The Combination of Panzem(R) and Velcade(R) in Multiple Myeloma

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Panzem(R) is currently being evaluated in Phase 1 and Phase 2 oncology clinical trials, including multiple myeloma. In anticipation of continued clinical trials using Panzem(R) in combination with approved agents, we evaluated the preclinical effectiveness of Panzem(R) alone or with Velcade(R). Part of the rationale for this combination stems from the inhibition of the nuclear transcription factors, NFkappaB and HIF-1alpha, by Velcade(R) and Panzem(R), respectively. Many of Velcade's anti-myeloma effects are believed to be due to the inhibition of proteosome function and blockage of NFkappaB, leading to a downregulation in the expression of various growth, survival, and angiogenic factors. Panzem(R) disrupts microtubule function and inhibits not only NFkappaB, but also the nuclear transcription factor, HIF-1alpha. In the presented work, preclinical in vitro studies showed the combination of Panzem(R) with Velcade(R) to have greater antiproliferative effects on two human multiple myeloma cell lines tested than either agent alone. The enhanced growth inhibition obtained with the combination was associated with an increase in apoptosis-related proteins, decreased levels of the nuclear transcription factors, HIF-1alpha, pSTAT3 and NFkappaB, and a decrease in the autocrine growth factor, IL-6. Increased antiproliferative activity against human multiple myeloma cells with the combination of Panzem(R) and Velcade(R) was also observed in vivo. Oral administration of Panzem(R) in combination with a maximally-tolerated dose of Velcade(R) resulted in 65% growth inhibition of advanced multiple myeloma. Administration of Velcade(R) or Panzem(R) alone inhibited tumor growth by approximately 35%. Tumor tissue and plasma samples from preclinical models showed that, in addition to decreased angiogenesis, the combined treatment mirrored the effects observed in vitro (increased apoptosis and decreased transcription factors and IL-6).

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