Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma

PLoS Med. 2008 Jan 22;5(1):e8. doi: 10.1371/journal.pmed.0050008.

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.

Methods and findings: 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.

Trial registration: http://www.ClinicalTrials.gov (#NCT00047073).

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / enzymology
  • Brain Neoplasms / genetics
  • Brain Neoplasms / surgery
  • Cell Division / drug effects
  • Combined Modality Therapy
  • Disease Progression
  • Feedback, Physiological
  • Female
  • Glioblastoma / drug therapy*
  • Glioblastoma / enzymology
  • Glioblastoma / genetics
  • Glioblastoma / surgery
  • Humans
  • Male
  • Middle Aged
  • Neoadjuvant Therapy
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm Recurrence, Local / surgery
  • PTEN Phosphohydrolase / deficiency*
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / physiology
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein Kinases / physiology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Ribosomal Protein S6 / metabolism
  • Salvage Therapy*
  • Signal Transduction / drug effects
  • Sirolimus / adverse effects
  • Sirolimus / pharmacology
  • Sirolimus / therapeutic use*
  • TOR Serine-Threonine Kinases

Substances

  • Antineoplastic Agents
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • Ribosomal Protein S6
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Sirolimus

Associated data

  • ClinicalTrials.gov/NCT00047073