment in such a way that the proliferation of resistant clones can be suppressed for prolonged periods of time. Therapy is applied in small doses to reduce the tumor population only sufficiently to improve symptoms. Furthermore, treatment is intermittent so that drug-sensitive cells will proliferate at the expense of the resistant ones. (B,C) Although the tumor will increase in size between treatments, the extant tumor cells will continue to be sensitive to therapy. Reproduced with permission from Trends in Cancer (Salgia and Kulkarni, 2018;4(2):110-118).Despite the promise and initial success of intermittent/adaptive therapy, more research is warranted to gain a deeper understanding and its broader application. For example, in one study it was observed that when a tumor is sensitive to two or more drugs, the simultaneous application of these drugs could result in the emergence of cells resistant to both therapies. However, when these drugs were applied one at a time, a subpopulation of cells were sensitive to one or the other drug, delaying the emergence of double resistant cell clones.10 On the other hand, another study demonstrated that concurrent targeting of multiple kinases that are active in lung cancer rather than the use of a single kinase inhibitor was remarkably efficient in inhibiting tumor growth (100%), presumably due to the inability of tumor cells to adapt well to the changing fitness threshold imposed by selection.11 More importantly, the latter strategy was effective only in the case of intermittent but not continuous therapy. It is obvious that multiple mechanisms regulate phenotypic switching and drug resistance, even within a given cancer type. Thus, a better understanding of the mechanisms involved is necessary before deciding a therapeutic approach. Nonetheless, these exciting developments are an embodiment of a true “team medicine” approach and expound the virtues of modern translational research. Incorporating these new treatment strategies in clinical protocols can enhance the precision with which we deliver personalized medicine to some if not all cancers at the present time. Additionally, lowering the dose of the drug and its frequency can have significant impact on lowering the toxicity and undesirable side effects of the drugs while bringing down the financial costs to the patient. SANDEEP MITTAN, PHD, is a Clinical Scientist at Montefiore Medical Center/The University Hospital for Albert Einstein College of Medicine. PRAKASH KULKARNI, PHD, is Research Professor in the Department of Medical Oncology and Therapeutics Research and the Department of Systems Biology at City of Hope National Medical Center. RAVI SALGIA, MD, PHD, is Professor and Chair in the Department of Medical Oncology and Therapeutics Research at the City of Hope National Medical Center.Sandeep Mittan, PhD: Sandeep Mittan, PhDPrakash Kulkarni, PhD: Prakash Kulkarni, PhDRavi Salgia, MD, PhD: Ravi Salgia, MD, PhD