HIV-related Kaposi's sarcoma (KS) is a disease of multi-focal vascular proliferation, which predominantly involves the skin but can also involve the visceral organs. Stem cell factor (SCF) and platelet derived growth factor (PDGF) have been implicated in the development of KS and inhibition of the pathways activated by these growth factors is potential therapeutic targets in KS. In a pilot study, ten male patients with AIDS-related cutaneous KS, which progressed despite chemotherapy and/or highly active antiretroviral therapy (HAART), received the PDGF and c-kit inhibitor, imatinib mesylate (Gleevec). At four weeks, five of ten patients had a partial response by tumor measurement and the remainder had clinically stable disease. The majority of patients required dose reductions for toxicity with diarrhea being the most frequent event. Biopsies showed inhibition of PDGF-R after four weeks of imatinib therapy correlated with histologic response. Our clinical data support the hypothesis that activation of the PDGF-R and c-kit are critical in KS tumorigenesis and inhibition of these pathways are potential therapeutic targets.
The specific aims of the proposed study are: 1. Evaluate the clinical efficacy and tolerability of imatinib mesylate treatment of Kaposi's sarcoma. 2. Determine if inhibition of PDGF receptor as assessed by immunohistochemistry predicts response to imatinib therapy in Kaposi's sarcoma. 3. Determine if mutations PDGF or c-kit receptors correlate with primary and secondary resistance to imatinib therapy in Kaposi's sarcoma. This translational study of therapeutic inhibition of PDGF/c-kit in KS would provide insights into etiology of KS and could have a major impact on KS treatment approaches.
| Koon, Henry B; Krown, Susan E; Lee, Jeannette Y et al. (2014) Phase II trial of imatinib in AIDS-associated Kaposi's sarcoma: AIDS Malignancy Consortium Protocol 042. J Clin Oncol 32:402-8 |
