Combinatorial therapy for glioblastoma: A therapeutic mix encompassing Metformin and Navitoclax (ABT-263) [MAN] inhibits the expression of JMJD6, impairs functioning of transcription elongation machinery, inhibits the proliferation of glioblastoma cells, suppresses tumor cell migration, reduces metastasis and prolongs survival via down-regulation of its target gene, 3/February/2019, 10.39 pm

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Introduction: What they say: 

A study from the Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Ohio, USA shows that “Transcription elongation factors represent in vivo cancer dependencies in glioblastoma.” This study was published, in the 5 July 2017 issue of the journal “Nature” [One of the best journals in Science with an I.F of 43 plus], by Prof.Rich JN, Miller TE, and others.


What we say:

On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that: Combinatorial therapy for glioblastoma: A therapeutic mix encompassing Metformin and Navitoclax (ABT263) [MAN] inhibits the expression of JMJD6, impairs functioning of transcription elongation machinery, inhibits the proliferation of glioblastoma cells, suppresses tumor cell migration, reduces metastasis and prolongs survival via down-regulation of its target gene


From significance of the study to Public health relevance:

Given that: (i) each year nearly 14 million people are diagnosed with cancer globally; (ii) Glioblastoma (brain tumor) is identified as one of the most lethal cancers with median survival not extending beyond little more than a year; (iii) there are not many druggable targets available for glioblastoma; (iv) metastasis is common to all forms of cancers; (iii) metastasis is the principle reason for most of the cancer deaths; (iv) even intense multimodal treatment saves only less than 50% of metastatic patients; (iv) our understanding is incomplete in terms of down stream molecular targets and the oncogenic/malignant pathways involved in metastatic cancers; (v) cancer deaths globally are expected to be doubled in the next decade; (vi) cancer treatment causes the highest economic loss compared to all the known causes of death worldwide, there is an urgent need to find: (i) a way to activate patients’ immune system against metastatic tumors (Cancer immunotherapy); (ii) anti-cancer drugs that target cancer stem cells that aid in tumor relapse and resistance; (iii) anti-cancer drugs that target cell adhesion molecules that aid in metastatic spread; (iv) a cheaper alternative to the existing expensive anticancer drugs; (v) a side-effect-free natural product-based drug; (vi) increase the therapeutic index of anti-cancer drugs; and (vii) a way to effectively treat and prevent metastatic progression and relapse of advanced/drug-resistant cancers.


What we infer from what they say:

Prof. Rich JN’s research team has recently: (1) identified protein factors that enable cells to survive the tumor microenvironment using pooled RNA interference (RNAi) screening technology; (2) shown that JMJD6, one of the protein factor identified in the screen, promotes cell survival through transcriptional pause-release and through up-regulation of a number of survival-promoting pathways; and (3) shown that inhibiting JMJD6 enhances the survival of orthotopic xenograft mouse models, suggesting that targeting transcription elongation machinery proteins, such as JMJD6, may inhibit the progression of metastatic glioblastoma.


From research findings to therapeutic opportunity :

Metformin and Navitoclax (previously ABT263) [MAN]  are, individually, known to function as anticancer agents. However, the detailed mechanistic insights is yet to emerge.

This study suggests, for the first time, that a therapeutic mix encompassing Metformin and Navitoclax (previously ABT-263) [MAN], by increasing the expression of its target genes, it may decrease the expression of JMJD6  (Bifunctional arginine demethylase and lysyl-hydroxylase). Thereby, it may: (i) inhibit transcription pause-release and elongation; and thereby, impair the functioning of transcription elongation machinery; (2) inhibit activation of a number of survival-promoting pathways; (iii) activate a number of tumor suppressor promoting pathways; (iii) inhibit proliferation and survival of glioblastoma stem cells; (iv) stifle tumor cell migration; (v) decrease metastatic capacity of cancer cells; (vi) stall glioblastoma progression; and (vii) promote survival (fig. 1).

Figure 1. Mechanistic insights into how a therapeutic mix encompassing  Metformin and Navitoclax (previously ABT-263) [MAN] suppresses the expression of JMJD6 to stall glioblastoma progression

Figure 2. The chemical structure of Metformin and Navitoclax (previously ABT-263) [MAN] suppresses the expression of JMJD6 to stall glioblastoma progression

Thus, pharmacological formulations encompassing “Metformin and Navitoclax (ABT263) [MAN] or their analogs, either alone or in combination with other known anticancer drugs,” may be used to inhibit metastatic progression of glioblastomas.


Details of the research findings: 

Idea formulated by Dr. L Boominathan Phd

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Citation: Boominathan, L., Combinatorial therapy for glioblastoma: A therapeutic mix encompassing Metformin and Navitoclax (ABT263) [MAN] inhibits the expression of JMJD6, impairs functioning of transcription elongation machinery, inhibits the proliferation of glioblastoma cells, suppresses tumor cell migration, reduces metastasis and prolongs survival via down-regulation of its target gene, 3/February/2019, 10.39 pm, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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