Journal
CLINICAL SARCOMA RESEARCH
Volume 8, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s13569-018-0107-9
Keywords
mTOR; Cancer stem cell; Chemoresistance; Sarcoma; Aldehyde dehydrogenase
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Funding
- National Comprehensive Cancer Network (NCCN) from Pfizer, Inc.
- Heather Brooke Foundation
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BackgroundRelapsed and refractory sarcomas continue to have poor survival rates. The cancer stem cell (CSC) theory provides a tractable explanation for the observation that recurrences occur despite dramatic responses to upfront chemotherapy. Preclinical studies demonstrated that inhibition of the mechanistic target of rapamycin (mTOR) sensitizes the CSC population to chemotherapy.MethodsHere we present the results of the Phase II portion of a Phase I/II clinical trial that aimed to overcome the chemoresistance of sarcoma CSC by combining the mTOR inhibitor temsirolimus (20mg/m(2) weekly) with the chemotherapeutic agent liposomal doxorubicin (30mg/m(2) monthly).ResultsFifteen patients with relapsed/refractory sarcoma were evaluable at this recommended Phase 2 dose level. The median progression free survival was 315days (range 27-799). Response rate, defined as stable disease or better for 60days, was 53%. Nine of the patients had been previously treated with doxorubicin. Therapy was well tolerated. In a small number of patients, pre- and post- treatment tumor biopsies were available for assessment of ALDH expression as a marker of CSCs and showed a correlation between response and decreased ALDH expression. We also found a correlation between biopsy-proven inhibition of mTOR and response.ConclusionsOur study adds to the literature supporting the addition of mTOR inhibition to chemotherapy agents for the treatment of sarcomas, and proposes that a mechanism by which mTOR inhibition enhances the efficacy of chemotherapy may be through sensitizing the chemoresistant CSC population. Further study, ideally with pre- and post-therapy assessment of ALDH expression in tumor cells, is warranted.Trial registration The trial was registered on clinicaltrials.gov (NCT00949325) on 30 July 2009. http://www.editorialmanager.com/csrj/default.aspx
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