Combinatorial therapy for targeting cancer stem cells in Myeloid leukaemia (ML): a pharmaceutical mixture encompassing Metformin and Navitoclax/ABT-263  inhibits cytosolic aminotransferase BCAT1 expression, increases a-ketoglutarate levels, promotes degradation of HIF1a levels, increases DNA demethylase levels, promotes hypomethylation, increases the expression of tumor suppressor genes, inhibits leukaemia-initiating potential of AML cells, promotes differentiation of AML cells, and inhibits cancer progression in AML, via up-regulation of its target gene, 6/February/2019, 11.22 pm

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Introduction to what they say:

A study from the Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany; and German Cancer Consortium (DKTK), DKFZ, 69120 Heidelberg, Germany shows that “BCAT1 restricts aKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation”. This study was published, in the 16 November 2017 issue of the journal “Nature” [One of the best journals in General Science with an I.F of 43 plus], by Prof. Trumpp, Simon Raffel, 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 targeting cancer stem cells in Myeloid leukaemia (ML): a pharmaceutical mixture encompassing Metformin and Navitoclax/ABT-263  inhibits cytosolic aminotransferase BCAT1 expression, increases a-ketoglutarate levels, promotes degradation of HIF1a levels, increases DNA demethylase levels, promotes hypomethylation, increases the expression of tumor suppressor genes, inhibits leukaemia-initiating potential of AML cells, promotes differentiation of AML cells, and inhibits cancer progression in 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 cannot be cured by current treatment methodologies (and hence they will die); (ii) cancer deaths globally are expected to be doubled by next decade or so; (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 adult leukemias, while Chronic myeloid leukemia (CML) accounts for about little less than 10% of all leukemias; (v) each year about 10,500 and 2900 new cases of AML are reported in the US and the UK, respectively; (vi) cure rates of AML ranges from 20-45% only, there is an urgent need to find: (i) a way to inhibit leukaemia-initiating potential of AML stem cells; (ii) activate patient’s own immune system (Cancer immunotherapy); (iii) target proteins that drug resistance during treatment; (iv) prevent disease relapse after conventional cancer therapy; (v) a cheaper alternative to the existing expensive anticancer drugs; (vi) a side-effect-free natural product-based drug; and (vii) a way to effectively treat and prevent metastatic progression and relapse of cancers.


What is known:

Prof.Trumpp and his research team members and others have recently shown that: (1) the cytosolic aminotransferase BCAT1 (branched-chain amino acid (BCAA) transaminase 1) is upregulated in human acute myeloid leukaemia (AML) stem-cells; (2) BCAT1 promotes homeostasis of tricarboxylic acid cycle component a-ketoglutarate (aKG); (3) deletion of BCAT1 in leukemic cells results in accumulation of aKG; (4) aKG, which is accumulated in BCAT1-deleted leukemic cells, promotes degradation of HIF1a, resulting in abrogation of leukaemia-initiating potential; (5) overexpression of BCAT1 in leukaemia cells results in (a) decreaed levels of aKG; (b) altered TET DNA demethylase; and (c) DNA hypermethylation; and (6) high levels of BCAT1 in leukaemic cells matches with a) shorter survival; and b) disease relapse, suggesting that suppression of BCAT1 in leukemic cells may (a) increase aKG levels; (b) increase DNA demethylase levels; and promote hypomethylation; (c) promote EGLN1-mediated degradation of HIF1a; (d) attenuate leukaemia-initiating potential of cancer cells; (d) promote survival; and (e) prevent disease relapse in patients with IDH(wt)TET2(wt) AML.


From research findings to therapeutic opportunity :

This study suggests a combinatorial therapy for IDH(wt)TET2(wt) AML. A pharmaceutical mixture encompassing Metformin and Navitoclax/ABT-263A by increasing the expression of its target genes, it may decrease the expression of BCAT1 and other genes (fig. 1). Thereby, it may: (i) increase the levels of aKG; (ii) promote degradation of HIF1a; (iii) alter TET DNA demethylase levels; (iv) promote DNA hypomethylation; (v) decrease the expression of oncogenic MiRs; (vi) increase the expression of tumor suppressor genes; (vii) inhibit leukaemia-initiating potential of AML stem cells; (viii) decrease BCAA (Branched-chain amino acid) production; (ix) promote differentiation of leukemic cells; (x) slow down CML and de novo acute myeloid leukaemia (AML) growth; and (vi) inhibit cancer progression in Myeloid leukemia (fig.1).

Figure 1. Mechanistic insights into how a pharmaceutical mixture encompassing Metformin and Navitoclax/ABT-263 suppresses the expression of BCAT1 and HIF1a to inhibit cancer progression in myeloid leukemia

Figure 2.  A pharmaceutical mixture encompassing Metformin and Navitoclax/ABT-263 functions as an anti-cancer agent in ML.

Thus, pharmacological formulations encompassing “Metformin and Navitoclax/ABT-263  or their analogs, either alone or in combination with other known anti-cancer drugs,” may be used to inhibit leukemia stem-cell function and slow down cancer proliferation in patients with IDH(wt)TET2(wt) AML.


Details of the Research findings:

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

Amount: $1, 500#

Undisclosed mechanistic information: How does a pharmaceutical mixture encompassing Metformin and Navitoclax/ABT-263  decrease the expression of BCAT1 and HIF1α ?

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References:

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Citation: Boominathan, L., Combinatorial therapy for targeting cancer stem cells in Myeloid leukaemia (ML): a pharmaceutical mixture encompassing Metformin and Navitoclax/ABT-263  inhibits cytosolic aminotransferase BCAT1 expression, increases a-ketoglutarate levels, promotes degradation of HIF1a levels, increases DNA demethylase levels, promotes hypomethylation, increases the expression of tumor suppressor genes, inhibits leukaemia-initiating potential of AML cells, promotes differentiation of AML cells, and inhibits cancer progression in AML, via up-regulation of its target gene, 6/February/2019, 11.22 pm, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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