Previously, no targeted agents have been able to cause tumor regression in a genetically
      engineered MPNST mouse model or human MPNST. Recently published data from Dr. Cichowski's
      laboratory demonstrated using Hsp90 inhibitors to enhance endoplasmic reticulum stress
      coupled with the mammalian target of rapamycin (mTOR) inhibitor sirolimus led to dramatic
      tumor shrinkage in a transgenic MPNST mouse model, which correlated with profound damage to
      the endoplasmic reticulum and cell death. Ganetespib is a novel, injectable, small molecule
      inhibitor of Hsp90 and is currently being investigated in adults with a broad range of tumor
      types with a favorable safety profile and promising early results. Ganetespib has been
      studied in preclinical in vivo models with a variety of targeted agents with no marked
      apparent pharmacological interactions. Sirolimus is a commercially available orally
      administered mTOR inhibitor and is the active metabolite of temsirolimus, which is FDA
      approved agent for advanced metastatic renal cell carcinoma. Sirolimus has been studied and
      tolerated in combination with multiple cytotoxic and targeted agents in a variety of tumor
      types. Based on strong preclinical rationale, the investigators hypothesize that ganetespib
      in combination with sirolimus will cause tumor regression in patients with refractory MPNSTs.

      The investigators propose a multi-institutional open label phase I/II trial of ganetespib in
      combination with sirolimus in patients with refractory sarcoma including MPNST. Hsp90
      inhibitors and mTOR inhibitors have also both demonstrated benefit in a variety of
      preclinical bone and soft tissue sarcoma models. The investigators hypothesize that these
      agents that work on separate and potentially synergistic pathways will also be beneficial for
      other refractory bone and soft tissue sarcomas. Thus, the phase I component will be open to
      patients with refractory sarcomas, which will also expedite enrollment. Upon determination of
      the recommended dosing, a phase II study will be conducted. The phase II study population
      will be limited to patients with a diagnosis of MPNST.