Ganetespib, a Novel Hsp90 Inhibitor in Patients With KRAS Mutated and Wild Type, Refractory Metastatic Colorectal Cancer

Abstract

Seventeen patients with refractory KRAS mutated and wild type metastatic colorectal adenocarcinoma received single agent ganetespib in a single institution phase II study. The drug was well tolerated but did not yield any responses, although two patients achieved durable stable disease. Background Heat shock protein 90 (Hsp90) is a cellular chaperone that is required for the maturation and stability of a variety of proteins that play key roles in colon cancer initiation and progression. The primary objective of the current study was to define the safety and efficacy of ganetespib, a novel, selective small-molecule Hsp90 inhibitor, in patients with refractory metastatic colorectal cancer. Patients and Methods The study was a single-arm, Simon 2-stage, phase II trial for patients with chemotherapy-refractory, metastatic colorectal cancer. Patients received ganetespib 200 mg/m2 intravenously. Tumor tissue was collected before treatment and 48 hours after treatment for changes in expression of Hsp90 client proteins and other potential pharmacodynamics markers. V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), v-Raf murine sarcoma viral oncogene homolog B, and phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutational status was also determined. Results Seventeen patients were treated (median age, 58; range, 44–79 years). No patients demonstrated objective regression of disease. Two patients had stable disease of 6.8 and 5.1 months duration. Serious adverse events that were potentially attributable to ganetespib included diarrhea (12%, n = 2), fatigue (17%, n = 3), and increased aspartate aminotransferase/alanine aminotransferase (12%, n = 2) and alkaline phosphatase (6%, n = 1) levels. Of the 17 evaluable patients, 9 (53%) including patients with stable disease as best response, had KRAS-mutant tumors. Conclusion In this first phase II investigation of an Hsp90 inhibitor in colorectal cancer, ganetespib as a single agent did not demonstrate activity in chemotherapy-refractory metastatic colorectal cancer. However, on the basis of the drug’s promising preclinical combination data and the relatively mild toxicity profile, further clinical investigation of this agent in combination with standard cytotoxic agents is planned.

Effects of treatment with an Hsp90 inhibitor in tumors based on 15 phase II clinical trials

“…Details of eligible trials with an Hsp90 inhibitor were noted in Table II. The majority of Hsp90 inhibitors were tested in trials of monotherapy: 17-AAG (13,19,20,23), ganetespib (15,24,25), IPI-504 (21,26) and BIIB021 (27). There were also trials of combination of Hsp90 inhibitors, 17-AAG (14,17,18)/IPI-504 (16), with other anticancer drugs, including cytotoxic and molecularly targeted agents.…”

“…The number of patients in these trials ranged between 11 and 99, with the median age between 51 and 68 years. A total of 10 types of cancer were described in these 15 trials, including breast cancer (13)(14)(15)(16), ovarian carcinoma (17), peritoneal carcinoma (17), multiple myeloma (18), renal cell cancer (19), prostate cancer (20,21), melanoma (22,23), colorectal cancer (24), lung cancer (25,26) and gastrointestinal stromal tumor (GIST) (27). The majority of patients had received prior therapies and had metastatic or recurrent diseases at baseline.…”

Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models Uncover Potentially Targetable Cancer Cell Dependencies

“…II trial reported in colorectal cancer, single-agent treatment with ganetespib demonstrated good tolerance but low efficacy in chemotherapy-refractory metastatic disease, independent of KRAS mutation status (42). Higher antitumor activity was seen in early clinical trials exploring combinations of HSP90 inhibitors with chemotherapies, including fluoropyrimidines (5-FU and capecitabine; ref.…”

“…S13). Previous studies have suggested that HSP90 inhibition may sensitize colorectal cancer cell lines to chemotherapy, and although monotherapy with HSP90 inhibitors has shown low efficacy in metastatic colorectal cancer (42), response has been obtained by combination therapy with HSP90 inhibitors and capecitabine (5-FU pro-drug) in patients who have progressed on fluoropyrimidines (43). Accordingly, to analyze a potential effect of HSP90 inhibition in vivo, we selected a CMS4 PDX model (MSS, KRAS/NRAS wild type, BRAF V600E mutated) for treatment in a randomized and controlled set-up.…”

Paricalcitol Enhances the Chemopreventive Efficacy of 5-Fluorouracil on an Intermediate-Term Model of Azoxymethane-Induced Colorectal Tumors in Rats

“…Notably, the potential carcinogenic role of HSP-90 in activation of various oncogenic proteins and growth factors is currently of intense interest, particularly in colorectal cancer, which is why specific HSP90 inhibitors are currently being investigated as potential anticancer drugs (36). More importantly, HSP90 dependence acquired resistance to 5-FU therapy, as well as its potential role as a proangiogenic factor for the induction of VEGF and iNOS for de novo angiogenesis has been reported recently (2).…”