The Novel HSP90 inhibitor, IPI-493, is highly effective in human gastrostrointestinal stromal tumor xenografts carrying heterogeneous KIT mutations.

Abstract

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.

• Authors: Giuseppe Floris, Raf Sciot, Agnieszka Wozniak, Thomas Van Looy, Jasmien Wellens, Gavino Faa, Emmanuel Normant, Maria Debiec-Rychter, Patrick Schöffski
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 17 Pg. 5604-14 (Sep 01 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21737509 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• Antineoplastic Agents
• Benzamides
• Benzoquinones
• HSP90 Heat-Shock Proteins
• Indoles
• Lactams, Macrocyclic
• Piperazines
• Pyrimidines
• Pyrroles
• Stem Cell Factor
• tanespimycin
• Imatinib Mesylate
• Proto-Oncogene Proteins c-kit
• Sunitinib

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Benzamides
• Benzoquinones (administration & dosage, pharmacology, therapeutic use)
• Cell Line, Tumor
• Gastrointestinal Neoplasms (drug therapy, genetics, pathology)
• Gastrointestinal Stromal Tumors (drug therapy, genetics, pathology)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Humans
• Imatinib Mesylate
• Indoles (administration & dosage, pharmacology, therapeutic use)
• Lactams, Macrocyclic (administration & dosage, pharmacology, therapeutic use)
• Mice
• Mice, Nude
• Piperazines (administration & dosage, pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-kit (genetics)
• Pyrimidines (administration & dosage, pharmacology, therapeutic use)
• Pyrroles (administration & dosage, pharmacology, therapeutic use)
• Stem Cell Factor (drug effects, genetics, metabolism)
• Sunitinib
• Xenograft Model Antitumor Assays