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Probiotic-based chemotherapy targeting cancer stem cells and immune-inhibitory receptors in advanced ovarian cancer and other metastatic cancers: A pharmaceutical mixture encompassing Olaparib, an FDA-approved poly (adenosine diphosphate-ribose) polymerase inhibitor, and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as KIBRA, p57Kip2,   p53, and TA-p73/p63, inhibits immune-inhibitory receptors/molecules, targets ovarian cancer stem cells, confers protection against chemoresistance and prolongs survival, via up-regulation of its target gene, 5/December/2018, 2.29 pm

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Introduction: What they say:

A study from the Stephenson Cancer Center at the University of Oklahoma, Oklahoma City (K.M.); University of Milan-Bicocca, European Institute of Oncology Istituto di Ricovero e Cura a Carattere Scientifico, Milan (N.C.), and Fondazione Policlinico Universitario A. Gemelli IRCCS Università Cattolica, Rome shows that “Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer.” This study was published, in the Oct 21 2018 issue of the journal “N Engl J Med.(NEJM)” [One of the best journals in Medicine with an I.F of 79.258], by Prof. DiSilvestro P, Moore K 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 advanced ovarian cancer and other metastatic cancers: A pharmaceutical mixture encompassing Olaparib, an FDA-approved poly (adenosine diphosphate-ribose) polymerase inhibitor, and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as KIBRA, p57Kip2,   p53, and TA-p73/p63, inhibits immune-inhibitory receptors/molecules, targets ovarian cancer stem cells, confers protection against chemoresistance and prolongs survival, 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; (iii) Ovarian cancer not only one among the most common women cancers, but also the one of the most common invasive cancers in women; (iv) Ovarian cancer not only metastasizes frequently, but also relapses; (v) there is an increased incidence of ovarian cancer, as it had caused 113,000 deaths in 1990, while in 2010 160,000 deaths; (vi) it is the fifth leading cause of cancer death in women; (vii) in 2008, cancers of female reproductive organs had caused economic loss of 88 billion US dollars worldwide; and (viii) 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 we infer from what they say:

Given that advanced ovarian cancer cannot be eradicated with surgery and chemotherapy and it relapses in most of the cases in 3 years, there is an urgent unmet clinical need to find drugs that stall the progression of advanced ovarian cancer. The poly (adenosine diphosphate-ribose) polymerase inhibitor Olaparib (trade name: Lynparza/AZD2281) has been found to be useful in the treatment of metastatic breast cancer, prostate cancer (including castration-resistant prostate cancer), colorectal cancer, and ovarian cancer.

Prof. DiSilvestro’s research team has revealed that:(1) treating advanced ovarian cancer patients, who carry germline BRCA1/2 mutation, with olaparib (300 mg twice daily) had brought down the risk of disease progression or death by 70% compared with placebo; and (2) maintenance therapy with Olaparib offers a substantial health benefit for advanced ovarian cancer patients, suggesting that Olaparib could be an anti-cancer agent of choice to treat advanced ovarian cancer patients carrying germline BRCA1/2 mutation. However, how olaparib functions as an anti-cancer (metastasis) agent is far from clear; and why it offers therapeutic benefit only to the 70% of cancer patients, but not to the rest of 30% of cancer patients, is also not clear. And this suggests that we need additional anti-cancer agents that may increase the efficacy (or, work synergistically with Olaparib) of Olaparib.


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: The poly (adenosine diphosphate-ribose) polymerase inhibitor olaparib had been shown to stall advanced ovarian cancer progression. However, the mechanism of action remains unknown. This study suggests, for the first time, that Olaparib, 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 KIBRA, and p57Kip2; (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 Olaparib and probiotic Lactobacillus rhamnosus  (1.0×103 CFU/ml). Thus, a pharmacological formulation encompassing “Olaparib or its analogs, either alone or in combination with other known anticancer drugs, or probiotics enriched with anti-cancer activity, such as  Lactobacillus rhamnosus,” may be used to inhibit the progression of advanced ovarian cancer and promote disease-free survival (Figure 3)

Figure 1. Mechanistic insights into how olaparib increases the expression of tumor/metastatic suppressors, such as KIBRA, p57Kip2,  p53, TAp73/p63, INK4a, p19ARF and others.

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

Figure 3. A pharmacological formulation encompassing “Olaparib and probiotic Lactobacillus rhamnosus” may attenuate the progression of advanced ovarian cancers through induction of tumor/metastatic suppressors, such as KIBRA, p57Kip2,  p53, TAp73/p63, INK4a, p19ARF and others

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 Olaparib increase the expression of tumor/metastatic suppressors KIBRA, p57Kip2?

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References:

Web: http://genomediscovery.org or http://newbioideas.com/

Citation: Boominathan, L., Probiotic-based chemotherapy targeting cancer stem cells and immune-inhibitory receptors in advanced ovarian cancer and other metastatic cancers: A pharmaceutical mixture encompassing Olaparib, an FDA-approved poly (adenosine diphosphate-ribose) polymerase inhibitor, and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as KIBRA, p57Kip2,   p53, and TA-p73/p63, inhibits immune-inhibitory receptors/molecules, targets ovarian cancer stem cells, confers protection against chemoresistance and prolongs survival, via up-regulation of its target gene, 5/December/2018, 2.29 pm, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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