inhibitors is believed to be a consequence of the simultaneous degradation of hsf1, thereby preventing the increased expression of these antiapoptotic Aurora Kinase proteins . Thus, targeting the Cterminal ATP site of the HSP90 protein may overcome some of the clinical failures of the traditional Nterminal HSP90 inhibitors. Despite this recent data, more than 20 active clinical trials are using Nterminal inhibitors either as single agents or in combination therapy for the treatment of a wide variety of malignancies. Clinical Trials A recent report by Kim found that there have been more than 40 clinical trials completed with Hsp90 inhibitors and 23 currently active trials, including 13 novel inhibitors of Hsp90. The first phase 1 clinical trials of the firstinclass inhibitors of Hsp90 began in 1999 with the use of 17AAG as an Nterminal inhibitor of Hsp90.
These early phase 1 studies involving 17AAG administration in patients with advanced solid tumors demonstrated an overall tolerable toxicity profile, as well as signs of clinical activity in a number of different tumor types, such as melanoma, breast, prostate, and also in multiple myeloma . Initial studies Dasatinib using 17AAG were hampered by poor solubility requiring dilution in a significant amount of dimethyl sulfoxide in an egg phospholipid solution, as well as steroid and antihistamine administration and specialized infusion sets . Despite the early promising results the phase 2 trials of 17AAG monotherapy have demonstrated very modest effectiveness and have been hampered by continued issues with solubility and moderate toxicity including transient hepatotoxicity.
In 2006, a group from Memorial Sloan–Kettering Cancer Center reported a phase 2 trial of 17AAG in 20 patients with either advanced, metastatic clear cell or papillary renal cell carcinoma . No patients in the study achieved a partial or complete response, and toxicities included transaminitis, optic neuritis, and gastrointestinal side effects. Six of twelve patients prokaryotic required eventual dose reduction. A phase 2 trial of 17 AAG alone performed in 15 patients with metastatic, hormonerefractory prostate cancer was reported in 2005 by a group from the Karmanos Cancer Institute . Enrollment in this study was halted secondary to a lack of prostatespecific antigen response, and grade three adverse events including fatigue, lymphopenia, and back pain in eight patients.
However, it was felt that perhaps the dosage and dosing schedule were suboptimal, but that further studies involving 17AAG as monotherapy at this schedule were deemed to be unwarranted. In 2008, a phase 2 study involving 15 patients with metastatic melanoma treated with 17AAG monotherapy was reported by Solit . The primary end point for this study was inhibition of mitogenactivated protein kinases , an important pathway in the proliferation of melanoma. The authors terminated the study early due to lack of patient response and a lack of a sustained effect on the MAPK pathway. One patient sustained a grade three event in the form of a myocardial infarction, although the patient was noted to have underlying associated coronary artery disease and other comorbidities. Again, however, pharmacodynamic studies conducted with the trial suggest that the drug was very short lived and that another .