Understanding the mechanism of mTOR inhibition in human herpes virus-8 associated malignancies Public Deposited

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  • March 22, 2019
Creator
  • Roy, Debasmita
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • In this dissertation, I have attempted to characterize the molecular features of Primary Effusion Lymphoma (PEL) and Kaposi's Sarcoma (KS) that render them addicted to the PI3K-mTOR pathway. PEL and KS constitute two signature diseases caused by Human Herpes Virus-8 (HHV8), or Kaposi's Sarcoma-associated Herpes Virus (KSHV), in immunocompromised individuals. KS is a cancer of endothelial cell origin and PEL a Diffuse-Large B-cell Lymphoma (DLBCL). We treated PEL cell lines in vitro and in vivo to show that sensitivity to Rapamycin, the major mTOR kinase inhibitor, is in part mediated by inhibition of interleukins: IL6 and IL10 (Sin, SH., Roy, D., et al.). We demonstrated that Phosphatase and Tensin homolog on chromosome-10 (PTEN), the major PI3K-mTOR negative regulator, is phosphorylated at Serine 380, in both PEL and KS. Reports in the literature have shown that phosphorylation at this residue results in a closed, inactive conformation of PTEN. This led us to speculate that unlike other cancers PTEN is inactivated not genetically, but via post-translational phosphorylation, in PEL and KS (Roy and Dittmer, in revision). Further, using the Affymetrix 6.0 SNP array we associated deletions in common fragile site tumor suppressor genes: FHIT and WWOX with PEL. We correlated EBV-negative PEL with increased genomic instability compared to EBV-positive (Roy et al., submitted). Using a newly developed L1T2 cell line we demonstrated efficacy of Rapamycin against KS-like tumors in mice. We showed that Rapamycin inhibited secretion of Vascular Endothelial Growth Factor (VEGF) in vitro, which translated into defective tumor vasculature and angiogenesis in vivo. Unlike treatment with chemotherapeutic Doxorubicin, Rapamycin did not increase tumor apoptosis. We noted that Rapamycin alone is more tumor inhibitory than in combination with Doxorubicin. This led us to speculate that tumorigenesis of KS is more dependent on optimal tumor microenvironment than tumor cell proliferation. Lastly, we conducted an AIDS Malignancy Consortium (AMC) study of Rapamycin in AIDS-associated KS. We noted partial response or stable disease in all the patients. Molecular analysis showed that we could target mTOR kinase activity in patients without adversely affecting their AIDS. These data collectively suggest that mTOR inhibition can be an effective therapeutic in transplant- and AIDS-associated HHV8 malignancies.
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  • In Copyright
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  • " ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Genetics and Molecular Biology."
Advisor
  • Dittmer, Dirk
Degree granting institution
  • University of North Carolina at Chapel Hill
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Place of publication
  • Chapel Hill, NC
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  • Open access
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