Combinatorial therapy for gynecologic cancers: A therapeutic mix encompassing Metformin and Navitoclax (ABT-263) (MAN) inhibits the expression of HDAC6, acetylates tumor suppressor proteins, activates tumor suppressor function, and stifles the progression of ARID1A-mutated ovarian cancers, via up-regulation of its target gene, 3/February/2019, 11.22 pm

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Introduction: What they say: 

A study from Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA shows that ARID1A-mutated ovarian cancers depend on HDAC6 activity” This study was published, in the 24 July 2017 issue of the journal “Nature Cell biology” [One of the best journals in Cell Biology with an I.F of 20.006 plus], by Prof.Zhang, Bitler BG, 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 gynecologic cancers: A therapeutic mix encompassing Metformin and Navitoclax (ABT-263) (MAN) inhibits the expression of HDAC6, acetylates tumor suppressor proteins, activates tumor suppressor function, and stifles the progression of ARID1A-mutated ovarian cancers, via up-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, and little more than half of them will die, due to lack of curative treatment; (ii) cancer deaths globally are expected to be doubled by 2030; (iii) Ovarian cancer is not only one among the most common women cancers, but also the one of the most common invasive cancers in women; (iv) Ovarian cancer not only metastasizes frequently, but also relapses; (v) there is an increased incidence of ovarian cancer, as it has caused 113,000 deaths in 1990, while in 2010 160,000 deaths; (vi) ovarian cancer is the fifth leading cause of cancer death in women; (vii) in 2008, cancers of female reproductive organs has caused economic loss of 88 billion US dollars worldwide; and (viii) cancer 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 prevent an individual from being susceptible to cancer by strengthening his/her own immune system (Cancer immunotherapy); (ii) a cheaper alternative to the existing expensive anticancer drugs; (iii) a side-effect-free natural product-based drug; and (iv) a way to effectively treat and prevent metastatic progression and relapse of cancers.


What we infer from what they say:

The epigenetic regulator ARIDIA (Mutations in AT rich interactive domain 1A)/BAF250A has been shown to be frequently mutated in all human cancers. In particular, it is mutated in 50% of ovarian clear cell carcinomas. However, the molecular  components that function downstream of ARID1A is far from understood.

Prof.Zhang’s research team has recently shown that: (1) HDAC6 is overexpressed in ARID1A-mutated ovarian cancers; (2) downregulation of HDAC6 in ARID1A-mutated ovarian cancers promotes survival of mice; (3) ARID1A transcriptionally represses the expression of HDAC6; (4) HDAC6 deacetylates Lys120 of tumor suppressor p53 and thereby inhibits its function; and (5) ARID1A mutation in cancer cells results in activation of HDAC6 and inactivation of tumor suppressorp53 function, suggesting that inhibition of HDAC6 may promote apoptosis,  selectively in ARID1A-mutated cancers, by increasing the expression of tumor suppressor p53 and its homologous proteins.


From research findings to therapeutic opportunity :

This study suggests a combinatorial therapy for ARID1A-mutated cancers, including clear cell ovarian cancers. Metformin and Navitoclax (ABT-263) (MAN) have individually been shown to function as anticancer agents (fig. 1). However, the exact mechanism of action these drugs is far from clear. A therapeutic mix encompassing Metformin and Navitoclax (ABT-263) (MAN), by increasing the expression of its target genes, it may inhibit the expression of HDAC6 (fig. 1). Thereby, it may: (i) acetylate tumor suppressor proteins; (ii) activate tumor suppressor proteins in ARID1A-mutated ovarian cancers; (iii) inhibit ovarian cancer progression; and (iv) promote survival (fig.1). Thus, pharmacological formulations encompassing “Metformin and Navitoclax (ABT-263) (MAN) or their analogs, either alone or in combination with other known anticancer drugs,” may be used to inhibit the progression of ARID1A-mutated ovarian cancers (fig. 2)

Figure 1. Mechanistic insights into how a therapeutic mix encompassing Metformin and Navitoclax (ABT-263) (MAN) functions as an anticancer agent in ARID1A-mutated ovarian cancers.

Figure 2. A therapeutic mix encompassing Metformin and Navitoclax (ABT-263) (MAN) may stall the progression of ARID1A-mutated ovarian cancers.


Details of the Research findings:

Idea Proposed/Formulated (with experimental evidence) by Dr L Boominathan Ph.D.

Amount: $500#

Undisclosed mechanistic information: How does a therapeutic mix encompassing Metformin and Navitoclax (ABT263) (MAN) decrease the expression of HDAC6?

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References:

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Citation: Boominathan, L., Combinatorial therapy for gynecologic cancers: A therapeutic mix encompassing Metformin and Navitoclax (ABT263) (MAN) inhibits the expression of HDAC6, acetylates tumor suppressor proteins, activates tumor suppressor function, and stifles the progression of ARID1A-mutated ovarian cancers, via up-regulation of its target gene, 3/February/2019, 11.22 pm, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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