Combinatorial therapy for EVI-1-Overexpressing Acute Myeloid Leukemia: a therapeutic mix encompassing Simvastatin and Navitoclax/ABT-263 (SAN) decreases the expression of MECOM/EVI-1 and its down target genes, including CKMT-1, alters Arginine-creatine metabolism, inhibits mitochondrial respiration, depletes ATP levels, and promotes regression of EVI-1-overexpressing AML via up regulation of its target gene, 3/March/2017, 11.23 am

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Introduction: What they say:

A study from the Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; and Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA shows that “The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia.” This study was published, in the 13 February 2017 issue of the journal “Nature Medicine” [the number 1 journal in General Medicine with an I.F of 30.357], by Prof. Stegmaier Kimberly, Fenouille N, 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 EVI-1-Overexpressing Acute Myeloid Leukemia: a therapeutic mix encompassing Simvastatin and Navitoclax/ABT-263 (SAN) decreases the expression of MECOM/EVI-1 and its down target genes, including CKMT-1, alters Arginine-creatine metabolism, inhibits mitochondrial respiration, depletes ATP levels, and promotes regression of EVI-1-overexpressing AML 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; (ii) cancer deaths globally are expected to be doubled by 2030; (iii) cancer treatment causes the highest economic loss compared to all the known causes of death worldwide; (iv) Acute myeloid leukemia (AML) is one of the most predominant leukemias among all the adult leukemias; (v) each year about 10, 500 and 2900 new cases of AML are reported in the US and the UK, respectively; (vi) complete  cure from AML is possible only in 20-45% cases, 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; (ii) a side-effect-free natural product-based drug; and (iii) a way to effectively treat and prevent metastatic progression and relapse of cancers.


What we infer from what they say:

Prof. Stegmaier Kimberly’s research team has recently shown that: (1) oncoprotein MECOM (MDS1 And EVI1 Complex Locus, also known as EVI1) suppresses the expression of myeloid differentiation regulator Runx1 [(Runt-related transcription factor 1 (RUNX1) also known as acute myeloid leukemia 1 protein (AML1)]; (2) increases the expression of the ATP-buffering, mitochondrial creatine kinase CKMT1; (3) inhibition of CKMT1 promotes cell cycle arrest, induces apoptosis of human EVI1-expressing AMLs; and promotes survival in mouse models of primary AMLs. Further, they shown that inhibition of CKMT1 results in (1) altered mitochondrial respiration; and (2) reduction in ATP levels, suggesting that suppressing CKMT in EVI1-driven AML may stall its progression. Together, these findings suggest that inhibition of EVI-1 and its downstream target gene CKMT1 expression in AML cells may prevent AML growth.


From research findings to therapeutic opportunity :

This study suggests a combinatorial therapy for cancer. This study suggests, for the first time, that Simvastatin and Navitoclax/ABT-263 (SAN), by decreasing the expression of its target genes, it may inhibit the expression of MECOM/EVI-1 and its downstream target gene CKMT1 (fig. 1).

Figure 1. Mechanistic insights into how a therapeutic mix encompassing Simvastatin and Navitoclax/ABT-263 (SAN) inhibits CKMT1 expression. SAN, by suppressing the expression of its target gene, it may down regulate the expression of CKMT1. Thereby, it may stall the progression of AML.

 

Figure 2. Combinatorial therapy for EVI-1 expressing AML.

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 AML progression.


Details of the Research findings:

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

Undisclosed mechanistic information: How does Simvastatin and Navitoclax/ABT-263 (SAN)  decrease the expression of EVI-1 and its downstream target gene CKMT1 ?

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References:

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Citation: Boominathan, L., Combinatorial therapy for EVI-1-Overexpressing Acute Myeloid Leukemia: a therapeutic mix encompassing Simvastatin and Navitoclax/ABT-263 (SAN) decreases the expression of MECOM/EVI-1 and its down target genes, including CKMT-1, alters Arginine-creatine metabolism, inhibits mitochondrial respiration, depletes ATP levels, and promotes regression of EVI-1-overexpressing AML via up regulation of its target gene, 3/March/2017, 11.23 am, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org

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