PMID- 18215105 OWN - NLM STAT- MEDLINE DCOM- 20080307 LR - 20220419 IS - 1549-1676 (Electronic) IS - 1549-1277 (Print) IS - 1549-1277 (Linking) VI - 5 IP - 1 DP - 2008 Jan 22 TI - Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PG - e8 LID - 10.1371/journal.pmed.0050008 [doi] LID - e8 AB - 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). FAU - Cloughesy, Tim F AU - Cloughesy TF AD - Department of Neurology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America. FAU - Yoshimoto, Koji AU - Yoshimoto K FAU - Nghiemphu, Phioanh AU - Nghiemphu P FAU - Brown, Kevin AU - Brown K FAU - Dang, Julie AU - Dang J FAU - Zhu, Shaojun AU - Zhu S FAU - Hsueh, Teli AU - Hsueh T FAU - Chen, Yinan AU - Chen Y FAU - Wang, Wei AU - Wang W FAU - Youngkin, David AU - Youngkin D FAU - Liau, Linda AU - Liau L FAU - Martin, Neil AU - Martin N FAU - Becker, Don AU - Becker D FAU - Bergsneider, Marvin AU - Bergsneider M FAU - Lai, Albert AU - Lai A FAU - Green, Richard AU - Green R FAU - Oglesby, Tom AU - Oglesby T FAU - Koleto, Michael AU - Koleto M FAU - Trent, Jeff AU - Trent J FAU - Horvath, Steve AU - Horvath S FAU - Mischel, Paul S AU - Mischel PS FAU - Mellinghoff, Ingo K AU - Mellinghoff IK FAU - Sawyers, Charles L AU - Sawyers CL LA - eng SI - ClinicalTrials.gov/NCT00047073 GR - CA108633/CA/NCI NIH HHS/United States GR - NS050151/NS/NINDS NIH HHS/United States GR - M01 RR000865/RR/NCRR NIH HHS/United States GR - R01 CA108633/CA/NCI NIH HHS/United States GR - M01-RR0865/RR/NCRR NIH HHS/United States GR - R01 NS050151/NS/NINDS NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - PLoS Med JT - PLoS medicine JID - 101231360 RN - 0 (Antineoplastic Agents) RN - 0 (Neoplasm Proteins) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Ribosomal Protein S6) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - EC 3.1.3.67 (PTEN protein, human) RN - W36ZG6FT64 (Sirolimus) SB - IM CIN - PLoS Med. 2008 Jan 22;5(1):e21. PMID: 18215108 MH - Adult MH - Aged MH - Antineoplastic Agents/adverse effects/pharmacology/*therapeutic use MH - Brain Neoplasms/*drug therapy/enzymology/genetics/surgery MH - Cell Division/drug effects MH - Combined Modality Therapy MH - Disease Progression MH - Feedback, Physiological MH - Female MH - Glioblastoma/*drug therapy/enzymology/genetics/surgery MH - Humans MH - Male MH - Middle Aged MH - Neoadjuvant Therapy MH - Neoplasm Proteins/*antagonists & inhibitors MH - Neoplasm Recurrence, Local/drug therapy/surgery MH - PTEN Phosphohydrolase/*deficiency/genetics/physiology MH - Protein Kinase Inhibitors/adverse effects/pharmacology/*therapeutic use MH - Protein Kinases/*physiology MH - Proto-Oncogene Proteins c-akt/metabolism MH - Ribosomal Protein S6/metabolism MH - *Salvage Therapy MH - Signal Transduction/drug effects MH - Sirolimus/adverse effects/pharmacology/*therapeutic use MH - TOR Serine-Threonine Kinases PMC - PMC2211560 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2008/01/25 09:00 MHDA- 2008/03/08 09:00 PMCR- 2008/01/22 CRDT- 2008/01/25 09:00 PHST- 2007/03/22 00:00 [received] PHST- 2007/11/15 00:00 [accepted] PHST- 2008/01/25 09:00 [pubmed] PHST- 2008/03/08 09:00 [medline] PHST- 2008/01/25 09:00 [entrez] PHST- 2008/01/22 00:00 [pmc-release] AID - 07-PLME-RA-0191 [pii] AID - 07-PLME-RA-0191R3 [pii] AID - 10.1371/journal.pmed.0050008 [doi] PST - ppublish SO - PLoS Med. 2008 Jan 22;5(1):e8. doi: 10.1371/journal.pmed.0050008.