Abstract
Purpose Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas. Combining Hsp90 inhibitors to enhance endoplasmic reticulum stress with mTOR inhibition results in dramatic MPNST shrinkage in a genetically engineered MPNST mouse model. Ganetespib is an injectable potent small molecule inhibitor of Hsp90. Sirolimus is an oral mTOR inhibitor. We sought to determine the safety, tolerability, and recommended dose of ganetespib and sirolimus in patients with refractory sarcomas and assess clinical benefits in patients with unresectable/refractory MPNSTs. Patients and Methods. In this multi-institutional, open-label, phase 1/2 study of ganetespib and sirolimus, patients ≥16 years with histologically confirmed refractory sarcoma (phase 1) or MPNST (phase 2) were eligible. A conventional 3 + 3 dose escalation design was used for phase 1. Pharmacokinetic and pharmacodynamic measures were evaluated. Primary objectives of phase 2 were to determine the clinical benefit rate (CBR) of this combination in MPNSTs. Patient-reported outcomes assessed pain. Results Twenty patients were enrolled (10 per phase). Toxicities were manageable; most frequent non-DLTs were diarrhea, elevated liver transaminases, and fatigue. The recommended dose of ganetespib was 200 mg/m2 intravenously on days 1, 8, and 15 with sirolimus 4 mg orally once daily with day 1 loading dose of 12 mg. In phase 1, one patient with leiomyosarcoma achieved a sustained partial response. In phase 2, no responses were observed. The median number of cycles treated was 2 (1–4). Patients did not meet the criteria for clinical benefit as defined per protocol. Pain ratings decreased or were stable. Conclusion Despite promising preclinical rationale and tolerability of the combination therapy, no responses were observed, and the study did not meet parameters for further evaluation in MPNSTs. This trial was registered with (NCT02008877).
Highlights
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas. e only known curative therapy for MPNSTs is complete surgical resection with wide negative margins [1,2,3,4,5], which is often not feasible due to location, size, and metastasis
Using an neurofibromatosis type 1 (NF1)/p53mutant MPNST model, the Cichowski laboratory demonstrated that Mammalian target of rapamycin (mTOR) inhibitors suppressed tumor growth in a potent, but cytostatic manner [9] and became resistant to treatment
Enhancing Endoplasmic reticulum (ER) stress using Hsp90 inhibitors coupled with mTOR inhibitors (mTORi) led to tumor shrinkage in a genetically engineered MPNST mouse model, which correlated with profound damage to the ER and cell death [12]. is was only seen in tumors treated with the combination, but not in tumors exposed to either agent alone
Summary
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas. e only known curative therapy for MPNSTs is complete surgical resection with wide negative margins [1,2,3,4,5], which is often not feasible due to location, size, and metastasis. Increased understanding in the pathogenesis of MPNSTs, availability of targeted agents, and sophisticated preclinical models have facilitated development of rational clinical trials for MPNSTs. Mammalian target of rapamycin (mTOR) has been reported to be hyperactivated in NF1-deficient tumors as a consequence of aberrant Ras signaling [8]. Oncogenic RAS causes ER stress [11], and when the ER stress level becomes insurmountable, cell death ensues, suggesting agents that enhance ER stress may be developed as anticancer agents. Enhancing ER stress using Hsp inhibitors coupled with mTORi led to tumor shrinkage in a genetically engineered MPNST mouse model, which correlated with profound damage to the ER and cell death [12]. No targeted agents have been able to cause tumor regression in a genetically engineered MPNST mouse model or human MPSNT trials
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