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Novel epigenetic therapies targeting angiogenesis, Modifying metastasis by regulating epigenome:
A Case review of multi targeted epigenetic therapy(MTET)
ABSTRACT
 Epigenetic regulation of angiogenesis, and heterogeneity
Background
The main barrier for an effective treatment of many types of solid tumors is heterogeneity and
genetic instability of cancer. It was primarily hypothesized that targeting the angiogenesis could
manage this problem, as it modifies microenvironmental cross talk with the tumor, reducing the
chemoresistance and improving the response to the available therapies. That said clinical
experience with this approach revealed unexpectedly distinct responses between different
tumors and organ sites, again re emphasizing the microenvironmental factors that biologically
impact such response to the point that many clinical trials failed to show an improved clinical
outcome and overall survival, using this approach alone. It was also postulated that the wide
spectrum of pre-clinical and clinical results obtained with using anti-angiogenic agents is a result
of deep functional linkage existing between genetic and epigenetic variabilities. This epigenetic
regulations on controlling tumor and microenvironment cross talk resulting in new blood vessel
formation is a dynamic process, causing heterogeneity and progressive characteristics to an
extent similar with the instability of the cancer cell genome. As a result, research around the
epigenetic regulations of targets in the process of angiogenesis seems very relevant and
exciting.
 Regulation of methylation via hypoxia
The aberrancies in DNA methylation in several genes is crucial for vasculogenesis. The methylCpG–binding domain 2 (MBD2) protein senses DNA methylation and mediates transcriptional
repression of promoter genes involved in many processes of cellular growth and survival
including angiogenesis. This process has been first described and linked in epigenetic changes in
endothelial cells and cardiovascular disease and related literature. Hypoxia drives the epigenetic
control, as ischemia promotes methylation. VEGF and VEGF-2 receptor expression, and this
cross talk is the major pathway responsible for vasculogenesis by inducing the growth,
migration, and permeability of endothelial cells, resulting in cancer cell invasion and
hematological metastasis. Tissue ischemia directly upregulates both VEGF and it’s receptors.
Endothelial Nitric oxide synthase( eNOS) expression is known to be sensitive to epigenetic
mechanisms, as methylation increases the NO production. Through this dynamic process at each
point of time, the microenvironment cross talk with the tumor influenced by the epigenetic
status of the host, is controlled by the oxygen concentration.
 Regulation of hypoxia via methylation, the other side of the coin. The case for Renal cell
carcinoma, Which one was first, the egg or the chicken?
A clinical example of hypoxia driven pathways regulation by epigenetics is the transcriptional
VHL in RCC. Mutated VHL in cases of patients with VHL disease, are unable to degrade the HIF (
by ubiquitination). This pattern is also relevant when the VHL is methylated. In these cases,
inactivation of the VHL causes accumulated HIF and further increased down stream molecules
related to both hypoxia response elements as well as EMT transition and angiogenesis. By
regulating this epigenetic mechanism, we show improved markers for survival in clinical
settings, in RCC. Another specific example is the regulation of HIF through HSP 90 ( which is a
chaperone that governs the conformational maturation and folding of the tyrosine kinase
targets) and the inhibition of HSP 90 is under the influence of it’s ubiquitination ( which is post
translational epigenetic modification) of the target.
 Heterogeneity and hypoxia,
Our understanding of heterogeneity of tumors has led us to look more in depth at cancer stem
cells and epidermomesenchymal transition (EMT). Logically, the tumors which have higher
heterogeneity have higher stem cell potentials and increased EMT transition. Here again,
hypoxia and related hypoxia induced factor (HIF-1) can also be the promoter or origin of such
increased activity in down stream targets, through Wnt, Snail and Slug pathways, increasing the
tendency of tumors to show more heterogeneity. Here again, as epigenetic regulations over the
hypoxia and it’s genomic transcription is discussed, this appears to be the key to the
mechanisms involved with heterogeneity of the tumor.
 Accordingly, here we present a summary of one hundred cases of advanced disease and in
detail, we present ten cases of advanced stage four patients with heterogenous cancer who
were treated using a novel epigenetic therapy, in a protocol called multi targeted epigenetic
therapy (MTET), resulting in independent “antiangiogenic response” identified by disseminated
circulatory tumor cells analysis and translated to improved progression free, or overall survival.
We follow the serum/plasma VEGF measurements, as a biomarker for vasculogenesis (and
possible intratumoral hypoxia) in addition to, circulatory tumor cells assay which can be used as
a prognostic marker, altogether, a meaningful companion diagnostic tool to translate to clinical
outcome, and predict overall survival. 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 targeting angiogenesis in refractory heterogeneous disease, by
regulating the epigenome.