17-(dimethylaminoethylamino)-17-demethoxygeldanamycin and Prostatic-Neoplasms

Specific inhibitors of Hsp90 have recently entered human clinical trials. At the time of writing, trials have been initiated only in metastatic cancer, although a rationale exists for using these agents in a variety of human diseases where protein (mis)folding is involved in the disease pathophysiology. Hsp90 inhibitors offer a unique anti-cancer opportunity because they provide simultaneous combinatorial blockade of multiple oncogenic pathways. The first compound in this class, 17-AAG, has completed phase I trials and phase II trials are in progress. The toxicity has been manageable and evidence of possible clinical activity has been seen in metastatic melanoma, prostate cancer and multiple myeloma. Other inhibitors with improved properties are approaching clinical trials. This chapter presents an update of the current clinical trials using Hsp90 inhibitors, focussing on the areas that will be increasingly relevant in the next 5 years.

Topics: Benzoquinones; Clinical Trials as Topic; Drug Design; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Male; Melanoma; Multiple Myeloma; Neoplasms; Prostatic Neoplasms; Quinones; Rifabutin

The ability to identify tumors that are susceptible to a given molecularly targeted radiosensitizer would be of clinical benefit. Towards this end, we have investigated the effects of a representative Hsp90 inhibitor, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17DMAG), on the radiosensitivity of a panel of human tumor cell lines. 17DMAG was previously shown to enhance the radiosensitivity of a number of human cell lines, which correlated with the loss of ErbB2. We now report on cell lines in which 17DMAG induced the degradation of ErbB2, yet had no effect on radiosensitivity. In a comparison of ErbB family members, ErbB3 protein was only detectable in cells resistant to 17DMAG-induced radiosensitization. To determine whether ErbB3 plays a casual role in this resistance, short interfering RNA (siRNA) was used to knockdown ErbB3 in the resistant cell line AsPC1. Whereas individual treatments with siRNA to ErbB3 or 17DMAG had no effect on radiosensitivity, the combination, which reduced both ErbB2 and ErbB3, resulted in a significant enhancement in AsPC1 radiosensitivity. In contrast to siRNA to ErbB3 or 17DMAG treatments only, AsPC1 cell exposure to the combination also resulted in a decrease in ErbB1 kinase activity. These results indicate that ErbB3 expression predicts for tumor cell susceptibility to and suggests that the loss of ErbB1 signaling activity is necessary for 17DMAG-induced radiosensitization. However, for cell lines sensitized by 17DMAG, treatment with siRNA to ErbB2, which reduced ErbB1 activity, had no effect on radiosensitivity. These results suggest that, whereas the loss of ErbB1 signaling may be necessary for 17DMAG-induced radiosensitization, it is not sufficient.

Topics: Benzoquinones; Cell Line, Tumor; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Male; Pancreatic Neoplasms; Prostatic Neoplasms; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Quinones; Radiation Tolerance; Radiation-Sensitizing Agents; raf Kinases; Receptor, ErbB-2; Receptor, ErbB-3; RNA, Small Interfering

Because of the potential for affecting multiple signaling pathways, inhibition of Hsp90 may provide a strategy for enhancing tumor cell radiosensitivity. Therefore, we have investigated the effects of the orally bioavailable Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) on the radiosensitivity of human tumor cells in vitro and grown as tumor xenografts.. The effect of 17-DMAG on the levels of three proteins (Raf-1, ErbB2, and Akt) previously implicated in the regulation of radiosensitivity was determined in three human solid tumor cell lines. A clonogenic assay was then used to evaluate cell survival after exposure to 17-DMAG followed by irradiation. For mechanistic insight, the G(2)- and S-phase checkpoints were evaluated in 17-DMAG-treated cells. Finally, the effect of in vivo administration of 17-DMAG in combination with radiation on the growth rate of xenograft tumors was determined.. 17-DMAG exposure reduced the levels of the three radiosensitivity-associated proteins in a cell line-specific manner with ErbB2 being the most susceptible. Corresponding concentrations of 17-DMAG enhanced the radiosensitivity of each of the tumor cell lines. This sensitization seemed to be the result of a 17-DMAG-mediated abrogation of the G(2)- and S-phase cell cycle checkpoints. The oral administration of 17-DMAG to mice bearing tumor xenografts followed by irradiation resulted in a greater than additive increase in tumor growth delay.. These data indicate that 17-DMAG enhances the in vitro and in vivo radiosensitivity of human tumor cells. The mechanism responsible seems to involve the abrogation of radiation-induced G(2)- and S-phase arrest.

Topics: Administration, Oral; Animals; Benzoquinones; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Combined Modality Therapy; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Female; G2 Phase; Glioma; HSP90 Heat-Shock Proteins; Humans; Immunoblotting; Lactams, Macrocyclic; Male; Mice; Mice, Nude; Prostatic Neoplasms; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-raf; Quinones; Radiation Tolerance; Receptor, ErbB-2; S Phase; Thymidine; Transplantation, Heterologous; Tumor Stem Cell Assay