Tanespimycin monotherapy in relapsed multiple myeloma: results of a phase 1 dose-escalation study.

摘要: Heat shock protein 90 (HSP90), one of a family molecular chaperones, is intimately involved in the survival tumour cells. Under normal conditions, HSP90 prevents aggregation proteins and functions as chaperone that preserves 3-dimensional conformation, intracellular localization, activity regulates proteolytic turnover range proteins. conditions stress, expression increases an adaptive response intended to enhance cell survival. This basic function also contributes proliferation, thereby driving oncogenesis. (Whitesell & Lindquist, 2005; Powers Workman, 2006). HSP90 uniformly expressed variety human multiple myeloma (MM) lines primary specimens from patients with MM. (Mitsiades et al, 2002, 2006) It has been shown be critical MM grown culture. (Chatterjee 2007) Investigators have demonstrated inhibitors suppress client including insulin-like growth factor-1 receptor (IGF-1R) interleukin 6 (IL-6R), which turn disrupts interactions between bone marrow stromal cells cells,(Mitsiades well upregulating other HSPs HSP70. Upregulation HSP70 marker inhibition, phase 1 clinical trials evaluating correlative increase presence inhibition. (Banerji Goetz Grem 2005). Tanespimycin (17-allylamino-17-demethoxygeldanamycin, 17-AAG) synthetic geldanamycin analogue was first inhibitor enter trials(Sausville 2003) advanced malignancies. Ramanathan Studies evaluated several dosing schedules this patient population identify maximum tolerated dose (MTD). Nowakowski 2006; Solit One trial infused tanespimycin on days 1, 8, 15 28-day cycle(Goetz 2005); another chose daily schedule 5 d every 3 weeks(Grem third used once weekly regimen. 2005) These were generally produced antitumour various solid types. As part vitro studies, potently induce apoptosis both drug-sensitive drug-resistant lines, relapsed/refractory Tanespimycin surface receptors for cytokines mediating growth, survival, drug resistance, related downstream signalling pathways among pleiotropic antiproliferative proapoptotic sequelae, allowing sensitize anticancer agents. 2006). Based preclinical rationale safety profile trials, study objective evaluate MTD given twice (day 4, 11 each 21-day cycle), up 8 cycles treatment relapsed refractory Secondary objectives measure plasma pharmacokinetics (PK) population, repeated doses, assess any preliminary evidence following treatment. Results showed anti-disease favorable tolerability, establishing framework subsequent exploration monotherapy combination regimens.