PMID- 30410720
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220330
IS  - 2045-3329 (Print)
IS  - 2045-3329 (Electronic)
IS  - 2045-3329 (Linking)
VI  - 8
DP  - 2018
TI  - A phase II study of temsirolimus and liposomal doxorubicin for patients with 
      recurrent and refractory bone and soft tissue sarcomas.
PG  - 21
LID - 10.1186/s13569-018-0107-9 [doi]
LID - 21
AB  - BACKGROUND: Relapsed 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. 
      METHODS: Here 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 (20 mg/m(2) weekly) with the 
      chemotherapeutic agent liposomal doxorubicin (30 mg/m(2) monthly). RESULTS: 
      Fifteen patients with relapsed/refractory sarcoma were evaluable at this 
      recommended Phase 2 dose level. The median progression free survival was 315 days 
      (range 27-799). Response rate, defined as stable disease or better for 60 days, 
      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. CONCLUSIONS: Our 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.
FAU - Trucco, Matteo M
AU  - Trucco MM
AD  - 1Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns 
      Hopkins University, Baltimore, MD USA. ISNI: 0000 0001 2171 9311. GRID: 
      grid.21107.35
AD  - 3Present Address: Sylvester Comprehensive Cancer Center, University of Miami, 
      Miami, FL USA. ISNI: 0000 0000 9902 6374. GRID: grid.419791.3
FAU - Meyer, Christian F
AU  - Meyer CF
AD  - 2Division of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns 
      Hopkins University, Baltimore, MD USA. ISNI: 0000 0001 2171 9311. GRID: 
      grid.21107.35
FAU - Thornton, Katherine A
AU  - Thornton KA
AD  - 2Division of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns 
      Hopkins University, Baltimore, MD USA. ISNI: 0000 0001 2171 9311. GRID: 
      grid.21107.35
AD  - 4Present Address: Dana Farber Cancer Institute, Boston, MA USA. ISNI: 0000 0001 
      2106 9910. GRID: grid.65499.37
FAU - Shah, Preeti
AU  - Shah P
AD  - 1Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns 
      Hopkins University, Baltimore, MD USA. ISNI: 0000 0001 2171 9311. GRID: 
      grid.21107.35
AD  - Present Address: Akan Biosciences, Gaithersburg, MD USA.
FAU - Chen, Allen R
AU  - Chen AR
AD  - 1Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns 
      Hopkins University, Baltimore, MD USA. ISNI: 0000 0001 2171 9311. GRID: 
      grid.21107.35
FAU - Wilky, Breelyn A
AU  - Wilky BA
AD  - 2Division of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns 
      Hopkins University, Baltimore, MD USA. ISNI: 0000 0001 2171 9311. GRID: 
      grid.21107.35
AD  - 3Present Address: Sylvester Comprehensive Cancer Center, University of Miami, 
      Miami, FL USA. ISNI: 0000 0000 9902 6374. GRID: grid.419791.3
FAU - Carrera-Haro, Maria A
AU  - Carrera-Haro MA
AD  - 1Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns 
      Hopkins University, Baltimore, MD USA. ISNI: 0000 0001 2171 9311. GRID: 
      grid.21107.35
AD  - 6Present Address: Columbia University College of Physicians and Surgeons, New 
      York, NY USA. ISNI: 0000000419368729. GRID: grid.21729.3f
FAU - Boyer, Lillian C
AU  - Boyer LC
AD  - 1Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns 
      Hopkins University, Baltimore, MD USA. ISNI: 0000 0001 2171 9311. GRID: 
      grid.21107.35
FAU - Ferreira, Margaret F
AU  - Ferreira MF
AD  - 1Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns 
      Hopkins University, Baltimore, MD USA. ISNI: 0000 0001 2171 9311. GRID: 
      grid.21107.35
FAU - Shafique, Umber
AU  - Shafique U
AD  - 1Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns 
      Hopkins University, Baltimore, MD USA. ISNI: 0000 0001 2171 9311. GRID: 
      grid.21107.35
FAU - Powell, Jonathan D
AU  - Powell JD
AD  - 2Division of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns 
      Hopkins University, Baltimore, MD USA. ISNI: 0000 0001 2171 9311. GRID: 
      grid.21107.35
FAU - Loeb, David M
AU  - Loeb DM
AUID- ORCID: 0000-0002-7319-5000
AD  - 1Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns 
      Hopkins University, Baltimore, MD USA. ISNI: 0000 0001 2171 9311. GRID: 
      grid.21107.35
AD  - 7Department of Pediatrics, Albert Einstein College of Medicine, Children's 
      Hospital at Montefiore, 3411 Wayne Ave., Room 910, Bronx, NY 10467 USA. ISNI: 
      0000000121791997. GRID: grid.251993.5
LA  - eng
SI  - ClinicalTrials.gov/NCT00949325
GR  - P01 AI072677/AI/NIAID NIH HHS/United States
GR  - R01 AI077610/AI/NIAID NIH HHS/United States
PT  - Journal Article
DEP - 20181105
PL  - England
TA  - Clin Sarcoma Res
JT  - Clinical sarcoma research
JID - 101577890
PMC - PMC6217787
OTO - NOTNLM
OT  - Aldehyde dehydrogenase
OT  - Cancer stem cell
OT  - Chemoresistance
OT  - Sarcoma
OT  - mTOR
EDAT- 2018/11/10 06:00
MHDA- 2018/11/10 06:01
PMCR- 2018/11/05
CRDT- 2018/11/10 06:00
PHST- 2018/05/16 00:00 [received]
PHST- 2018/08/12 00:00 [accepted]
PHST- 2018/11/10 06:00 [entrez]
PHST- 2018/11/10 06:00 [pubmed]
PHST- 2018/11/10 06:01 [medline]
PHST- 2018/11/05 00:00 [pmc-release]
AID - 107 [pii]
AID - 10.1186/s13569-018-0107-9 [doi]
PST - epublish
SO  - Clin Sarcoma Res. 2018 Nov 5;8:21. doi: 10.1186/s13569-018-0107-9. eCollection 
      2018.