Abstract
In the absence of curative therapies, treatment of metastatic castrate-resistant prostate cancer (mCRPC) using currently available drugs can be improved by integrating evolutionary principles that govern proliferation of resistant subpopulations into current treatment protocols. Here we develop what is coined as an ‘evolutionary stable therapy’, within the context of the mathematical model that has been used to inform the first adaptive therapy clinical trial of mCRPC. The objective of this therapy is to maintain a stable polymorphic tumor heterogeneity of sensitive and resistant cells to therapy in order to prolong treatment efficacy and progression free survival. Optimal control analysis shows that an increasing dose titration protocol, a very common clinical dosing process, can achieve tumor stabilization for a wide range of potential initial tumor compositions and volumes. Furthermore, larger tumor volumes may counter intuitively be more likely to be stabilized if sensitive cells dominate the tumor composition at time of initial treatment, suggesting a delay of initial treatment could prove beneficial. While it remains uncertain if metastatic disease in humans has the properties that allow it to be truly stabilized, the benefits of a dose titration protocol warrant additional pre-clinical and clinical investigations.
Highlights
While the search for truly curative therapies continues, there is some evidence that patient outcomes can be improved using currently available therapies by integrating evolutionary principles that govern
Early preclinical in-vivo studies of adaptive therapy in OVCAR xenografts treated with carboplatin, and in MDA-MB-231/luc triple-negative and MCF7 estrogen receptor–positive (ER+) breast cancers treated with paclitaxel showed the ability to stabilize tumor volume, though the underlying subpopulations were not explicitly measured [32, 33]
Polymorphic stability in heterogeneous tumor cell populations has been shown to exist explicitly in breast cancer and neuroendocrine pancreatic cancer in-vitro [34, 35]. If these stable equilibria exist, the clinically relevant question is how can we use currently available drugs to arrive at these equilibria? The ‘evolutionary stable therapies’ attempt to maintain a stable polymorphic tumor composition of cells sensitive and resistant to therapy, in order to prolong treatment efficacy and progression free survival [36, 37]
Summary
Early preclinical in-vivo studies of adaptive therapy in OVCAR xenografts treated with carboplatin, and in MDA-MB-231/luc triple-negative and MCF7 estrogen receptor–positive (ER+) breast cancers treated with paclitaxel showed the ability to stabilize tumor volume, though the underlying subpopulations were not explicitly measured [32, 33] In both of these studies, once initial tumor volume control using the maximum tolerable dose was achieved, it could be maintained with progressively smaller drug doses, suggestive of a stable equilibria. Polymorphic stability in heterogeneous tumor cell populations has been shown to exist explicitly in breast cancer and neuroendocrine pancreatic cancer in-vitro [34, 35] If these stable equilibria exist, the clinically relevant question is how can we use currently available drugs to arrive at these equilibria? The clinical and psychological implications of this new strategy are discussed
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