Following therapy, essentially all multiple myeloma patients relapse due to a population of chemoresistant cells leading to eventual patient death. Our lab has identified heparanase, an endoglycosidase, as a master regulator of aggressive myeloma disease. In the present study that was designed to probe the role of heparanase in chemoresistance, we made the striking finding that heparanase promotes survival of tumor cells post-therapy. Using an array of cellular viability assays, we tested for differences in viability and apoptosis between myeloma cells engineered to express high levels of heparanase (HPSE-high) and cells expressing low levels of heparanase (HPSE-low) following their exposure to frontline anti-myeloma drugs (bortezomib, carfilzomib). Results revealed a much smaller apoptotic fraction and higher cell viability following treatment of the HPSE-high cells compared to HPSE-low cells. In addition to promoting tumor survival, we also discovered that myeloma cell expression and secretion of heparanase is dramatically enhanced in response to chemotherapy. Using small molecule inhibitors, we were able to pinpoint that activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was driving the heparanase expression upon chemotherapy. The secreted heparanase generated by chemotherapy was readily taken up by tumor cells growing in culture, consistent with previous studies demonstrating that heparanase is taken up by myeloma tumor cells and that this activates aggressive tumor behavior. Extending our findings to the clinic revealed that in tumor cells from seven out of nine myeloma patients examined, there was a dramatic increase in heparanase gene expression following chemotherapy. Together, these results demonstrate a pivotal role for heparanase in regulating myeloma response to therapy and indicate that the use of heparanase inhibitors may inhibit or delay relapse in myeloma.

Citation Format: Vishnu Prakash C. Ramani, Fenghuang Zhan, Guido Tricot, Ralph D. Sanderson. Heparanase regulates response to chemotherapy in myeloma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1708. doi:10.1158/1538-7445.AM2014-1708