Probiotic-based Chemotherapy (PCT) targeting cancer stem cells and immune-inhibitory receptors in metastatic breast cancer and in other advanced metastatic cancers: A pharmaceutical mixture encompassing Palbociclib,  Fulvestrant and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as TPM1 and 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 metastatic breast cancer  progression, via up-regulation of its target gene, 19/September/2019, 10.29 pm

Polypill for cardioprotection: Combinatorial therapy for postnatal Cardiomyocyte proliferation, repair and regeneration:  A four-component Polypill consisting of Hydrochlorothiazide (12·5 mg), Aspirin (81 mg), Atorvastatin (20 mg), and Enalapril (5 mg) or Valsartan (40 mg) [Polypill-HAAE/HAAV]  decreases tumor suppressor MiR-128 and cyclin-dependent kinase inhibitor p27 expression, increases SUZ12 expression, increases Cyclin E and CDK2 expression, promotes proliferation/re-entry of postnatal/adult cardiomyocytes, attenuates fibrosis, ameliorates cardiac dysfunction, and promotes heart repair in response to myocardial infarction, via up-regulation of its target gene, 13/September/2019, 7.43 pm
September 13, 2019
Senolytics therapy for cardiac repair, cardiac regeneration and cardioprotection: Combinatorial therapy for postnatal Cardiomyocyte proliferation, repair and regeneration:  A two-component Pill consisting of Dasatinib and Quercetin (Pill-DQ) decreases tumor suppressor MiR-128 and cyclin-dependent kinase inhibitor p27 expression, increases SUZ12 expression, increases Cyclin E and CDK2 expression, promotes proliferation/re-entry of postnatal/adult cardiomyocytes, attenuates fibrosis, ameliorates cardiac dysfunction, and promotes heart repair in response to myocardial infarction, via up-regulation of its target gene, 20/September/2019, 7.39 am
September 20, 2019
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Introduction: What they say

A study from Institute of Cancer Research and Royal Marsden Hospital, London, David Geffen School of Medicine at University of California, Los Angeles, Santa Monica, and Pfizer Oncology, San Diego, California, USA; and  the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Feinberg School of Medicine, Chicago, USA and others shows that Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer.” This research paper was published, in the 10 Oct 2018 issue of the journal “N Engl J Med.” (one of the world’s leading medical Journal with an Impact Factor of 70.670), by  Prof. Cristofanilli M, MD. (Associate Director for Precision Medicine and Translational Research), Turner NC 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 metastatic breast cancer and in other advanced metastatic cancers: A pharmaceutical mixture encompassing Palbociclib,  Fulvestrant and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as TPM1 and 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 metastatic 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?

Prof. Cristofanillis research team has recently shown that treating advanced metastatic breast cancers (Hormone receptor positive (HR+)/Epidermal growth factor receptor negative (HER2-) with a pharmaceutical mixture encompassing Palbociclib (a CDK4/CDK6 inhibitor) and Fulvestrant(1)  the overall anti-tumor response; and cytotoxic response was much greater when compared with other anti-metastatic breast cancer drugs, such as Fulvestrant alone [Palbociclib plus fulvestrant (overall survival was 34.9 months) or placebo plus fulvestrant [overall survival was 28 months], suggesting that the CDK inhibitor Palbociclib, in combination with Fulvestrant,  is an effective treatment regimen for hormone receptor positive (HR+)/Epidermal growth factor receptor negative (HER2-) advanced metastatic breast cancer patients. However, the molecular mechanism of action of  Palbociclib-Fulvestrant in stalling the progression of advanced metastatic breast cancer remains largely unknown.  Palbociclib, whose brand name is Ibrance, & Palbonix, marketed by Pfizer company, has been shown  to be 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 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 Fulvestrant (Faslodex), 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  a pharmacological formulation encompassing Palbociclib and Fulvestrant 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 Fulvestrant 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 advanced metastatic breast cancer (HR+/HER2- ).

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

Figure 3 A pharmacological formulation encompassing Palbociclib and Fulvestrant  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, Fulvestrant and Probiotic Lactobacillus rhamnosus may attenuate the progression of advanced  metastatic cancers, including metastatic breast cancer, through induction of tumor/metastatic suppressors, such as TPM1, CADM1/2, p53, TAp73/p63, INK4a, p19ARF and others

Figure 5. While the CDK4/6 inhibitor Palbociclib (developed by Pfizer) and Fulvestrant have been shown to attenuate the progression of metastatic breast cancer, their mechanism of action remain largely unknown.  This study presented here suggests, for the first time, that Palbociclib and Fulvestrant, by up regulating the expression of  tumor/metastasis suppressors TPM1, CADM1/2  and others (figs.1-4), they may attenuate the progression of metastatic breast cancer  and other advanced cancers.

Thus, a pharmacological formulation encompassing “Palbociclib and Fulvestrant or their analogs/functional 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 Fulvestrant increase the expression of tumor/metastatic suppressors TPM1 and 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 metastatic breast cancer and in other advanced metastatic cancers: A pharmaceutical mixture encompassing Palbociclib,  Fulvestrant and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as TPM1 and 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 metastatic breast cancer  progression, via up-regulation of its target gene, 19/September/2019, 10.28 pm, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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