Phase I study of the heat shock protein 90 (Hsp90) inhibitor onalespib (AT13387) administered on a daily for 2 consecutive days per week dosing schedule in patients with advanced solid tumors

Abstract

Inhibition of heat shock 90 (Hsp90) molecular chaperones allows targeting of multiple proteins involved in tumorigenesis. We investigated the safety, recommended phase 2 dose (RP2D), and pharmacokinetic and pharmacodynamic profile of onalespib (AT13387), a potent synthetic Hsp90 inhibitor, administered on days 1, 2, 8, 9, 15, and 16 of 28 day cycles (QDx2/week) in a phase I trial. This study followed an accelerated titration design with a starting dose of 20 mg/m(2)/dose and a standard 3 + 3 dose escalation design for dose level 4 (120 mg/m(2)/dose) and above. Additional patients were enrolled at the RP2D with mandatory paired tumor biopsies to assess modulation of 210 client proteins using reverse phase protein array analysis. Thirty-one patients were treated; RP2D was established at 160 mg/m(2)/dose on the QDx2/week schedule. Common toxicities were gastrointestinal, hepatic, and hematologic. Pharmacokinetic profile was linear and plasma levels increased proportionally with dose (T½ ~8 h). No responses were observed; eight patients had stable disease for > 2 cycles with one patient remaining on study for 6 cycles. Target engagement was demonstrated by transcriptional upregulation of Hsp70 and Hsp27 in PBMCs. Statistically significant modulation of client proteins was not achieved in the 9 paired tumor biopsies evaluated; however, hierarchical clustering revealed two subgroups of patients with differential patterns of protein expression. Further combination studies are needed in order to target prospective driver oncoproteins.

The radiosensitizer Onalespib increases complete remission in 177Lu-DOTATATE-treated mice bearing neuroendocrine tumor xenografts

“…The list of HSP90 client proteins is long and includes proteins involved in proliferation, DNA repair and angiogenesis, such as EGFR and VEGFR [17,18]. In addition, HSP90 inhibition may also lead to upregulation of a related heat shock protein, HSP70 (HSP72, HSPA1A) [19][20][21], a protein thought to play a protective role in renal damage [22][23][24].…”

Efficacy of Onalespib, a Long-Acting Second-Generation HSP90 Inhibitor, as a Single Agent and in Combination with Temozolomide against Malignant Gliomas

“…This suggests that targeting HSP90 could potentially overcome these resistance mechanisms and improve sensitivity to therapies (15, 16). Currently, several HSP90 inhibitors are being evaluated in trials against solid tumors and are in different stages of clinical development (17–19). They bind to the N-terminal ATPase-pocket, affecting the chaperone activity and leading to the depletion of HSP90 substrates by subsequent proteosomal degradation (11–13).…”

“…Recent studies in several solid tumor models have shown sensitization to currently used chemotherapeutic agents when combined with new generation HSP90 inhibitors (20, 21). Onalespib, a potent second-generation HSP90 inhibitor differs from other HSP90 inhibitors in its longer duration of target inhibition (22) and its favorable toxicity profile in phase I studies in patients with refractory solid tumors (17). However, there is no significant preclinical data regarding the effects of onalespib against glioblastoma; in addition, the potential for chemosensitization of onalespib in combination with alkylating agents such as temozolomide (TMZ) has not been previously studied.…”

Alzheimer cells on their way to derailment show selective changes in protein quality control network

“…A decrease in HSP90 can contribute to the upregulation of HSF-1, as inhibition of HSP90 triggers the heat shock response (Zou et al, 1998). Upon upregulation of HSF-1, there is an elongated occupation of HSF-1 on the HSP70 gene resulting in increased levels of HSP70 (Do et al, 2015;Shapiro et al, 2015). Downregulation of HSP90 and upregulation of sHSP-HSP70-BAG3 may thus be functionally linked in Alzheimer neurons.…”