Probiotic-based Chemotherapy (PCT) targeting cancer stem cells and immune-inhibitory receptors in relapsed chronic lymphocytic leukemia (CLL) and in advanced metastatic cancers: A pharmaceutical mixture encompassing Acalabrutinib, and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as TPM1, CADM1/2, 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, 15/August/2019, 4.53 pm

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Introduction: What they say

A study from the the Division of Hematology, Department of Internal Medicine, Ohio State University, and the Department of Veterinary Biosciences, College of Veterinary Medicine – both in Columbus; UC Irvine Health Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange; University of Oxford, Oxford, NHS Foundation Trust, King’s College Hospital, London, and the Department of Haematology, St. James’s University Hospital, Leeds- all in the United Kingdom; Northwest Medical Specialties, Tacoma, and the Swedish Cancer Institute, Seattle – both in Washington; the Department of Leukemia, Division of Cancer Medicine, University of Texas, and M.D. Anderson Cancer Center – both in Houston; the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston; Huntsman Cancer Institute, University of Utah, Salt Lake City; Università Vita-Salute San Raffaele and Istituto Scientifico San Raffaele, Milan; Hofstra North Shore-LIJ School of Medicine, Chronic Lymphocytic Leukemia Research and Treatment Center, Lake Success, and the Department of Pathology and Cell Biology, Columbia University Medical Center, and New York-Presbyterian/Weill Cornell Medical Center, New York- all in New York; and Acerta Pharma, Oss, the Netherlands  shows  the role of Acalabrutinib in controlling the progression of Relapsed Chronic Lymphocytic LeukemiaThis research paper was published, in the 7 December 2015 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  Dr. Furman RR., M.D., (Director of CLL Research center), Dr. Byrd JC., M.D.,  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 (PCT) targeting cancer stem cells and immune-inhibitory receptors in relapsed chronic lymphocytic leukemia (CLL) and in advanced metastatic cancers: A pharmaceutical mixture encompassing Acalabrutinib, and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as TPM1, CADM1/2, 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?

Dr. Furman MD’s research team has recently shown that treating  relapsed chronic lymphocytic leukemia (CLL) patients with Acalabrutinib (a second- generation, more selective, irreversible inhibitor of Bruton’s tyrosine kinase (BTK) (1) the overall response rate was 95% (total number of patients: 61; and Dose: 100 to 400 mg once daily );  (2) the overall response rate was 100% in patients with chromosome 17p13.1 deletion; and (3) resulting in no adverse side effects compared with ibrutinib, suggesting that selective BTK inhibitor Acalabrutinib is an effective treatment regimen for elderly patients (62+ years of age) with relapsed CLL. However, the molecular mechanism of action of Acalabrutinib  in stalling the progression of CLL remains 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 Acalabrutinib, 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 TPM1 and CADM1/2; (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 1-4). Further, the efficacy of Acalabrutinib can be increased by treating cancer patients with probiotic Lactobacillus rhamnosus  (1.0×103 CFU/ml).

Figure 1. Mechanistic insights into how a pharmacological formulation encompassing Acalabrutinib increases the expression of tumor/metastatic suppressors, such as TPM1, CADM1/2, p53, TAp73/p63, INK4a, p19ARF and others, inhibits the expression of immune-inhibitory receptors, stops the proliferation of cancer stem cells, and stalls the progression of relapsed CLL. 

Figure 2 Acalabrutinib may not only function as a tumor/metastatic suppressors agent in advanced cancers, such as relapsed CLL,  but also in mutant-p53 expressing human tumors.

Figure 3 BTK inhibitor Acalabrutinib  functions as a tumor/metastatic suppressors agent in relapsed CLL and in other cancers.  Acalabrutinib, by turning on the expression of tumor/mestastasis suppressor genes, such as p53, TA-p73/p63, INK4a, ARF, TPM1, CADM1/2 and others, stalls the progression of relapsed CLL  and other cancers. 

Figure 4. A pharmacological formulation encompassing Acalabrutinib and probiotic Lactobacillus rhamnosus may attenuate the progression of advanced  cancers, including in relapsed CLL, through induction of tumor/metastatic suppressors, such as TPM1, CADM1/2,  p53, TAp73/p63, INK4a, p19ARF and others

Figure 5. While a second- generation, more selective, irreversible Bruton’s tyrosine kinase (BTK) inhibitor Acalabrutinib has been shown to attenuate the progression of relapsed CLL, its mechanism of action remains largely unknown.  This study presented here suggests, for the first time, that Acalabrutinib, by upregulating the expression of  tumor/metastasis suppressors TPM1, CADM1/2, and others (figs.1-4), it may attenuate the progression of relapsed CLL and other advanced cancers.

 

Thus, a pharmacological formulation encompassing “Acalabrutinib  or its 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 3-4).

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 Acalabrutinib increase the expression of tumor/metastatic suppressors TPM1, & CADM1/2?

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References:

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Citation: Boominathan, L., Probiotic-based Chemotherapy (PCT) targeting cancer stem cells and immune-inhibitory receptors in relapsed chronic lymphocytic leukemia (CLL) and in advanced metastatic cancers: A pharmaceutical mixture encompassing Acalabrutinib, and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as TPM1, CADM1/2, 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, 15/August/2019, 4.52 pm, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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