Abstract
In this paper we discuss the rationale of applying a “sequential” targeted therapy with a specific application in clinical practice, given our understanding of cancer heterogenous and dynamic biology. We explore the advantages of “single inhibition” to combinational therapies and dual inhibition on key pathways, as well as a multi-step approach to use “oncological addiction” and “oncogenic shock” as a suicide plan for cancer. We specifically explain how the downstream targets can be used to “create” feedback loops in an advantage for creating actionable targets in upstream signaling molecules. We apply this hypothesis in the clinical setting, with superior outcomes shown in a series of case studies. We conclude that “sequential and dual inhibition” can be considered a meaningful approach to checkmate the tumor, with minimum chance of tumor resistance. We recommend further clinical studies to generate further hypotheses based on each actionable target.
Highlights
It is well described in the literature that oncogenic driver events decisively influence the viability and clinical behavior of a given tumor [1]
We explore the advantages of “single inhibition” to combinational therapies and dual inhibition on key pathways, as well as a multi-step approach to use “oncological addiction” and “oncogenic shock” as a suicide plan for cancer
Tumor cells mainly grow when there is over expression, augmentation, or activation of mutations present in two key pathways: PI3k/mTOR, and EGFR/KRAS pathways
Summary
It is well described in the literature that oncogenic driver events decisively influence the viability and clinical behavior of a given tumor [1]. Our knowledge of modern sequencing of tumor DNA enables us to look at the point mutations (as well as the copy numbers, and chromosomal alterations) and has prompted us to further explore a “roadmap” to create a plan of attack based on the tumor’s driver status, and the sequential strategy of inhibition, which we discuss here in detail In this approach, instead of using combination therapy which has been claimed to improve patient outcomes, by definition, we create an oncological addiction. In our model of treatment, the initial stage of the therapy would consist of treating a target that is effectively inhibited, creating “maximum” feedback loops In this initial stage we see benefit from a biologic phenomenon described as “Genetic Streamlining” to induce addiction. This stage inhibits the driver, a process which by reversing oncogenic shock reverses the disengagement of proapoptotic safeguards
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