Combinatorial therapy for prostate cancer:  A therapeutic mix encompassing  Simvastatin and Navitoclax/ABT-263 (SAN) inhibits the expression of mTORC1 and its downstream target AMD1, dismantles mTORC1-AMD1 signaling network, decreases polyamine levels, and inhibits prostate cancer progression via up regualtion of its target gene, 20/February/2019, 12.09 am

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Introduction: What they say:

A study from CIC bioGUNE (Center for Cooperative Research in Biosciences), Bizkaia Technology Park, 801 Building, 48160 Derio, Spain shows that “mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer.” This study was published, in the 28 June 2017 issue of the journal “Nature” [One of the best journals in General Science with an I.F of 43], by Profs.Carracedo A, Amaia Zabala-Letona, 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 prostate cancer:  A therapeutic mix encompassing  Simvastatin and Navitoclax/ABT-263 (SAN) inhibits the expression of mTORC1 and its downstream target AMD1, dismantles mTORC1-AMD1 signaling network, decreases polyamine levels, and inhibits prostate cancer progression via upregualtion of its target gene


From Significance of the study to Public health relevance:

Given that: (i) prostate cancer is one of the most common form of disease in men; and about 1 in 8 will get it in their lifetime; (ii) each year nearly 14 million people are diagnosed with cancer globally; (iii) each year 176,000 cases of prostate cancer are identified in the US and about 28,000 of them will die, while in the UK each year 47,000 cases are identified and about one fourth of them will die; (iv) about 70% of Prostate cancers are deficient in tumor suppressor gene PTEN, the second most mutated gene in cancer, the first being tumor suppressor Tp53; (v) cancer deaths globally are expected to be doubled in the next decade; (vi) metastasis is the principle reason for most of the cancer deaths; (vii) cancer treatment causes the highest economic loss compared to all the known causes of death worldwide, there is an urgent need to find: (i) activate patients’ immune system against 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. Carracedo’s research team has recently shown that:(1) S-adenosylmethionine decarboxylase 1 (AMD1) is highly expressed in prostate cancers with activated mTORC1; (2) mTORC1-activated signals stabilize AMD1; (3) decarboxylated S-adenosylmethionine and polyamine levels are increased in a mouse model and human biopsies of prostate cancer; and (4) mTORC1 inhibitor everolimus: a) decreases the expression of AMD1 and the production of decarboxylated S-adenosylmethionine and polyamines; and b) inhibits proliferation, suggesting that inhibition of the components of the mTORC1-AMD1 signalling may stall prostate cancer progression.


From research findings to therapeutic opportunity :

A therapeutic mix encompassing Simvastatin and Navitoclax/ABT-263 (SAN)  have, individually, been shown to function as anti-cancer agents. However, the detailed mechanism of action is yet to emerge.

This study suggests, for the first time that, a therapeutic mix encompassing  Simvastatin and Navitoclax/ABT-263 (SAN), by increasing the expression of its target genes, it may decrease the expression of mTORC1 (fig. 1). Thereby, it may: (i) decrease the stability and levels of AMD1; (ii) decrease decarboxylated S-adenosylmethionine and polyamine levels; (iii) inhibit prostate cancer proliferation; (v) reduce metastasis; and (vi) promote survival (Fig.1).

Figure 1. Mechanistic insights into how a therapeutic mix encompassing Simvastatin and Navitoclax/ABT-263 (SAN) decreases the levels of mTORC1 and its down stream target AMD1 and stalls prostate cancer metastasis

Figure 2 Combinatorial therapy for Prostate cancer.

Thus, pharmacological formulations encompassing “Simvastatin and Navitoclax/ABT-263 (SAN) or their analogues, either alone or in combination with other known anticancer drugs” may be used to inhibit metastatic progression of prostate cancers.


Details of the Research findings:

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

Amount: $500#

Undisclosed mechanistic information: How a therapeutic mix encompassing  Simvastatin and Navitoclax/ABT-263 (SAN) decreases the levels of MTORC1 and AMD1 to promote metastatic prostate cancer regression?

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References:

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Citation: Boominathan, L.,  Combinatorial therapy for prostate cancer:  A therapeutic mix encompassing  Simvastatin and Navitoclax/ABT-263 (SAN) inhibits the expression of mTORC1 and its downstream target AMD1, dismantles mTORC1-AMD1 signaling network, decreases polyamine levels, and inhibits prostate cancer progression via up regualtion of its target gene, 20/February/2019, 12.11 am, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org

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