at-13387 and Neoplasms

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.

Topics: Adult; Aged; Benzamides; Drug Administration Schedule; Female; Heat-Shock Proteins; HSP27 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Isoindoles; Male; Maximum Tolerated Dose; Middle Aged; Molecular Chaperones; Neoplasms; RNA, Messenger

Oncogenic client-proteins of the chaperone Heat shock protein 90 (HSP90) insure unlimited tumor growth and are involved in resistance to chemo- and radiotherapy. The HSP90 inhibitor Onalespib initiates the degradation of oncoproteins, and might also act as a radiosensitizer. The aim of this study was therefore to evaluate the efficacy of Onalespib in combination with external beam radiotherapy in an in vitro and in vivo approach. Onalespib downregulated client proteins, lead to increased apoptosis and caused DNA-double-strands. Monotherapy and combination with radiotherapy reduced colony formation, proliferation and migration assessed in radiosensitive HCT116 and radioresistant A431 cells. In vivo, a minimal treatment regimen for 3 consecutive days of Onalespib (3 × 10 mg/kg) doubled survival, whereas Onalespib with radiotherapy (3 × 2 Gy) caused a substantial delay in tumor growth and prolonged the survival by a factor of 3 compared to the HCT116 xenografted control group. Our results demonstrate that Onalespib exerts synergistic anti-cancer effects when combined with radiotherapy, most prominent in the radiosensitive cell models. We speculate that the depletion and downregulation of client proteins involved in signalling, migration and DNA repair mechanisms is the cause. Thus, individually, or in combination with radiotherapy Onalespib inhibits tumor growth and has the potential to improve radiotherapy outcomes, prolonging the overall survival of cancer patients.

Topics: Animals; Apoptosis; Benzamides; Cell Movement; Cell Proliferation; Chemoradiotherapy; DNA Breaks, Double-Stranded; DNA Repair; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; HCT116 Cells; HSP90 Heat-Shock Proteins; Humans; Isoindoles; Mice; Neoplasms; Radiation Tolerance; Xenograft Model Antitumor Assays

A series of novel B and C-rings truncated deguelin derivatives have been designed and synthesized in the present study as heat shock protein 90 (Hsp90) inhibitors. The synthesized compounds exhibited micromolar antiproliferative potency toward a panel of human cancer cell lines. Their structure-activity relationships (SARs) were investigated in a systematic manner. Compound 21c was identified to have high Hsp90 binding potency (60 nM) and caused degradation of client proteins through ubiquitin proteasome system. Further biological studies showed that compound 21c induced a dose-dependent S and G2-phase cell cycle arrest on human breast cancer MCF-7 cells. Flow cytometry and Western blot analyses confirmed that compound 21c caused apoptosis of MCF-7 cells. In addition, compound 21c showed much potent inhibition on the migration and invasion of MCF-7 cells. Taken together, these results suggest that 21c might be a promising lead compound for further development of Hsp90 inhibitors.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Drug Design; Drug Screening Assays, Antitumor; HSP90 Heat-Shock Proteins; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Proteasome Endopeptidase Complex; Rotenone; Structure-Activity Relationship

Topics: Antineoplastic Agents; Benzamides; Dose-Response Relationship, Drug; HSP90 Heat-Shock Proteins; Humans; Isoindoles; Maximum Tolerated Dose; Neoplasms

AT13387, a non-geldanamycin inhibitor of heat-shock protein 90 (HSP90), was tested against the PPTP in vitro panel (1.0 nM to 10 µM) and against the PPTP in vivo panels (40 or 60 mg/kg) administered orally twice weekly. In vitro AT13387 showed a median EC(50) value of 41 nM and exhibited activity consistent with a cytotoxic effect. In vivo AT13387 induced significant differences in EFS distribution compared to controls in 17% evaluable solid tumor xenografts, but in none of the ALL xenografts. No objective tumor responses were observed. In vivo AT13387 demonstrated only modest single agent activity.

Topics: Animals; Benzamides; Cell Line, Tumor; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; HSP90 Heat-Shock Proteins; Humans; Isoindoles; Mice; Mice, Inbred BALB C; Mice, Nude; Mice, SCID; Neoplasms; Xenograft Model Antitumor Assays