Probiotic-based chemotherapy targeting cancer stem cells and immune-inhibitory receptors in chronic lymphocytic leukemia (CLL) and in advanced metastatic cancers: A pharmaceutical mixture encompassing Venetoclax and Ibrutinib (VAI) and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as HNF4α, PP2A, p53, and TA-p73/p63, inhibits immune-inhibitory receptors/molecules, targets cancer stem cells, confers protection against chemoresistance and prolongs survival, and stalls CLL progression, via up-regulation of its target gene, 20/June/2019, 7.33 am

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Introduction: What they say

A study from the University of Texas M.D. Anderson Cancer Center, Houston, USA shows that “Ibrutinib and Venetoclax for First-Line Treatment of CLL.” This research paper was published, in the 30 May 2019 issue of the journal “N Engl J Med. 2019 (NEJM)” [One of the best research journals in Medical Sciences with an I.F of 78 plus], by Prof. William G. Wierda (Executive Medical Director), Prof. Gandhi Varsha, Nitin Jain and others.


What we say:

On the foundation of this interesting finding, Dr L Boominathan PhD, the Director-cum-chief Scientist of GBMD, reports that:  Probiotic-based chemotherapy targeting cancer stem cells and immune-inhibitory receptors in chronic lymphocytic leukemia (CLL) and in advanced metastatic cancers: A pharmaceutical mixture encompassing Venetoclax and Ibrutinib (VAI) and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as HNF4α, PP2A, p53, and TA-p73/p63, inhibits immune-inhibitory receptors/molecules, targets cancer stem cells, confers protection against chemoresistance and prolongs survival, and stalls CLL progression, via up-regulation of its target gene


The Significance of the study to Public health relevance:

First, 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 available at present; (ii) cancer deaths globally are expected to be doubled by 2030;  and (iii) 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 anticancer drugs that target cancer stem cells; and (iv) a way to effectively treat and prevent metastatic progression and relapse of ovarian cancers.

Second, given that: (1) cancer suppressor p53 is mutated in more than 50% of human cancers of different tissue origin; (2) p53 pathway is altered in about 80% of tumors; (3) our understanding is incomplete in terms of molecular targets and the oncogenic/malignant pathways involved in mutant p53-overexpressing tumors; (4) cancer causes the highest economic loss compared to all the known causes of death worldwide; and (5) cancer causes the considerable economic loss worldwide, there is an urgent need to find a way to effectively treat and stall metastatic progression and relapse of mutant p53-overexpressing human cancers.


What is known?

Prof. William G. Wierda MD., PhD’s research team has recently shown that treating  chronic lymphocytic leukemia (CLL) patients (Size: 80; 92% of patients had tumor suppressor p53 aberration and deletion of chromosome 11) with Ibrutinib (an inhibitor of Bruton’s tyrosine kinase (BTK)) and Venetoclax (an inhibitor of Bcl-2): (1) 88% of patients had complete remission; and (2) 61% of patients had remission with undetectable minimal residual disease, suggesting that the combinatorial therapy comprising Ibrutinib and Venetoclax is an effective oral regimen for elderly patients. However, the molecular mechanism of action of the combination of anti-cancer drugs Ibrutinib and Venetoclax is largely unknown.


From research findings to therapeutic opportunity :


(i) Therapeutic strategy:

This study suggests a therapeutic strategy for stalling the progression of p53-deficient/deleted or mutant-p53 expressing metastatic cancers. By activating tumor suppressor p53’s unmutated “homologous protein such as TAp73/p63” in p53-deficient or mutant-p53 expressing metastatic cancer cells, one can stall their progression.

(ii) Research findings: This study presented here suggests, for the first time, that a pharmacological formulation encompassing Vinetoclax/ABT-199, & Ibrutinib (VAI), by increasing the expression of its target genes, it may: (i) decrease the expression of a number of oncogenes and DNA repair proteins; (ii) increase the expression of tumor/metastasis suppressor genes, such as HNF4α, and PP2A; (iii) increase the expression of a number of other tumor suppressor genes, including p53/TA-p73/p63, and their target genes, INKa, p19ARF and others (Figure 1);(iv) activate tumor/metastasis suppressor network; (v) inhibit immunosuppressive/immune-inhibitory receptors/ molecules; (vi) inhibit the activity and proliferation of cancer stem cells; (vii) inhibit tumor growth; and (viii) promote survival (Figures 1-2). Further, the efficacy of Olaparib can be increased by treating cancer patients with a pharmaceutical mixture encompassing Vinetoclax/ABT-199, & Ibrutinib (VAI) and probiotic Lactobacillus rhamnosus  (1.0×103 CFU/ml). Thus, a pharmacological formulation encompassingVinetoclax/ABT-199, & Ibrutinib (VAI) or their analogs, either alone or in combination with other known anticancer/metabolic drugs, or probiotics enriched with anti-cancer activity, such as  Lactobacillus rhamnosus,” may be used to inhibit the progression of advanced  cancers, including CLL, and promote disease-free survival (Figure 3)

Figure 1. Mechanistic insights into how a pharmacological formulation encompassing Vinetoclax/ABT-199, & Ibrutinib (VAI) increases the expression of tumor/metastatic suppressors, such as HNF4α, PP2A,  p53, TAp73/p63, INK4a, p19ARF and others.

Figure 2.VAI functions as a tumor/metastatic suppressors agent not only in advanced cancers but also in mutant-p53 expressing human tumors.

Figure 3. A pharmacological formulation encompassing Vinetoclax/ABT-199, & Ibrutinib (VAI) and probiotic Lactobacillus rhamnosus” may attenuate the progression of advanced  cancers through induction of tumor/metastatic suppressors, such as HNF4α, PP2A, p53, TAp73/p63, INK4a, p19ARF and others

Figure 4. Mechanistic insights into how a pharmacological formulation encompassing Vinetoclax/ABT-199, & Ibrutinib (VAI) may attenuate the progression of CLL and other cancers. VAI, by upregulating the expression of  HNF4α, PP2A,  and other tumor suppressor genes, it may attenuate the progression of CLL and other cancers.

 

 

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 pharmacological formulation encompassing Vinetoclax/ABT-199, & Ibrutinib (VAI) increase the expression of tumor/metastatic suppressors HNF4α, and PP2A?

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References:

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Citation: Boominathan, L., Probiotic-based chemotherapy targeting cancer stem cells and immune-inhibitory receptors in chronic lymphocytic leukemia (CLL) and in advanced metastatic cancers: A pharmaceutical mixture encompassing Venetoclax and Ibrutinib (VAI) and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as HNF4α, PP2A, p53, and TA-p73/p63, inhibits immune-inhibitory receptors/molecules, targets cancer stem cells, confers protection against chemoresistance and prolongs survival, and stalls CLL progression, via up-regulation of its target gene, 20/June/2019, 7.33 am, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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