IPI-504, a selective Hsp90 inhibitor is biologically active and tolerated in combination with trastuzumab in preclinical models of HER2 positive tumor xenografts

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IPI-504 is a highly soluble small molecule inhibitor of heat shock protein 90 (Hsp90). Hsp90 is a protein chaperone that stabilizes many oncoproteins and cell signaling proteins important for cell proliferation and survival. We have previously reported that IPI-504 was highly effective in inhibiting the growth of both HER2 positive trastuzumab-sensitive and -resistant tumor xenograft models. In this study, we investigated the biological activity of IPI-504 in combination with trastuzumab using HER2 positive human tumor xenografts that are trastuzumab-sensitive and - resistant. In the N87 (trastuzumab-sensitive) study, both IPI-504 and trastuzumab were highly effective in inhibiting the growth of this xenograft. In combination, as assessed by tumor growth delay and response rates, the two agents together yielded greater efficacy than single drug alone. In the JIMT-1 (trastuzumab-resistant) study, trastuzumab alone did not exhibit any anti-tumor activity as expected. In contrast, IPI-504 administered as a single agent resulted in significant inhibition of tumor growth. In combination, trastuzumab did not enhance the anti-tumor activity of IPI-504, although in one combination arm, (10 mg/kg trastuzumab and 75 mg/kg IPI-504), greater tumor growth delay was observed for the combination arm than the respective single agent groups. In the clinic, it is anticipated that drug holidays will be required for IPI-504. To mimic this clinical schedule, a combination study with trastuzumab and IPI-504 (with built-in drug holidays) was performed using JIMT-1 xenograft model. The results indicate that the combination of the two agents yielded greater biological activity than single drug alone. These findings support the development of IPI-504 in combination with trastuzumab in HER2 positive trastuzumab-sensitive and -resistant cancers.