Phase I Evaluation of STA-1474, a Prodrug of the Novel HSP90 Inhibitor Ganetespib, in Dogs with Spontaneous Cancer

Abstract

BackgroundThe novel water soluble compound STA-1474 is metabolized to ganetespib (formerly STA-9090), a potent HSP90 inhibitor previously shown to kill canine tumor cell lines in vitro and inhibit tumor growth in the setting of murine xenografts. The purpose of the following study was to extend these observations and investigate the safety and efficacy of STA-1474 in dogs with spontaneous tumors.Methods and FindingsThis was a Phase 1 trial in which dogs with spontaneous tumors received STA-1474 under one of three different dosing schemes. Pharmacokinetics, toxicities, biomarker changes, and tumor responses were assessed. Twenty-five dogs with a variety of cancers were enrolled. Toxicities were primarily gastrointestinal in nature consisting of diarrhea, vomiting, inappetence and lethargy. Upregulation of HSP70 protein expression was noted in both tumor specimens and PBMCs within 7 hours following drug administration. Measurable objective responses were observed in dogs with malignant mast cell disease (n = 3), osteosarcoma (n = 1), melanoma (n = 1) and thyroid carcinoma (n = 1), for a response rate of 24% (6/25). Stable disease (>10 weeks) was seen in 3 dogs, for a resultant overall biological activity of 36% (9/25).ConclusionsThis study provides evidence that STA-1474 exhibits biologic activity in a relevant large animal model of cancer. Given the similarities of canine and human cancers with respect to tumor biology and HSP90 activation, it is likely that STA-1474 and ganetespib will demonstrate comparable anti-cancer activity in human patients.

Targeting HSP70 and GRP78 in canine osteosarcoma cells in combination with doxorubicin chemotherapy

“…In other studies, increased expression of HSP70 reduced the efficacy of HSP90 inhibitors at inducing apoptosis (Guo et al 2005). Furthermore, following the use of an HSP90 inhibitor in canine OSA patients, HSP70 was overexpressed in tumor tissue (London et al 2011), which is considered a hallmark of effective HSP90 inhibition. Despite these findings, we are unaware of studies attempting to inhibit HSP70 and/or GRP78 as a single or dual target in canine OSA.…”

Defining the Value of a Comparative Approach to Cancer Drug Development

“…Collectively, this data informed the design of human clinical trials of ganetespib and demonstrates the strengths of a naturally-occurring canine model by highlighting the ease of serial biopsy procurement, rapid assessment of differential dose and schedule, and correlative assessment of multiple clinical parameters. (10) In another similar example, an orally-bioavailable XPO1 inhibitor verdinexor, a companion agent to a lead human compound KPT-330 (Selinexor, Karyopharm Therapeutics), was studied in tumor-bearing dogs. Based upon profound clinical benefit observed in dogs with non-Hodgkin’s lymphoma (NHL) and the marked similarities between canine and human NHL, the data generated within this study provided critical new information in support of related compounds in humans with hematologic malignancies.…”

HSP90 inhibitors in the context of heat shock and the unfolded protein response: effects on a primary canine pulmonary adenocarcinoma cell line*

“…While perhaps somewhat esoteric compared to human and murine cell studies, extension of tumor biology investigations to true spontaneous forms as found in companion animals has long been seen as a boon to cancer research [111, 112]. The use of HSP90 inhibitors has reached clinical stages in canines [113], and we hope our contributions add to rational designs for further utility with applications to both veterinary and human clinical situations.…”