Liposarcomas
Liposarcomas are the second most common soft-tissue sarcoma. All liposarcomas share a common adipocyte or pre-adipocyte origin. The use of HIV protease inhibitors (PIs) is associated with the “HIV protease-induced lipodystrophy syndrome.” This syndrome is characterized by peripheral fat wasting, central fat accumulation, insulin resistance and hyperlipidemia. Pre-clinical studies suggested alteration of sterol regulatory element binding protein-1 (SREBP-1), a lipogenic transcription factor, in the development of this syndrome. Based upon this syndrome and its proposed pathophysiology, we hypothesized that HIV protease inhibitors might serve as novel, targeted agents against liposarcoma.

Our laboratory has demonstrated that HIV PIs selectively inhibit liposarcoma clonogenic cell growth by inducing both a dose-dependent G1 cell cycle block, which results in reduced proliferation, and apoptosis. Molecular studies have demonstrated that PIs lead to selective post-transcriptional upregulation of SREBP-1 expression and activity in liposarcoma cells only. This results in upregulation of anti-proliferative and pro-apoptotic proteins. Studies are now focused upon understanding the signaling pathway(s) regulating SREBP-1 expression. Based upon these in vitro studies, in vivo studies of PIs in severe-combined immunodeficient (SCID) mice xenografted with human liposarcomas are presently being performed. These liposarcomas have been transduced with a luciferase-expressing retrovirus for more accurate and painless in vivo imaging for tumor response. Based upon these pre-clinical studies, we have developed a clinical trial of PIs for recurrent liposarcomas, which is sponsored by the Food and Drug Administration Orphan Products Development Grants Program.

Chondrosaromcas
Chondrosarcomas are the second most common bone sarcoma. Chondrosarcomas are poorly responsive to chemotherapy. In collaboration with the Cleveland Clinic Foundation, we have demonstrated frequent deletions of the methylthioadenosine phosphorylase (MTAP) gene in primary tumors. MTAP protein is essential for the salvage of adenosine and in methionine synthesis. Cells deficient in this enzyme are totally dependent upon the de novo synthesis of adenine nucleotides. A novel, multi-targeted, anti-folate drug, pemetrexed has been shown to potently inhibit the de novo synthesis of adenine nucleotides. Based upon these laboratory studies, we have developed an international clinical trial of pemetrexed for recurrent chondrosarcomas.