Combinatorial therapy for gynecologic cancers: A therapeutic mix encompassing Fenofibrate and Paclitaxel(PTX) (FAP)  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, 20/February/2019, 12.23 am

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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 Fenofibrate and Paclitaxel(PTX) (FAP)  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. Fenofibrate and Paclitaxel(PTX) (FAP)  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 Fenofibrate and Paclitaxel(PTX) (FAP), 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 “Fenofibrate and Paclitaxel(PTX) (FAP) 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 Simvastatin and Navitoclax (ABT-263) (SAN) functions as an anticancer agent in ARID1A-mutated ovarian cancers.

Figure 2. A therapeutic mix encompassing Fenofibrate and Paclitaxel(PTX) (FAP) 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 Fenofibrate and Paclitaxel(PTX) (FAP) 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 Fenofibrate and Paclitaxel(PTX) (FAP)  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, 20/February/2019, 12.23 am, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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