Studies of targeted therapies against human T lymphotropic virus type-1 adult T-cell lymphoma in preclinical animal models.

摘要

Human T lymphotropic virus type 1 (HTLV-1) infects 20 million people worldwide. It is the causative agent of adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). ATL is a refractory T-cell malignancy with a poor prognosis due to its highly aggressive nature and resistance of neoplastic cells to conventional chemotherapies. Herein, the impact of multiple novel therapeutics was investigated in vitro in multiple HTLV-1 cell lines, in an immunodeficient mouse model of ATL, and a rabbit model of early infection.;The proteasome inhibitor bortezomib (PS-341 or Velcade) and the heat shock protein inhibitor 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) exhibited efficacy against multiple cell lines in vitro. In Chapter 2, we document the efficacy of PS-341 and 17-AAG alone and in combination in a preclinical model of ATL. We demonstrate that the combination of PS-341 and 17-AAG synergistically promoted cell death in ATL cell lines and reduced tumor burden in mice during cycles of drug treatments. Positive effects of 17-AAG required continuous drug treatments suggesting requirements for treatment protocols in human subjects.;Histone deacetylase inhibitors (HDACi) have shown efficacy against a variety of cancers. In Chapter 3, we tested the histone deacetylase inhibitors valproic acid and OSU-HDAC42 in our ATL mouse model. Both compounds reduced proliferation of ATL cell lines by promoting apoptosis and histone hyperacetylation. To further test the efficacy of this approach we evaluated OSU-HDAC42 for survival in an ATL NOD/SCID mouse model. Our data provide new directions for the treatment of ATL and support the further development of this class of drug against HTLV-1-associated lymphoid malignancies.;In Chapter 4, we tested the effects of the histone deacetylase inhibitor, valproic acid (VPA), on HTLV-1 proviral load in the rabbit model of early infection. Our data demonstrated that VPA can be safely administered in the rabbit model and altered proviral copy numbers in infected rabbits when compared to controls. This model will be useful to test other HDACi for their effects on HTLV-1 gene expression.;In this thesis, we investigated targeted therapeutics in a preclinical, NOD/SCID ATL mouse model and in a rabbit model of HTLV-1 infection. Our data indicated new directions in the development of targeted therapies against ATL and provide new directions for the design of treatment protocols for future studies.