The main barrier to effective treatment of many types of solid tumors is heterogeneity and genetic instability of cancer. The efforts to investigate such phenomenon revealed that the tumors that were heavily pretreated showed higher heterogeneity through the process of selective pressure or selective advantage of untreated colonies. It was also later demonstrated that the tumor stroma or microenvironment can also affect the so called selective pressure. Primarily it had been hypothesized that targeting angiogenesis could modify the selective pressure from the cytotoxic therapy or the influence of microenvironment.The process that controls tumor and microenvironment cross-talk, resulting in new blood vessel formation, is a dynamic process and is regulated by hypoxia and epigenetic regulation of its upstream targets. As a result, research around the epigenetic regulators of hypoxia response targets involved with the process of angiogenesis seems very relevant, as it bridges the gap between the tumor behavior and its genomic variability and signature.
Here we discuss the epigenetic regulations of hypoxia and its genomic transcription, the key mechanisms involved with heterogeneity of the tumor and cancer stem cell plasticity. In our subset of patients, circulatory DNA is suggested as a biomarker for heterogeneity of the tumor, and can be used to correlate with clinical outcome.
We present a summary of one hundred cases of advanced disease. We present four cases in detail of patients with advanced, Stage IV, heterogenous disease, who were treated using this novel epigenetic therapy. This protocol, called multi targeted epigenetic therapy (MTET), resulted in an independent “antiangiogenic response” identified by disseminated circulatory tumor cells and circulatory DNA analysis, and translated to improved progression free, or overall survival. We follow plasma VEGF as a biomarker for vasculogenesis, and circulatory tumor cell and circulatory DNA assays, as a biomarker for tumor heterogeneity.
We conclude that this sample, although small, presents considerable effect size and can impact the current practice of oncology by providing better prognostic and therapeutic tools in refractory heterogeneous disease, through regulation of the epigenome.
Clinical trial identification
M.A. Nezami, A. Gould-Simon, S. Hager, D. Stobbe: Advisory board member.