sta-9090 and Leukemia--Mast-Cell

STA-1474, prodrug of the heat shock protein 90 inhibitor (HSP90i) ganetespib, previously demonstrated activity in canine preclinical models of cancer; interestingly, prolonged infusions were associated with improved biologic activity. The purpose of this study was to identify the ideal treatment schedule for HSP90i in preclinical models of KIT-driven malignancies and in dogs with spontaneous mast cell tumors (MCT), where KIT is a known driver.. These data provide further evidence that prolonged HSP90i exposure improves biologic activity through sustained downregulation of client proteins.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Disease Models, Animal; Dogs; HSP90 Heat-Shock Proteins; Leukemia, Mast-Cell; Mice; Oncogenes; Proteolysis; Proto-Oncogene Proteins c-kit; Treatment Outcome; Triazoles; Xenograft Model Antitumor Assays

Mutations of the receptor tyrosine kinase Kit occur in several human and canine cancers. While Kit inhibitors have activity in the clinical setting, they possess variable efficacy against particular forms of mutant Kit and drug resistance often develops over time. Inhibitors of heat shock protein 90 (HSP90), a chaperone for which Kit is a client protein, have demonstrated activity against human cancers and evidence suggests they downregulate several mutated and imatinib-resistant forms of Kit. The purpose of this study was to evaluate a novel HSP90 inhibitor, STA-9090, against wild-type (WT) and mutant Kit in canine bone marrow-derived cultured mast cells (BMCMCs), malignant mast cell lines, and fresh malignant mast cells.. BMCMCs, cell lines, and fresh malignant mast cells were treated with STA-9090, 17-AAG, and SU11654 and evaluated for loss in cell viability, cell death, alterations in HSP90 and Kit expression/signaling, and Kit mutation. STA-9090 activity was tested in a canine mastocytoma xenograft model.. Treatment of BMCMCs, cell lines, and fresh malignant cells with STA-9090 induced growth inhibition, apoptosis that was caspase-3/7-dependent, and downregulation of phospho/total Kit and Akt, but not extracellular signal-regulated kinase (ERK) or phosphoinositide-3 kinase (PI-3K). Loss of Kit cell-surface expression was also observed. Furthermore, STA-9090 exhibited superior activity to 17-AAG and SU11654, and was effective against malignant mast cells expressing either WT or mutant Kit. Lastly, STA-9090 inhibited tumor growth in a canine mastocytoma mouse xenograft model.. STA-9090 exhibits broad activity against mast cells expressing WT or mutant Kit, suggesting it may be an effective agent in the clinical setting against mast cell malignancies.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; DNA Primers; Dog Diseases; Dogs; HSP90 Heat-Shock Proteins; Leukemia, Mast-Cell; Mastocytoma; Mice; Mice, SCID; Proto-Oncogene Proteins c-kit; Reverse Transcriptase Polymerase Chain Reaction; Transplantation, Heterologous; Triazoles