Abstract

The Multi-Potent Novel Biomolecule T11 Target Structure (T11TS) helps in Malignant Glioma Abrogation: A Preclinical Study

Swapna Chaudhuri, Professor, Calcutta School of Tropical Medicine

Patients with Glioblastoma multiforme have a life span of 12 – 18 months in spite of conventional treatments. So, molecular therapy including immunotherapy is the option to lengthen the life span of these patients. Glioma generated immunosuppressive factors like TGF ß, IL10, PGE2 and the Gangliosides devastate the immune machinery. In our lab, the disease relevance of the anti-neoplastic biomolecule T11TS has been first deciphered. Immunotherapy with T11TS (a glycopeptide derived from SRBC) on an established rat model of glioma rejuvenates the deserted immune system and causes profound immune potentiation both at the peripheral and intracranial levels. T-cell signaling when channeled in the positive direction leads to T-cell activation, survival and proliferation and serves to eliminate the neoplastic antigenic challenge. Although, certain molecules of the T-cell signaling pathway have been shown to be disrupted in glioma, a holistic view of the changes that occur in the pathway in glioma conditions has never been observed before. We are the first group to show a completely devastated T-cell signaling pathway in glioma conditions. We have also shown that the T11TS, when administered in three doses to glioma-bearing rats, helps in glioma abrogation by reversing the glioma-induced changes in the T-cell signaling pathway and by steering the pathway in the positive direction. It will be discussed how signals are transduced through the lymphocytes to armor them against glioma. The potentiated lymphocytes along with other phagocytic cells like polymorphonuclear cells, macrophages and microglia strike against glioma to eradicate them and ensue apoptotic or programmed cell death. It has been observed that glioma causes severe immune suppression. To unearth the root of this suppression the modulation of hematopoietic stem cells and their apoptotic death were also studied. Hematopoietic stem cells are the mother of all immune cells. Their modulation during glioma and with T11TS therapy indicates the regenerative power of T11TS.Toxicity studies with T11TS revealed that it is totally non toxic. Apart from the immunotherapeutic potential of T11TS the anti-angiogenic property of T11TS will also be discussed. The crucial role of angiogenesis in malignant glioma progression makes it a potential target of therapeutic intervention in glioma. The present preclinical study deciphers the anti-angiogenic potential of T11TS and the underlying molecular mechanisms in malignant glioma. Glioma associated brain endothelial cells (GABEC) were isolated and characterised with phenotypic markers of endothelial cells (CD31 and CD34), whose level diminished with T11TS administration, inhibiting the cell grip. Modulation of matrix metalloproteinases MMP-2 and -9and integrin av and their inhibitors TIMP-1 and TIMP-2 were studied.In GABEC T11TS administration disrupt initiation of glioma angiogenesis by significantly downregulating VEGF/VEGFR-2 expression and pro-survival PI3K/Akt/eNOS proteins alongwith eNOS phosphorylation and NO production, but significantly upregulates PTEN expression. T11TS therapy remarkably inhibits endothelial angiopoietin-1/Tie-2 signaling associated with vessel maturation and stabilization. It simultaneously antagonizes EGFR activation and components of Raf/MEK/ERK pathway, which are essential for angiogenesis induction and proliferation. T11TS dampens pro-inflammatory cytokines which are indispensable for tumour growth and metastatic propagation but upregulates anti–inflammatory cytokines resulting complete abrogation of glioma inflammation and angiogenesis. T11TS triggers apoptosis in GABEC via activation of intrinsic pathway as well extrinsic pathway. Taken together our findings suggest that T11TS can be introduced as an effective anti- neoplastic agent.