Probiotic-based Chemo-Antibody Therapy (PCAT) targeting cancer stem cells and immune-inhibitory receptors in chronic lymphocytic leukemia (CLL) and in advanced metastatic cancers: A pharmaceutical mixture encompassing Ibrutinib, Rituximab 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, 13/August/2019, 12.11 am

Mechanistic insights into how Alendronate attenuates Arthritis: Alendronate (brand name:  Fosamax), used to treat osteoarthritis and paget’s disease of bone, increases IL-9 levels, augments proliferation of ILC2s (type 2 innate lymphoid cells) and regulatory T (Treg) cells, promotes resolution of inflammation, attenuates cartilage destruction, decreases bone loss, and inhibits pathological features associated with arthritis, via up-regulation of its target genes, 10/August/2018, 6.02 pm
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Mechanistic insights into how Rituximab attenuates Arthritis: Rituximab (brand name: Ritusan), used to treat bone-related disorders, increases IL-9 levels, augments proliferation of ILC2s (type 2 innate lymphoid cells) and regulatory T (Treg) cells, promotes resolution of inflammation, attenuates cartilage destruction, decreases bone loss, and inhibits pathological features associated with arthritis, via up-regulation of its target genes, 13/August/2019, 12.24 am
August 12, 2019
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Introduction: What they say

A study from the Stanford University, Stanford, the University of California, Irvine, Medical Center, Orange, and Kaiser Permanente National Cancer Institute Community Oncology Research Program (NCORP)-Permanente Medical Group, Oakland – all in California; Dana-Farber Cancer Institute, Boston; Mayo Clinic, Rochester and Minnesota Oncology, Burnsville- both in Minnesota; Northwell Health Cancer Institute, Donald and Barbara Zucker School of Medicine at Hofstra-Northwell, Lake Success, and University of Rochester, Rochester- both in New York; Mayo Clinic, Phoenix, AZ; Washington University School of Medicine, St. Louis; Memorial Sloan Kettering Cancer Center, New York; Aurora Cancer Care, West Allis, WI; National Cancer Institute, Bethesda, MD; and the University of Alabama, Tuscaloosa  shows that “Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia.” This research paper was published, in the 1 August 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 Vice-president Prof. Tallmann Martin M.D.,  Dr. Tait Shanafelt 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 Chemo-Antibody Therapy (PCAT) targeting cancer stem cells and immune-inhibitory receptors in chronic lymphocytic leukemia (CLL) and in advanced metastatic cancers: A pharmaceutical mixture encompassing Ibrutinib, Rituximab  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?

Prof. Tallmann Martin MD’s research team has recently shown that treating  chronic lymphocytic leukemia (CLL) patients with Ibrutinib (an inhibitor of Bruton’s tyrosine kinase (BTK) and Rituximab (an antibody raised against CD20): (1)  resulting in disease progression-free survival in 89.4% of patients (total number of patients: 354);  (2) resulting in increased overall survival rate (98.8%); and (3) is superior to standard chemoimmunotherapy regimen, suggesting that the combinatorial therapy comprising Ibrutinib and Rituximab is an effective for elderly patients (70+ years of age). However, the molecular mechanism of action of the combination of  Ibrutinib and Rituximab 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 Ibrutinib-Rituximab, 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 Ibrutinib-Rituximab  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 Ibrutinib-Rituximab increases the expression of tumor/metastatic suppressors, such as TPM1, CADM1/2, p53, TAp73/p63, INK4a, p19ARF and others.

Figure 2 Ibrutinib-Rituximab 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 Ibrutinib-Rituximab and probiotic Lactobacillus rhamnosus may attenuate the progression of advanced  cancers through induction of tumor/metastatic suppressors, such as TPM1, CADM1/2,  p53, TAp73/p63, INK4a, p19ARF and others

Figure 4. Mechanistic insights into how a pharmacological formulation encompassing Ibrutinib-Rituximab may attenuate the progression of CLL and other cancers. Ibrutinib-Rituximab, by upregulating the expression of TPM1, CADM1/2, and other tumor suppressor genes, it may attenuate the progression of CLL and other cancers.

 

Thus, a pharmacological formulation encompassing “Ibrutinib & Rituximab or their analogs/functional equivalents” 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 Ibrutinib-Rituximab increase the expression of tumor/metastatic suppressors TPM1, & CADM1/2?

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References:

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Citation: Boominathan, L., Probiotic-based Chemo-Antibody Therapy (PCAT) targeting cancer stem cells and immune-inhibitory receptors in chronic lymphocytic leukemia (CLL) and in advanced metastatic cancers: A pharmaceutical mixture encompassing Ibrutinib, Rituximab  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, 13/August/2019, 12.12 am, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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