The Novel HSP90 Inhibitor, IPI-493, Is Highly Effective in Human Gastrostrointestinal Stromal Tumor Xenografts Carrying Heterogeneous KIT Mutations
| Autor: | Jasmien Wellens, Patrick Schöffski, Maria Debiec-Rychter, Gavino Faa, Emmanuel Normant, Agnieszka Wozniak, Thomas Van Looy, Giuseppe Floris, Raf Sciot |
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| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Pathology medicine.medical_specialty Indoles Stromal cell Gastrointestinal Stromal Tumors Lactams Macrocyclic Mice Nude Antineoplastic Agents Apoptosis Piperazines Hsp90 inhibitor Mice Cell Line Tumor hemic and lymphatic diseases Benzoquinones Sunitinib medicine Animals Humans Pyrroles HSP90 Heat-Shock Proteins Stromal tumor neoplasms Gastrointestinal Neoplasms Stem Cell Factor GiST business.industry Cancer Imatinib medicine.disease Xenograft Model Antitumor Assays digestive system diseases Proto-Oncogene Proteins c-kit Pyrimidines Imatinib mesylate Oncology Benzamides Imatinib Mesylate Cancer research business medicine.drug |
| Zdroj: | Clinical Cancer Research. 17:5604-5614 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: KIT activity is crucial for gastrointestinal stromal tumors (GIST). Imatinib (IMA) and sunitinib (SUN) are very effective KIT-inhibitors in patients with advanced GIST but have no curative potential. We evaluated the efficacy of the novel HSP90 inhibitor IPI-493 alone, or in combination with IMA or SUN in GIST xenografts with KIT mutations. Experimental Design: Nude mice (n = 98) were grafted bilaterally with human GIST carrying KIT exon 11 (GIST-PSW), KIT exon 9 (GIST-BOE), or double, KIT imatinib-sensitive exon 11 and imatinib-resistant exon 17 mutations (GIST-48). Mice were divided into six treatment groups and dosed orally for 15 days as follows: (i) control group, sterile water; (ii) IMA alone; (iii) SUN alone; (iv) IPI-493 alone; (v) IPI-493+IMA; and (vi) IPI-493+SUN. Results: Treatment with IPI-493 resulted in tumor growth stabilization, variable proliferation arrest, induction of apoptosis and necrosis, and downregulation of KIT and its signaling cascade, especially in the GIST-BOE model. Significant reduction of vessel density was observed with IPI-493 treatment, and was equal to SUN treatment in GIST-PSW and GIST-BOE xenografts. IPI-493 treatment effects were enhanced in combination with TKIs, especially with IPI-493+SUN. In our hands, IPI-493 showed dose-dependent liver damages. Conclusions: When administered as a single agent in a xenograft model, the HSP90 inhibitor IPI-493 has consistent antitumor activity and induces KIT downregulation in GISTs with heterogeneous KIT mutations. IPI-493 synergizes with TKIs that are commonly used for the treatment of advanced or IMA-resistant GIST. The antitumor response of IPI-493 is particularly enhanced in combination with SUN. Clin Cancer Res; 17(17); 5604–14. ©2011 AACR. |
| Databáze: | OpenAIRE |
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