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Introduction: What they say

A study from the Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, California, USA highlights the role of “Docomitinib (PF-00299804), an irreversible Pan-HER inhibitor, inhibits proliferation of HER2-amplified breast cancer cell lines resistant to trastuzumab and lapatinib This research paper was published, in the 3 July 2012 issue of the journal “Molecular Cancer ther.”, by  Prof. Richard Finn M.D., the 2019 Laskar award winner Prof. Dennis J Slamon, MD., PhD., Kalous 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: Treating advanced cancers resistant to Herceptin and LapatinibProbiotic-based Chemotherapy (PCT) targeting cancer stem cells and immune-inhibitory receptors in advanced breast cancers and in other advanced metastatic cancers resistant to Herceptin and Lapatinib: A pharmaceutical mixture encompassing Dacomitinib  (Trade name: Vizimpro, and PF-00299804)  and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as PIAS3, VHL, p53, and TA-p73/p63, INK4a and others, decreases PP2A and Her2 expression, inhibits immune-inhibitory receptors/molecules, targets cancer stem cells, confers protection against chemoresistance mediated by Herceptin and Lapatinib, and stalls advanced breast cancers  progression, and prolongs survival, via up-regulation of its target gene, 8/November/2019, 6.39 pm


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?

To treat HER2-amplified breast cancers, Trastuzumab (Herceptin) and Lapatinib are more commonly used. However, a significant number of patients develop resistance to these drugs.

Profs. Finn’s, & Dennis J Slamon’s research team had shown that treating advanced breast cancers with Dacomitinib (PF-00299804-an irreversible small molecule pan-HER inhibitor)(1)  reduces the expression of HER2, EGFR, HER4, AKT, and ERK; (2) promotes growth inhibition and apoptosis of breast cancer cells; (3) inhibits the growth of HER2-amplified breast cancer cells that are resistant to Trastuzumaband (4) increases the anti-cancer activity and inhibits the growth of HER-2-amplified breast cancer cells that are resistant to LapatinibHowever, the molecular mechanism of action of  Dacomitinib in stalling the progression of advanced breast cancer that are resistant to Trastuzumab and Lapatinib remains largely unknown.

Dacomitinib, whose brand name is Vizimpro, and PF-00299804, is marketed by Pfizer company, and is predicted to sell for         $ 4.17 billion in 2022. 


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 Dacomitinib (Trade name: Vizimpro, and PF-00299804), 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  PIAS3 (Protein Inhibitor Of Activated STAT 3), & VHL (Von Hippel-Lindau); (iii) increase the expression of a number of other tumor suppressor genes, including p53/TA-p73/p63, and their target genes, INK4a, p19ARF and others (Figure 1);(iv) decreases the expression of Protein phosphatase 2A (PP2A) and Her2/4 and others; (v)activate tumor/metastasis suppressor network; (vi) inhibit immunosuppressive/immune-inhibitory receptors/ molecules; (vii) inhibit the activity and proliferation of cancer stem cells; (viii) inhibit tumor growth; and (ix) promote survival (Figures 1-4). Further, the efficacy of  Dacomitinib 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 Dacomitinib and/or Lactobacillus Rhamnosus increases the expression of tumor/metastatic suppressors, such as PIAS3, VHL, p53, TAp73/p63, INK4a, p19ARF and others, inhibits the expression of immune-inhibitory receptors, PP2A and Her2/4, promotes drug sensitivity to breast cancer cells that are resistant to the treatment of Herceptin and Lapatinib, stops the proliferation of cancer stem cells, and stalls the progression of advanced metastatic breast cancers.

Figure 2 The fact sheet that reveals the current status of HER2/EGFR inhibitor Dacomitinib.

Figure 3 A pharmacological formulation encompassing  Dacomitinib may not only function as a tumor/metastatic suppressors agent in advanced metastatic breast cancers that are resistant to herceptin and lapatinib,  but also in mutant-p53 expressing human cancers.

Figure 4. A pharmacological formulation encompassing Dacomitinib 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 PIAS3, VHL, p53, TAp73/p63, INK4a, p19ARF and others, and down regulation of PP2A and Her2/4.

Figure 5. While the HER2/EGFR inhibitor Dacomitinib (developed by Pfizer) have been shown to attenuate the progression of advanced breast cancer that are resistant to Hereceptin and Lapatinib, its mechanism of action remains largely unknown.  This study presented here suggests, for the first time, that Dacomitinib, by up regulating the expression of  tumor/metastasis suppressors PIAS3, VHL, and others (figs.1-4), and down regulating the expression of PP2A and Her2/4 , it may sensitize breast cancer cells resistant to Hereceptin and Lapatinib, and attenuate the progression of advanced metastatic breast cancers  and other advanced cancers.

Thus, a pharmacological formulation encompassingDacomitinib  or its 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 3-6).

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 Dacomitinib  increase the expression of tumor/metastatic suppressors PIAS3, and VHL?

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References:

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

Citation: Boominathan, L., Treating advanced cancers resistant to Herceptin and LapatinibProbiotic-based Chemotherapy (PCT) targeting cancer stem cells and immune-inhibitory receptors in advanced breast cancers and in other advanced metastatic cancers resistant to Herceptin and Lapatinib: A pharmaceutical mixture encompassing Dacomitinib  (Trade name: Vizimpro, and PF-00299804)  and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as PIAS3, VHL, p53, and TA-p73/p63, INK4a and others, decreases PP2A and Her2 expression, inhibits immune-inhibitory receptors/molecules, targets cancer stem cells, confers protection against chemoresistance mediated by Herceptin and Lapatinib, and stalls advanced breast cancers  progression, and prolongs survival, via up-regulation of its target gene, 8/November/2019, 6.39 pm, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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