Vascular-immuno-phenotypic (VIP) model for locally advanced and oligo-metastatic cancer: A hypothesis

Primary Hypothesis: In cancer therapy, normalization of the vasculature, and not disruption, to facilitate the reversal of the immuno-phenotypic changes, is the sine-qua-non for cancer elimination. The triad of normalization of the vasculature, leading to the improved immunological tumour microenvironment and increased susceptibility of resistant phenotypic cancer cells (VIP model), forms the basis of this hypothesis. This article hypothesizes the absolute need for vascular normalization for the eradication of cancer. Locally advanced and oligometastatic cancers have the potential to be cured with aggressive therapy. The focus on vascular normalization its clinical relevance in this situation is essential. Most traditional approaches have focused on the elimination of cancer by targeting and disrupting vasculature. Initially, antiangiogenic drugs showed significant promise in animal experiments. However, this vascular disruption approach has not paid the expected long-term dividends in the clinical setup. However, antiangiogenics are playing a significant role when used concurrently with chemotherapy/immunotherapy. Antiangiogenics have dual temporal actions - an initial normalization effect with improved oxygenation followed by pruning of blood vessels, resulting in exaggerated hypoxia along with a rebound progression. The literature is replete with phenomena of initial vascular normalization with a paradigm shift in the immuno-phenotypic milieu of cancer as part of vascular targeting approaches. The hypothesis in this article stresses the need to have strategies to extend this normalization window or to have pre-clinical trials to optimize the dose scheduling of antiangiogenics cyclically along with chemo/targeted/immune therapy and other combination therapies. We can implement this hypothesis by a combinatorial harmonization of present-day cancer therapies in the setting of tumor vasculature integrity. In addition, based on the proposed hypothesis, the current normalization effect of antiangiogenics and newer therapy development should focus primarily on normalization of the vasculature as well as targeting hypoxia-Inducible-factor-1 alpha (HIF-1 α) in the presence of differential genetic modulation of vascular endothelial cell resistance enhancement along with cancer cell sensitization. Also, the article enumerates six supporting hypotheses supplementing the primary hypothesis.