[Hsp90 inhibitors versus pancreatic cancer]
So far as I can remember, the Hsp90 inhibitors didn't do much for pancreatic cancer patients in P1, but this article suggests that they could help . . . combos anyone?
>>Clin Cancer Res. 2007 Nov 1;13(21):6459-6468.
Targeting Heat Shock Protein 90 in Pancreatic Cancer Impairs Insulin-like Growth Factor-I Receptor Signaling, Disrupts an Interleukin-6/Signal-Transducer and Activator of Transcription 3/Hypoxia-Inducible Factor-1{alpha} Autocrine Loop, and Reduces Orthotopic Tumor Growth.
Lang SA, Moser C, Gaumann A, Klein D, Glockzin G, Popp FC, Dahlke MH, Piso P, Schlitt HJ, Geissler EK, Stoeltzing O.
Authors' Affiliations: Departments of Surgery and Surgical Oncology, and Institute of Pathology, University of Regensburg Medical Center, Regensburg, Germany.
PURPOSE: Inhibitors of heat-shock protein 90 (Hsp90) may interfere with oncogenic signaling pathways, including Erk, Akt, and hypoxia-inducible factor-1alpha (HIF-1alpha). Because insulin-like growth factor-I receptor (IGF-IR) and signal transducer and activator of transcription 3 (STAT3) signaling pathways are implicated in the progression of pancreatic cancer, we hypothesized that blocking Hsp90 with geldanamycin derivates [17-allylamino-geldanamycin (17-AAG), 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG)] would impair IGF-I- and interleukin-6-mediated signaling and thus reduce pancreatic tumor growth and angiogenesis in vivo. EXPERIMENTAL DESIGN: Human pancreatic cancer cells (HPAF-II, L3.6pl) were used for experiments. Changes in signaling pathway activation upon Hsp90 blockade were investigated by Western blotting. Effects of Hsp90 inhibition (17-AAG) on vascular endothelial growth factor were determined by ELISA and real-time PCR. Effects of 17-DMAG (25 mg/kg; thrice a week; i.p.) on tumor growth and vascularization were investigated in a s.c. xenograft model and in an orthotopic model of pancreatic cancer. RESULTS: 17-AAG inhibited IGF-IR signaling by down-regulating IGF-IRbeta and directly impairing IGF-IR phosphorylation. Hypoxia- and IL-6-mediated activation of HIF-1alpha or STAT3/STAT5 were substantially inhibited by 17-AAG. Moreover, a novel IL-6/STAT3/HIF-1alpha autocrine loop was effectively disrupted by Hsp90 blockade. In vivo, 17-DMAG significantly reduced s.c. tumor growth and diminished STAT3 phosphorylation and IGF-IRbeta expression in tumor tissues. In an orthotopic model, pancreatic tumor growth and vascularization were both significantly reduced upon Hsp90 inhibition, as reflected by final tumor weights and CD31 staining, respectively. CONCLUSIONS: Blocking Hsp90 disrupts IGF-I and IL-6-induced proangiogenic signaling cascades by targeting IGF-IR and STAT3 in pancreatic cancer, leading to significant growth-inhibitory effects. Therefore, we suggest that Hsp90 inhibitors could prove to be valuable in the treatment of pancreatic cancer.<<
See also:
>>2007 AAPS Annual Meeting & Exposition 11/9/2007 - 11/15/2007
A Novel Hsp90 Inhibitor Disrupts Hsp90/Cdc37 Complex for Pancreatic Cancer therapy
Tracks: Contributed Papers: 43 Cancer, Cardiovascular, Metabolic Disorder and Other Therapeutics
Date/Time: Tuesday, November 13, 2007
1:00 PM - 5:00 PM
Location: Exhibit Hall
Description:
To identify a novel Hsp90 inhibitor for disrupting Hsp90/Cdc37 complex without blocking ATP binding pocket for pancreatic cancer therapy. Computational modeling and co-immunoprecipitation were used to confirm a new compound (Tao-1) that disrupts the interaction of Hsp90 with its co-chaperone Cdc37. Werstern blot was used to measured the degradation of Hsp90 client protein. ATP-sepharose binding assay was performed to prove that the compound does not bind to the ATP/ADP pocket as currently found for classic Hsp90 inhibitors such as geldanamycin (GA). The anticancer activity of this new compound (Tao-1) was examined in vitro by MTS assay and in vivo in pancreatic cancer xenograft model and RIP1-Tag2 transgenic mice. The new compound (Tao-1) induced cell apoptosis and inhibited pancreatic cancer cells (panc-1) growth with an IC50 of 3 ìM. Computational modeling reveled that the new compound (Tao-1) interrupts Hsp90-Cdc37 interaction. Co-immunoprecipitation demonstrated that the new compound (Tao-1) induced the dissociation of Cdc37 from Hsp90. The new compound (Tao-1) induced Hsp90 client protein degradation similar to classic Hsp90 inhibitor geldanamycin (GA); however, unlike GA, Tao-1 did not inhibit ATP binding to Hsp90. In panc-1 xenografts, 3 mg/kg Tao-1 inhibited 80% of tumor growth. In RIP1-Tag2 transgenic mice with pancreatic cancer, Tao-1 reduced the metastasis by 80%. A novel Hsp90 inhibitor by disrupting the Hsp90-Cdc37 complex offers a potential therapeutic option for pancreatic cancer therapy.
Speakers:
Author
Dr. Xianhua Cao
Senior Scientist, The Ohio State University
Author
Guang Jia
The Ohio State University
Author
Dr. Duxin Sun
Assistant Professor, The Ohio State University
Author
Bing Wang
The Ohio State University
Author
Mr. Tao Zhang
Graduate Student, The Ohio State University<<
Cheers, Tuck |
