formulation or dosing regimen should be used. As a result, a number of new formulations of 17AAG have been developed, with reported improvements in solubility and toxicity. Several of these new formulations Kinesin Spindle Protein are currently in clinical trials . A list of many clinical trials currently open for Hsp90 inhibitors is presented in Table 1. Combination therapy involving 17AAG has garnered recent attention, and several studies have demonstrated the improved effectiveness of combining traditional cytotoxic chemotherapy or other targeted agents with HSP90 inhibitors. Phase 1 trials of 17AAG in combination with irinotecan, as well as paclitaxel, have demonstrated overall acceptable levels of toxicity . None of the patients in either trial experienced a partial or complete response, but several disease stabilizations were reported.
Both sets of authors CC-5013 conclude that combination therapy certainly warrants further clinical development, and that improved methods of delivery of 17AAG may demonstrate increased future therapeutic potential. Additional data presented in 2007 at the Annual Meeting of the American Society of Hematology showed favorable results for patients with refractory multiple myeloma treated with 17AAG in combination with bortezomib including a response rate of 47% in bortezomibnaïve patients, 47% in bortezomib pretreated patients, and 17% in bortezomibrefractory patients. This included three complete responses, one nearcomplete response, four partial responses, and 11 minor responses overall . Additionally, patients experienced less neuropathy during combination therapy, an effect thought to be secondary to a protective effect from 17AAG.
Finally, a study published in 2007 demonstrated a benefit of 17AAG in combination with trastuzumab for patients with HER2+ metastatic breast cancer prokaryotic refractory to initial treatment with trastuzumab . In this study, 25 patients were treated with a combination of tanespimycin and trastuzumab, resulting in one partial response, four minor responses, and four disease stabilizations. Overall, treatment was welltolerated, with only grade 3 toxicities including mild transaminitis, hypersensitivity reactions Phase 2 trials are currently underway, and 17 AAG is in continued development particularly in combination therapy for treatment of multiple myeloma and metastatic breast cancer.
Another potential use for combination therapy with Hsp90 inhibitors is in the field of radiation therapy. Since Hsp90 is required for cellular stabilization under stress conditions such as those presented by radiotherapy, agents which inhibit the cell’s ability to stabilize under radiationinduced stress may improve the effectiveness of radiotherapy. Furthermore, based on the theory that cancer cells are more sensitive to Hsp90 inhibitors this increase in radiosensitivity is theoretically selective for cancer cells. Several client proteins of Hsp90 have been associated with responses to radiation therapy . In in vitro studies of cells, different cancer cell lines—including cervical, prostate and pancreatic cells, as well as several in vivo studies on xenografts—have shown improved radiosensitivity of the tumors when treated with Hsp90 inhibitors . The mechanism by which Hsp90 inhibitors improve radiosensitivity appears to be largely .