Here is an abstract that describes the mouse experiment
(RPMI-8226 human MM cells were implanted as subcutaneous xenografts in NOD/SCID mice )
Activity of IPI-504, a Water-Soluble Hsp90 Inhibitor,
Combined with Bortezomib in a Human Multiple Myeloma
Xenograft Model
Margaret A. Read, PhD
IPI-504 is a novel chemical reduction product of 17-AAG, a well-characterized Hsp90 inhibitor. Unlike 17-AAG, which suffers from poor aqueous solubility, IPI-504 exists as a hydrochloride salt which ishighly water soluble. In vivo, IPI-504 inter-converts with 17-AAG and exists in a pH and enzyme-mediated dynamic redox equilibrium. Thus, IPI-504 recapitulates the Hsp90 inhibitory properties and biological activity of 17-AAG without its formulation liabilities. IPI-504 has demonstrated in vitro and in vivo anti-tumor effects in a variety of cancers including xenograft and orthotopic models of multiple myeloma (MM), and is currently in a phase 1 dose-escalation trial in patients with relapsed/refractory MM. A preclinical study was conducted to evaluate activity of IPI-504 in combination with agents thatare active in MM, including the proteasome inhibitor bortezomib. Both IPI-504 and bortezomib are known to impact cellular protein homeostasis, and they showed robust synergistic cytotoxic activity invitro against MM cell lines. These data provided rationale for the combination of the two agents in anin vivo study to evaluate efficacy and pharmacodynamic markers of Hsp90 and proteasome inhibition. RPMI-8226 human MM cells were implanted as subcutaneous xenografts in NOD/SCID mice and animals were randomized into the following treatment groups once tumors reached approximately 100mm3: vehicle, 75mg/kg IPI-504, 0.25mg/kg bortezomib, combination of IPI-504 with bortezomib. All mice were dosed by intravenous injection 2x/week for up to 4 weeks. No significant body weight loss was seen in any groups. Administration of IPI-504 and bortezomib at these sub-effective concentrationsresulted in tumor growth inhibition of 54%-56% and 10%-56%, respectively. The combination of IPI-504 and bortezomib resulted in tumor growth inhibition that was significantly greater than with either agent alone, ranging from 77% to 100%. Hsp70 levels in tumors increased in the IPI-504 treated groups, indicating inhibition of Hsp90, and levels of 20S proteasome inhibition were consistent withthe bortezomib doses used. Plasma M protein levels decreased relative to decreases in tumor volume. Thus, destabilization of Hsp90 client proteins with IPI-504 while blocking their degradation with the proteasome inhibitor bortezomib can result in inhibition of tumor growth significantly more than either agent alone. These data provide rationale for clinical evaluation of these agents in combination.
Submitted by Margaret A. Read, PhD, Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts, USA, on behalf ofMM Pink, CS Pien, VT Travaglione, E Normant, J Patterson, JK Tong, C Fritz, V Palombella, J Adams, and M Read November 21–22, 2005
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