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The PD1-PD-L1 pathway blockade enhances the efficacy of Cancer immunotherapy in Glioblastoma: A therapeutic mix encompassing Temozolomide, Mevastatin, Cyclabezaprine, Hydralizine, SNX5422, Salinomycin (TMCHSS) inhibits oncoproteins EGFR, and Bcl-xl expression, increases tumor suppressor p53 expression, inhibits glioblastoma proliferation, increases interferon-IFNγ signaling, increase antigen presentation and unfolding response, increases Cytotoxic activity of T-cells, decreases tumor burden and increases survival via up-regulation of its target gene, 9/October/2018, 12.16 pm

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Introduction:What they say:

A recent study from Department of Molecular and Medical Pharmacology, David Geffen UCLA School of Medicine, Los Angeles, California, USA; Jonsson Comprehensive Cancer Center, David Geffen UCLA School of Medicine, Los Angeles, California, USA; and Ahmanson Translational Imaging Division, David Geffen UCLA School of Medicine, Los Angeles, California, USA shows that Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma”. This study was published, in the 9 October 2017 issue of Nature medicine (one of the best journals in General medicine with an impact factor of 29 plus), by Prof Nathanson DA, Mai WX and others


What we say:

On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that:  The PD1-PD-L1 pathway blockade enhances the efficacy of Cancer immunotherapy in Glioblastoma: A therapeutic mix encompassing Temozolomide, Mevastatin, Cyclabezaprine, Hydralizine, SNX5422, Salinomycin (TMCHSS) inhibits oncoproteins EGFR, and Bcl-xl expression, increases tumor suppressor p53 expression, inhibits glioblastoma proliferation, increases interferon-IFNγ signaling, increase antigen presentation and unfolding response, increases Cytotoxic activity of T-cells, decreases tumor burden and increases survival via up-regulation of its target gene


From significance of the study to Public health relevance: 

Given that: (i) glioblastoma is the most aggressive cancer and it accounts for 15% of all brain cancers; (ii) the chances of survival of people diagnosed with glioblastoma are less than one-and-a-half-years; (iii) Epidermal growth factor receptor (EGFR) gene is either overexpressed or carries an extra copy in classical subtype of glioblastoma; (iv) Glioblastoma multiforme (GBM) is resistant to apoptosis induced by conventional chemotherapeutic agents; (v) the molecular pathways involved in the development of glioblastoma are not completely understood yet; (iv) blockade of immune evasion molecule such as PD-1 is effective only in minority of cancer patients; (iv) each year nearly 14 million people are diagnosed with cancer globally; (v) cancer deaths globally are expected to be doubled in the next decade; (vi) metastasis is the principle reason for most of the cancer deaths; (vii) cancer treatment 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 effectively activate patients’ immune system against tumors (Cancer immunotherapy); (ii) a way to improve the efficacy of immunotherapy by targeting more immune evasion molecules at a time; (iii) anti-cancer drugs that target cancer stem cells that aid in tumor relapse and resistance; (iv) anti-cancer drugs that target cell adhesion molecules that aid in metastatic spread; (v) a cheaper alternative to the existing expensive anticancer drugs; (vi) a side-effect-free natural product-based drug; (vii) increase the therapeutic index of anti-cancer drugs; and (viii) a way to effectively treat and prevent metastatic progression and relapse of advanced/drug-resistant cancers.


What is known?

It has recently been shown that blocking cell surface receptor PD-1 with antibodies one could make tumors shrink. This work, relating to Cancer immunotherapy, has been chosen as Science’s breakthrough of the year recently.

Prof Nathanson DA’s research team has shown recently that: (i) suppression of EGFR-mediated glucose metabolism in glioblastoma cells results in minimal cancer cell death only; (2) oncosurvival protein Bcl-XL inhibits cytoplasmic p53 from inducing apoptosis; and (3) combination of EGFR inhibition and stabilzation of p53 using the brain-penetrating compound Idasanutlin results in inhibition of cancer progression in glioblastoma xenograft models, suggesting that combinatorial inhibition of EGFR-mediated signaling and activation of tumor suppressor p53 may stall glioblastoma progression and improve cancer therapy.


From research findings to Therapeutic opportunity:

A therapeutic mix encompassing Temozolomide, Mevastatin, Cyclobenzaprine, Hydralazine, SNX5422, Salinomycin (TMCHSS), by increasing the expression of its target gene, it may decrease and increase EGFR/Bcr-XL and p53 expression, respectively (fig. 1). Thereby, it may: (i) diminish the expression of a number of immune evasion molecules in cancer cells; (ii) increase IFNγ signaling; (iii) increase antigen presentation; (iv) augment unfolded protein response: (v) the number of tumor-infiltrating immune cells; (vi) increase T-cell anti-tumor immunity; (vii) inhibits glioblastoma proliferation; (viii) decrease tumor burden and promote growth suppression; (ix) increase survival of patients with glioblastoma; and (x) increase the efficacy of immunotherapy (fig. 1).

Figure 1. Mechanistic insight into how a pharmaceutical mixture encompassing  Temozolomide, Mevastatin, Cyclabezaprine, Hydralizine, SNX5422, Salinomycin (TMCHSS) simultaneously decreases oncoproteins EGFR and Bcl-xl, while increasing the expression of tumor suppressor proteins, including p53 expression. TMCHSS, by down-regulating the expression of EGFR and Bcl-xl and by up-regulating the expression of p53, it augments T-cell mediated anti-tumor immunity and cancer immunotherapy efficacy

Figure 2. The chemical structure of Temozolomide, Mevastatin, Cyclabezaprine, Hydralizine, SNX5422, Salinomycin (TMCHSS)TMCHSS may augment anti-tumor immunity and attenuate glioblastoma progression.

Thus, pharmacological formulations encompassing Temozolomide, Mevastatin, Cyclabezaprine, Hydralizine, SNX5422, Salinomycin (TMCHSS) or their analogs, either alone or in combination with other drugs“ may be used to (i) inhibit the progression of glioblastoma; and (ii) enhance the efficacy of Cancer Immunotherapy.


Details of the research findings:

Idea Proposed/Formulated (with experimental evidence) by:

Dr L Boominathan Ph.D.

Terms & Conditions apply http://genomediscovery.org/registration/terms-and-conditions/

Amount: $1, 500#

Undisclosed mechanistic information: How a therapeutic mix encompassing  Temozolomide, Mevastatin, Cyclobenzaprine, Hydralazine, SNX5422, Salinomycin (TMCHSS) suppresses the expression of EGFR, and Bcl-XL and augments anti-tumor immunity

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References:

Citation: Boominathan, L., The PD1-PD-L1 pathway blockade enhances the efficacy of Cancer immunotherapy in Glioblastoma: A therapeutic mix encompassing Temozolomide, Mevastatin, Cyclabezaprine, Hydralizine, SNX5422, Salinomycin (TMCHSS) inhibits oncoproteins EGFR, and Bcl-xl expression, increases tumor suppressor p53 expression, inhibits glioblastoma proliferation, increases interferon-IFNγ signaling, increase antigen presentation and unfolding response, increases Cytotoxic activity of T-cells, decreases tumor burden and increases survival via up-regulation of its target gene, 9/October/2018, 12.16 pm, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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