Combinatorial therapy for brain tumor and oesophageal squamous cell carcinoma:  A therapeutic mix encompassing metformin and navitoclax/ABT263 (MAN) inhibits the expression of Integrin a7 (ITGA7), impairs laminin-induced/FAK-mediated signalling, inhibits the proliferation of glioblastoma and oesophageal squamous cell carcinoma stem cells, suppresses tumor cell migration, reduces metastasis and prolongs survival, via down-regulation of its target gene, 5/February/2019, 6.21 am

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Introduction: What they say:

A study from the Institute of General Pathology, Università Cattolica del Sacro Cuore and Fondazione Policlinico Universitario A. Gemelli, 00168 Rome, Italy; Department of Oncology and Molecular Medicine – Istituto Superiore di Sanità, 00161 Rome, Italy; National Cancer Institute Regina Elena, 00144 Rome, Italy shows that “Integrin a7 Is a Functional Marker and Potential Therapeutic Target in Glioblastoma.” This study was published in the 9 June 2017 issue of the journal “Cell Stem Cell” [One of the best journals in Stem cell Biology with an I.F of 22.268 plus] by Prof. Ruggero De Maria, Tobias L. Haas, and others.

Another study from the Centre for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 852, China; and State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China shows that Integrin a7 is a functional cancer stem cell surface marker in oesophageal squamous cell carcinoma.” This study was published in the 7 December 2016 issue of the journal “Nature communications” [One of the best journals in General Biology with an I.F of 11.329 plus] by Prof.Guan XY, Ming XY and others.


What we say:

On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that:  Combinatorial therapy for brain tumor and oesophageal squamous cell carcinoma:  A therapeutic mix encompassing metformin and navitoclax/ABT263 (MAN) inhibits the expression of Integrin a7 (ITGA7), impairs laminin-induced/FAK-mediated signaling, inhibits the proliferation of glioblastoma and oesophageal squamous cell carcinoma stem cells, suppresses tumor cell migration, reduces metastasis and prolongs survival, via down-regulation of its target gene


From Significance of the study to Public health relevance:

Given that: (i) each year nearly 14 million people are diagnosed with cancer globally; (ii) metastasis is common to all forms of cancers; (iii) metastasis is the principle reason for most of the cancer deaths; (iv) even intense multimodal treatment saves only less than 50% of metastatic patients; (iv) our understanding is incomplete in terms of down stream molecular targets and the oncogenic/malignant pathways involved in metastatic cancers; (v) cancer deaths globally are expected to be doubled in the next decade; (vi) 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 activate patients’ immune system against metastatic tumors (Cancer immunotherapy); (ii) anti-cancer drugs that target cancer stem cells that aid in tumor relapse and resistance; (iii) anti-cancer drugs that target cell adhesion molecules that aid in metastatic spread; (iv) a cheaper alternative to the existing expensive anticancer drugs; (v) a side-effect-free natural product-based drug; (vi) increase the therapeutic index of anti-cancer drugs; and (vii) a way to effectively treat and prevent metastatic progression and relapse of advanced/drug-resistant cancers.


What we infer from what they say:

Prof. De Maria’s research team has recently shown that: (1) Integrin a7 (ITGA7) is highly expressed in glioblastoma stem cells (GSCs) and in high-grade gliomas; (2) increased expression of ITGA7 in glioblastoma stem cells (GSCs) and in high-grade gliomas correlate with poor survival of patients; (3) highly expressed ITGA7 promotes growth and invasion of glioblastoma stem cells (GSCs); (4)tumor-enriched ITGA7 promotes metastatic capacity of glioma cells; and (5) inhibiting the expression of ITGA7 with RNAi or with monoclonal antibodies stalled the metastatic glioblastoma progression, suggesting that inhibition of ITGA7 may inhibit metastatic glioblastoma.

Earlier, Prof.Guan XY’s research team had shown that: (1) Integrin a7 (ITGA7) is highly expressed in oesophageal squamous cell carcinoma (OSCC); (2) ITGA7+ve cells are associated with poor differentiation, lymph node metastasis and worse prognosis; (3) ITGA7 expressing cells have increased expression of stemness-associated genes, enriched with epithelial-mesenchymal transition features, increased abilities to self-renew, differentiate and resist anticancer drug therapy;(4) ITGA7 promotes cancer stem cell properties through activation of FAK(Focal Adhesion kinase)-mediated signalling pathways, suggesting that inhibition of ITGA7 may inhibit stemness associated with oesophageal squamous cell carcinoma and thereby inhibit its metastatic progression.


From research findings to therapeutic opportunity :

This study suggests a combinatorial therapy for metastatic glioblastoma and oesophageal squamous cell carcinoma. A therapeutic mix encompassing metformin and navitoclax/ABT263 (MAN), by increasing the expression of its target genes, it may decrease the expression of ITGA7 (fig. 1). Thereby, it may: (i) inhibit ITGA7-laminin receptor signaling in glioblastoma; (ii) inhibit ITGA7-FAK-mediated signaling pathways in oesophageal squamous cell carcinoma (OSCC); (iii) inhibit proliferation and survival of glioblastoma and OSCC stem cells; (iv) stifle tumor cell migration; (v) decrease metastatic capacity of cancer cells; (vi) stall glioblastoma progression; and (vii) promote survival. Thus, pharmacological formulations encompassing “metformin and navitoclax/ABT263 (MAN) or their analogs, either alone or in combination with other known anticancer drugs” may be used to inhibit metastatic progression of glioblastomas and oesophageal squamous cell carcinoma (fig. 1).

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Figure 1. Mechanistic insights into how a therapeutic mix encompassing metformin and navitoclax/ABT263 (MAN) suppresses the expression of ITGA7-Laminin receptor and ITGA7-FAK-mediated signaling to stall the metastatic progression of glioblastomas and oesophageal squamous cell carcinoma, respectively.

Figure 2. Combinatorial therapy for glioblastomas and oesophageal squamous cell carcinoma. A therapeutic mix encompassing metformin and navitoclax/ABT263 (MAN) attenuates the progression of metastatic progression of glioblastomas and oesophageal squamous cell carcinoma.


Details of the Research findings:

Idea Proposed/Formulated (with experimental evidence) by Dr L Boominathan Ph.D.

Amount: $500#

Undisclosed mechanistic information: How does a therapeutic mix encompassing metformin and navitoclax/ABT263 (MAN) decrease the expression of ITGA7-Laminin receptor signaling?

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References:

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Citation: Boominathan, L., Combinatorial therapy for brain tumor and oesophageal squamous cell carcinoma:  A therapeutic mix encompassing metformin and navitoclax/ABT263 (MAN) inhibits the expression of Integrin a7 (ITGA7), impairs laminin-induced/FAK-mediated signalling, inhibits the proliferation of glioblastoma and oesophageal squamous cell carcinoma stem cells, suppresses tumor cell migration, reduces metastasis and prolongs survival, via down-regulation of its target gene, 5/February/2019, 6.21 am, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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