title: Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma.
abstract: BACKGROUND
  There is much discussion in the cancer drug development community about how to incorporate molecular tools into early-stage clinical trials to assess target modulation, measure anti-tumor activity, and enrich the clinical trial population for patients who are more likely to benefit. Small, molecularly focused clinical studies offer the promise of the early definition of optimal biologic dose and patient population.
  
  
  RESULTS
  Based on preclinical evidence that phosphatase and tensin homolog deleted on Chromosome 10 (PTEN) loss sensitizes tumors to the inhibition of mammalian target of rapamycin (mTOR), we conducted a proof-of-concept Phase I neoadjuvant trial of rapamycin in patients with recurrent glioblastoma, whose tumors lacked expression of the tumor suppressor PTEN. We aimed to assess the safety profile of daily rapamycin in patients with glioma, define the dose of rapamycin required for mTOR inhibition in tumor tissue, and evaluate the antiproliferative activity of rapamycin in PTEN-deficient glioblastoma. Although intratumoral rapamycin concentrations that were sufficient to inhibit mTOR in vitro were achieved in all patients, the magnitude of mTOR inhibition in tumor cells (measured by reduced ribosomal S6 protein phosphorylation) varied substantially. Tumor cell proliferation (measured by Ki-67 staining) was dramatically reduced in seven of 14 patients after 1 wk of rapamycin treatment and was associated with the magnitude of mTOR inhibition (p = 0.0047, Fisher exact test) but not the intratumoral rapamycin concentration. Tumor cells harvested from the Ki-67 nonresponders retained sensitivity to rapamycin ex vivo, indicating that clinical resistance to biochemical mTOR inhibition was not cell-intrinsic. Rapamycin treatment led to Akt activation in seven patients, presumably due to loss of negative feedback, and this activation was associated with shorter time-to-progression during post-surgical maintenance rapamycin therapy (p < 0.05, Logrank test).
  
  
  CONCLUSIONS
  Rapamycin has anticancer activity in PTEN-deficient glioblastoma and warrants further clinical study alone or in combination with PI3K pathway inhibitors. The short-term treatment endpoints used in this neoadjuvant trial design identified the importance of monitoring target inhibition and negative feedback to guide future clinical development.
  
  
  BACKGROUND
  http://www.ClinicalTrials.gov (#NCT00047073).
authors.affiliation: Department of Neurology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Tim F
authors.initials: TF
authors.lastname: Cloughesy
authors.forename: Koji
authors.initials: K
authors.lastname: Yoshimoto
authors.forename: Phioanh
authors.initials: P
authors.lastname: Nghiemphu
authors.forename: Kevin
authors.initials: K
authors.lastname: Brown
authors.forename: Julie
authors.initials: J
authors.lastname: Dang
authors.forename: Shaojun
authors.initials: S
authors.lastname: Zhu
authors.forename: Teli
authors.initials: T
authors.lastname: Hsueh
authors.forename: Yinan
authors.initials: Y
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: David
authors.initials: D
authors.lastname: Youngkin
authors.forename: Linda
authors.initials: L
authors.lastname: Liau
authors.forename: Neil
authors.initials: N
authors.lastname: Martin
authors.forename: Don
authors.initials: D
authors.lastname: Becker
authors.forename: Marvin
authors.initials: M
authors.lastname: Bergsneider
authors.forename: Albert
authors.initials: A
authors.lastname: Lai
authors.forename: Richard
authors.initials: R
authors.lastname: Green
authors.forename: Tom
authors.initials: T
authors.lastname: Oglesby
authors.forename: Michael
authors.initials: M
authors.lastname: Koleto
authors.forename: Jeff
authors.initials: J
authors.lastname: Trent
authors.forename: Steve
authors.initials: S
authors.lastname: Horvath
authors.forename: Paul S
authors.initials: PS
authors.lastname: Mischel
authors.forename: Ingo K
authors.initials: IK
authors.lastname: Mellinghoff
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000601:surgery; D002455:Cell Division / Q000187:drug effects; D003131:Combined Modality Therapy; D018450:Disease Progression; D025461:Feedback, Physiological; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000601:surgery; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000601:surgery; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011494:Protein Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism; D016879:Salvage Therapy; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D038601:Ribosomal Protein S6; D011494:Protein Kinases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020123:Sirolimus