Introduction:What they say:
A recent study from Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands has identified CMTM6 and CMTM4 as PD-L1 protein regulators. This study was published, in the 16 August 2017 issue of Nature (one of the best journals in General science with an impact factor of 43 plus), by Prof Schumacher TNM, Mezzadra R and others. Relating to this finding, a research paper,entitled “CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity”, was published in the same issue of Nature. This study was conducted by Prof. Mark A. Dawson, Marian L. Burr and others, from Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3052, Australia; Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK; Centre for Cancer Research, University of Melbourne, Melbourne, Australia; and Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia.
Yet another research paper, in correspondence with the research findings mentioned above, entitled “CDK4/6 inhibition triggers anti-tumour immunity”, was also published in the same issue of Nature. This research work was carried out, by Prof. Jean J. Zhao, Shom Goel and others, at the Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA; and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
What we say:
On the foundation of these interesting findings,Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that: Natural product-derived CDK4/6 pathway blockade enhances the efficacy of Cancer immunotherapy: A pharmacological mixture encompassing natural products Berberine, Nimbolide, N-Acetyl-cysteine (BNN) and the anticancer drug Doxorubicin(D) inhibits the expression of cell cycle protein CDK4/CDK6, increases levels of T-III IFNs, inhibits the proliferation of Treg cells, decreases DNMT1 expression, inhibits the expression of a number of immune evasion molecules, increases antigen presentation and unfolding response, increases Cytotoxic activity of T-cells, decreases tumor burden and increases survival via up-regulation of its target genes
From Significance of the study to Public health relevance:
Given that: (i) PD-1 checkpoint blockade is effective only in minority of cancer patients; (ii) each year nearly 14 million people are diagnosed with cancer globally; (iii) cancer deaths globally are expected to be doubled in the next decade; (iv) metastasis is the principle reason for most of the cancer deaths; (v) cancer treatment causes the highest economic loss compared to all the known causes of death worldwide, there is an urgent need to find: (i) an effective way to activate patients’ own immune system against tumors (Cancer immunotherapy); (ii) a way to improve the efficacy of immunotherapy by targeting more than one immune evasion molecules; (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.
Profs. Mark A. Dawson, Schumacher and their research team members have shown that CMTM6/4 (a type-3 transmembrane protein): (1) function as positive regulators of programmed death-1 (PD-1) ligand 1 (PD-L1)[(also known as CD274 or B7-H1] and they used a genome-wide CRISPR–Cas9 screen and a haploid genetic screen to identify them; (2) co-localize with PD-L1 protein at the plasma transmembrane; and maintain its cell surface expression; (3) stabilize PD-L1 by decreasing its ubiquitination; (4) prevent PD-L1 from lysosome-mediated degradation; (5) increase PD-L1 half-life; (6) depletion decrease PD-L1 levels; and (7) augment the ability of PD-L1 to inhibit T-cells, suggesting that inhibition of CMTM6/4 may decrease the levels of PD-L1 and enhance the efficacy of cancer immunotherapy.
Followed by this study, Prof. Jean J. Zhao and his research team members have shown that inhibition of CDK4/6 (Cyclin-dependent kinase-4/6) results in: (1) activation of endogenous retroviral elements; (2) increased levels of double-stranded RNA (dsRNA); (3) increased production of type III interferons (T-III IFNs); (4) increased presentation of tumor antigens; (5) suppression of proliferation of regulatory T cells (Treg); (6) decreased activity of E2F target, DNA methyltransferase 1 (DNMT1); (7) activation of cytotoxic T-cell (CD8(+)-mediated clearance of cancer cells; and (8) increased clearance of tumor cells, which is further augmented by immune checkpoint blockade, suggesting that inhibition of CDK4/6, together with other immune checkpoint inhibitors, may effectively augment immune-mediated attack on tumor cells and clear them.
From Research Findings to Therapeutic opportunity:
A pharmacological mixture encompassing natural products Berberine, Nimbolide, N-Acetyl-cysteine (BNN) and the anticancer drug Doxorubicin (D), by increasing the expression of its target gene, it may decrease CDK4/6 expression (fig. 1). Thereby, it may: (i) inhibit tumor cell cycle; (ii) increase the expression of endogenous retroviral elements; (iii) increase the levels of dsRNA; (iv) augment the levels of T-III IFNs; (v) increase the expression of tumor antigens; (vi) inhibits the proliferation of Treg cells: (vii) decrease DNMT1 expression; (viii) diminish the expression of a number of immune evasion molecules in cancer cells; (ix) increase IFNγ signaling; (x) increase transcription factor T-bet expression; (xi) increase antigen presentation; (xii) increase CD8(+) cytotoxic T lymphocyte function; (xiii) augment unfolded protein response: (xiv) the number of tumor-infiltrating immune cells; (xv) increase T-cell anti-tumor immunity; (xvi) decrease tumor burden and promote growth suppression; (xvii) inhibit metastatic cancer progression; (xviii) increase survival of patients with cancers; and (xviiii) increase the efficacy of immunotherapy (fig. 1).
Thus, pharmacological formulations encompassing “Berberine, Nimbolide, N-Acetyl-cysteine and Doxorubicin (BNND) or their analogues, either alone or in combination with other known anticancer agents“ may be used to (i) inhibit the progression of tumors; 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.
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Undisclosed mechanistic information: How a pharmacological mixture encompassing Berberine, Nimbolide, N-Acetyl-cysteine and Doxorubicin (BNND) suppresses the expression of CDK4/6 and augments anti-tumor immunity
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Citation: Boominathan, L., Natural product-derived CDK4/6 pathway blockade enhances the efficacy of Cancer immunotherapy: A pharmacological mixture encompassing natural products Berberine, Nimbolide, N-Acetyl-cysteine (BNN) and the anticancer drug Doxorubicin(D) inhibits the expression of cell cycle protein CDK4/CDK6, increases levels of T-III IFNs, inhibits the proliferation of Treg cells, decreases DNMT1 expression, inhibits the expression of a number of immune evasion molecules, increases antigen presentation and unfolding response, increases Cytotoxic activity of T-cells, decreases tumor burden and increases survival via up-regulation of its target genes, 31/August/2017, 1.33 am, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org
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