P-G3 Unravelling the mechanism of action of HLBT-100 molecule against Adult T-Cell leukemia

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Adult T-cell leukemia-lymphoma (ATL) is a leukemia of mature CD4 T cells that develops after long-term infection of human T-cell leukemia virus (HTLV-1). The prognosis for patients living with the disease is poor, with chronic ATL median survival is 2 years. Once they are diagnosed with acute/lymphomatous ATL, patients have less than 1 year of life left. Current standard of care involves chemotherapy, combination of zidovudine (AZT) and IFN-α or Arsenic Trioxide and IFNa, antibody therapy (CD25, CCR4) and/or allogeneic stem cell transplantation, all of which will improve the median survival but are not effective for long term treatment. Hence there is an unmet need to discover and develop new and effective treatments against ATL. Strategies targeting signaling networks activated in ATL has been tried with some success. We have been testing a novel targeting of the JAK-STAT pathway with our novel small molecule inhibitor HLBT-100. In vitro experiments showed that HLBT-100 enhances serine-threonine phophorylation of STAT3 by blocking the tyrosine phosphorylation of this molecule. In normal cells, this would allow mitochondrial translocation of the phosphorylated STAT3 after which STAT3 sustains homeostasis of cells through the enhancement of mitochondrial energy generation. However this pathway seems non-functional in ATL cells. Thus, we hypothesize HLBT-100 seems to preferentially induce apoptotic death of ATL cells without damaging normal cells. We are currently validating this using a novel in vivo mouse model of ATL.

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