Probiotic-based Chemotherapy (PCT) targeting cancer stem cells and immune-inhibitory receptors in advanced breast cancer and in other advanced metastatic cancers: A pharmaceutical mixture encompassing Palbociclib,  Letrozole  and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as PDCD4, ACAT1,  p53, and TA-p73/p63, inhibits immune-inhibitory receptors/molecules, targets cancer stem cells, confers protection against chemoresistance and prolongs survival, and stalls advanced breast cancer  progression, via up-regulation of its target gene, 5/October/2019, 1.00 am

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Introduction: What they say

A study from Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at the University of California, Los Angeles, Santa Monica, the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, and Pfizer, La Jolla;  Hospital Gregorio Maranon, Universidad Complutense, Madrid; U.S. Oncology Research, The Woodlands, TX ; Cancer Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea; British Columbia Cancer Agency, Vancouver, Canada; Brustzentrum der Universität München, Munich, Germany; State Budget Medical Institution Republican Clinical Oncology, Ufa, Russia; All-Ireland Cooperative Oncology Research Group, Dublin; M.D. Anderson Cancer Center, University of Texas, Houston; and Institut Curie, Paris highlights the role of Palbociclib and Letrozole in Advanced Breast Cancer.” This research paper was published, in the 17 Nov 2016 issue of the journal “N Engl J Med.” (one of the world’s leading medical Journal with an Impact Factor of 70.670), by  Laskar award winner Prof. DennisSlamon, MD., PhD., Finn RS 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 advanced breast cancer and in other advanced metastatic cancers: A pharmaceutical mixture encompassing Palbociclib,  Letrozole  and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as PDCD4, ACAT1,  p53, and TA-p73/p63, inhibits immune-inhibitory receptors/molecules, targets cancer stem cells, confers protection against chemoresistance and prolongs survival, and stalls advanced breast cancer  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–more than 2 50,000 patients are diagnosed with breast cancer ever year in the US– 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?

Laskar award winner (2019) Prof. Dennis J Slamons research team has recently shown that treating advanced breast cancers (Hormone receptor positive (HR+)/Epidermal growth factor receptor negative (HER2-) with a pharmaceutical mixture encompassing Palbociclib (a CDK4/CDK6 inhibitor) and Letrozole (an aromatase inhibitor)(1)  the overall anti-tumor response; and cytotoxic response was much greater when compared with other anti-metastatic breast cancer drugs. For instance, with Palbociclib plus Letrozole, the overall survival was 24.8 months, while with placebo plus Letrozole, the overall survival was 14.5 months, suggesting that the CDK inhibitor Palbociclib, in combination with Letrozole is an effective treatment regimen for hormone receptor positive (HR+)/Epidermal growth factor receptor negative (HER2-) advanced breast cancer patients. However, the molecular mechanism of action of  Palbociclib-Letrozole in stalling the progression of advanced breast cancer remains largely unknown.  Palbociclib, whose brand name is Ibrance, & Palbonix, marketed by Pfizer company, was sold for $ 4.118 billion, in 2018.


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 advanced metastatic breast 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 Palbociclib (Trade name: Ibrance, Palbonix & PD-0332991) and Letrozole (Femara), 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 PDCD4 (Programmed Cell Death 4), & ACAT1 (Acetyl-Coenzyme A acetyltransferase 1); (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  a pharmacological formulation encompassing Palbociclib and Letrozole 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 Palbociclib and Letrozole increases the expression of tumor/metastatic suppressors, such as PDCD4, ACAT1, 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 advanced metastatic breast cancer (HR+/HER2- ).

Figure 2 The fact sheet that reveals the current status of CDK4/6 inhibitor Palbociclib and the aromatase inhibitor Letrozole.

Figure 3 A pharmacological formulation encompassing Palbociclib and Letrozole may not only function as a tumor/metastatic suppressors agent in advanced metastatic breast cancers,  but also in mutant-p53 expressing human cancers.

Figure 4. A pharmacological formulation encompassing  Palbociclib, Letrozole and Probiotic Lactobacillus rhamnosus may attenuate the progression of advanced  metastatic cancers, including advanced metastatic breast cancer, through induction of tumor/metastatic suppressors, such as PDCD4, ACAT1, p53, TAp73/p63, INK4a, p19ARF and others

Figure 5. While the CDK4/6 inhibitor Palbociclib (developed by Pfizer) and Letrozole have been shown to attenuate the progression of advanced breast cancer, their mechanism of action remain largely unknown.  This study presented here suggests, for the first time, that Palbociclib and Letrozole, by up regulating the expression of  tumor/metastasis suppressors PDCD4 and ACAT1  and others (figs.1-4), they may attenuate the progression of advanced metastatic breast cancer  and other advanced cancers.

Figure 6. While the CDK4/6 inhibitor Palbociclib (developed by Pfizer) and  the aromatase inhibitor Letrozole have been shown to attenuate the progression of metastatic breast cancer, their mechanism of action remain largely unknown.  This study presented here highlights the importance of the first antibody-drug, Herceptin, discovered by Prof. Dennis J Slamon, who shared the Laskar award for this year (2019), with others, targets the cancer causing oncoprotein Her2/neu  in advanced breast cancers.

Thus, a pharmacological formulation encompassing “Palbociclib and Letrozole or their analogs/functional/mechanistic equivalents”, either alone or in combination with other known anti-cancer/metabolic drugs, or probiotics enriched with anti-cancer activity, such as  Lactobacillus rhamnosus,” may be used to inhibit the progression of advanced  cancers, including metastatic breast cancer, and thereby 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 Palbociclib and  Letrozole increase the expression of tumor/metastatic suppressors PDCD4 and ACAT1?

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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 advanced breast cancer and in other advanced metastatic cancers: A pharmaceutical mixture encompassing Palbociclib,  Letrozole  and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as PDCD4, ACAT1,  p53, and TA-p73/p63, inhibits immune-inhibitory receptors/molecules, targets cancer stem cells, confers protection against chemoresistance and prolongs survival, and stalls advanced breast cancer  progression, via up-regulation of its target gene, 5/October/2019, 1.00 am, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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