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Cited by 593Glioma Diagnosis and TreatmentPI3K/AKT/mTOR signaling in cancerTuberous Sclerosis Complex Research

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

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Cloughesy, Tim F, Yoshimoto, Koji, Nghiemphu, Phioanh, Brown, Kevin, Dang, Julie, Zhu, Shaojun, Hsueh, Teli, Chen, Yinan +15 more·2008·PLoS Medicine
DOI 10.1371/journal.pmed.0050008PMC PMC2211560
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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).

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  • SREBP-1 activation and consequent LDLR expression are rapamycin resistant in preclinical models and in GBM patients treated with rapamycin.

    “In pre-clinical models (Figure 1F) and in GBM patients treated with rapamycin (14, 64), we have shown that SREBP-1 activation, and consequent LDLR expression, are rapamycin resistant (Figure 1F).”

    From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [64]

    The Results sections describe rapamycin treatment in GBM patients and measure mTOR activity through S6 phosphorylation, but they do not report SREBP-1 activation or LDLR expression. Searches for SREBP-1, LDLR, and their expanded names found no passage addressing whether either is rapamycin resistant. (LLM, conf=0.75)

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Research works printed but not linked: 48

  1. Arteaga CL Baselga J 2004 Tyrosine kinase inhibitors: why does the current process of clinical development not apply to them? Cancer Cell 5 525 531 15193255
  2. Sarker D Workman P 2007 Pharmacodynamic biomarkers for molecular cancer therapeutics Adv Cancer Res 96 213 268 17161682
  3. Michaelis LC Ratain MJ 2006 Measuring response in a post-RECIST world: from black and white to shades of grey Nat Rev Cancer 6 409 414 16633367
  4. Smith IE Walsh G Skene A Llombart A Mayordomo JI 2007 A phase II placebo-controlled trial of neoadjuvant anastrozole alone or with gefitinib in early breast cancer J Clin Oncol 25 3816 3822 17679728
  5. Dowsett M Smith IE Ebbs SR Dixon JM Skene A 2007 Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer J Natl Cancer Inst 99 167 170 17228000
  6. Bjornsti MA Houghton PJ 2004 The TOR pathway: a target for cancer therapy Nat Rev Cancer 4 335 348 15122205
  7. Hudes G Carducci M Tomczak P Dutcher J Figlin R 2007 Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma N Engl J Med 356 2271 2281 17538086
  8. Neshat MS Mellinghoff IK Tran C Stiles B Thomas G 2001 Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR Proc Natl Acad Sci U S A 98 10314 10319 11504908 PMC56958
  9. Podsypanina K Lee RT Politis C Hennessy I Crane A 2001 An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/- mice Proc Natl Acad Sci U S A 98 10320 10325 11504907 PMC56959
  10. Yu K Toral-Barza L Discafani C Zhang WG Skotnicki J 2001 mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer Endocr Relat Cancer 8 249 258 11566616
  11. Shi Y Gera J Hu L Hsu JH Bookstein R 2002 Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779 Cancer Res 62 5027 5034 12208757
  12. Wendel HG De Stanchina E Fridman JS Malina A Ray S 2004 Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy Nature 428 332 337 15029198
  13. Yilmaz OH Valdez R Theisen BK Guo W Ferguson DO 2006 Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells Nature 441 475 482 16598206
  14. Quinn JA Desjardins A Weingart J Brem H Dolan ME 2005 Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma J Clin Oncol 23 7178 7187 16192602
  15. Choe G Horvath S Cloughesy TF Crosby K Seligson D 2003 Analysis of the phosphatidylinositol 3′-kinase signaling pathway in glioblastoma patients in vivo Cancer Res 63 2742 2746 12782577
  16. Mellinghoff IK Wang MY Vivanco I Haas-Kogan DA Zhu S 2005 Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors N Engl J Med 353 2012 2024 16282176
  17. Wullschleger S Loewith R Hall MN 2006 TOR signaling in growth and metabolism Cell 124 471 484 16469695
  18. Pende M Um SH Mieulet V Sticker M Goss VL 2004 S6K1(-/-)/S6K2(-/-) mice exhibit perinatal lethality and rapamycin-sensitive 5′-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway Mol Cell Biol 24 3112 3124 15060135 PMC381608
  19. Roux PP Shahbazian D Vu H Holz MK Cohen MS 2007 RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation J Biol Chem 282 14056 14064 17360704 PMC3618456
  20. Yatscoff R LeGatt D Keenan R Chackowsky P 1993 Blood distribution of rapamycin Transplantation 56 1202 1206 8249123
  21. Sun XJ Goldberg JL Qiao LY Mitchell JJ 1999 Insulin-induced insulin receptor substrate-1 degradation is mediated by the proteasome degradation pathway Diabetes 48 1359 1364 10389839
  22. Haruta T Uno T Kawahara J Takano A Egawa K 2000 A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1 Mol Endocrinol 14 783 794 10847581
  23. Tremblay F Marette A 2001 Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells J Biol Chem 276 38052 38060 11498541
  24. Takano A Usui I Haruta T Kawahara J Uno T 2001 Mammalian target of rapamycin pathway regulates insulin signaling via subcellular redistribution of insulin receptor substrate 1 and integrates nutritional signals and metabolic signals of insulin Mol Cell Biol 21 5050 5062 11438661 PMC87231
  25. Sun SY Rosenberg LM Wang X Zhou Z Yue P 2005 Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition Cancer Res 65 7052 7058 16103051
  26. O'Reilly KE Rojo F She QB Solit D Mills GB 2006 mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt Cancer Res 66 1500 1508 16452206 PMC3193604
  27. Kovacina KS Park GY Bae SS Guzzetta AW Schaefer E 2003 Identification of a proline-rich Akt substrate as a 14-3-3 binding partner J Biol Chem 278 10189 10194 12524439
  28. Vander Haar E Lee SI Bandhakavi S Griffin TJ Kim DH 2007 Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40 Nat Cell Biol 9 316 323 17277771
  29. Sarbassov DD Guertin DA Ali SM Sabatini DM 2005 Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex Science 307 1098 1101 15718470
  30. Sarbassov DD Ali SM Sengupta S Sheen JH Hsu PP 2006 Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB Mol Cell 22 159 168 16603397
  31. Ichimura K Ohgaki H Kleihues P Collins VP 2004 Molecular pathogenesis of astrocytic tumours J Neurooncol 70 137 160 15674475
  32. Cui X Kim HJ Kuiatse I Kim H Brown PH 2006 Epidermal growth factor induces insulin receptor substrate-2 in breast cancer cells via c-Jun NH(2)-terminal kinase/activator protein-1 signaling to regulate cell migration Cancer Res 66 5304 5313 16707456
  33. Zhang H Bajraszewski N Wu E Wang H Moseman AP 2007 PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR J Clin Invest 117 730 738 17290308 PMC1784000
  34. Parsons R 2004 Human cancer, PTEN and the PI-3 kinase pathway Semin Cell Dev Biol 15 171 176 15209376
  35. Sawyers CL 2003 Will mTOR inhibitors make it as cancer drugs? Cancer Cell 4 343 348 14667501
  36. Galanis E Buckner JC Maurer MJ Kreisberg JI Ballman K 2005 Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study J Clin Oncol 23 5294 5304 15998902
  37. Chang SM Kuhn J Wen P Greenberg H Schiff D 2004 Phase I/pharmacokinetic study of CCI-779 in patients with recurrent malignant glioma on enzyme-inducing antiepileptic drugs Invest New Drugs 22 427 435 15292713
  38. Chang SM Wen P Cloughesy T Greenberg H Schiff D 2005 Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme Invest New Drugs 23 357 361 16012795
  39. Guertin DA Sabatini DM 2007 Defining the role of mTOR in cancer Cancer Cell 12 9 22 17613433
  40. Sawyers CL 2005 Making progress through molecular attacks on cancer Cold Spring Harb Symp Quant Biol 70 479 482 16869786
  41. Vredenburgh JJ Desjardins A Herndon JE 2nd Dowell JM Reardon DA 2007 Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma Clin Cancer Res 13 1253 1259 17317837
  42. Waldherr C Mellinghoff IK Tran C Halpern BS Rozengurt N 2005 Monitoring antiproliferative responses to kinase inhibitor therapy in mice with 3′-deoxy-3′-18F-fluorothymidine PET J Nucl Med 46 114 120 15632041
  43. Bianco R Shin I Ritter CA Yakes FM Basso A 2003 Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors Oncogene 22 2812 2822 12743604
  44. Wang MY Lu KV Zhu S Dia EQ Vivanco I 2006 Mammalian target of rapamycin inhibition promotes response to epidermal growth factor receptor kinase inhibitors in PTEN-deficient and PTEN-intact glioblastoma cells Cancer Res 66 7864 7869 16912159
  45. Li D Shimamura T Ji H Chen L Haringsma HJ 2007 Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy Cancer Cell 12 81 93 17613438
  46. Fan QW Knight ZA Goldenberg DD Yu W Mostov KE 2006 A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma Cancer Cell 9 341 349 16697955 PMC2925230
  47. Faivre S Kroemer G Raymond E 2006 Current development of mTOR inhibitors as anticancer agents Nat Rev Drug Discov 5 671 688 16883305
  48. Kummar S Kinders R Rubinstein L Parchment RE Murgo AJ 2007 Compressing drug development timelines in oncology using phase '0' trials Nat Rev Cancer 7 131 139 17251919

Cited by

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Authors
Cloughesy, T. F., Yoshimoto, K., Nghiemphu, P., Brown, K., Dang, J., Zhu, S., Hsueh, T., Chen, Y., Wang, W., Youngkin, D., Liau, L., Martin, N., Becker, D., Bergsneider, M., Lai, A., Green, R., Oglesby, T., Koleto, M., Trent, J., Horvath, S., Mischel, P. S., Mellinghoff, I. K., & Sawyers, C. L.
Affiliations
  • University of California, Los Angeles (US)
  • Translational Genomics Research Institute (US)
  • Kaiser Permanente (US)
  • Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Sawyers, Charles L
ORCID
Venue
PLoS Medicine
Publisher
Public Library of Science (PLoS)
Published
2008-01-22
Volume
5
Issue
1
Pages
e8
ISSN
  • 1549-1277 (ISSN-L)
  • 1549-1676
DOI
10.1371/journal.pmed.0050008
PMC
PMC2211560
OpenAlex
W2116622644
Cited by
593
References
4
Citations by year
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FWCI
31.13
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
Funders
  • Exelixis
  • National Cancer Institute (R01CA108633, CA 108633)
  • National Institute of Neurological Disorders and Stroke (R01NS050151, NS 050151)
  • National Center for Research Resources (M01-RR0865, M01RR000865)
Topics
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
Keywords
rapamycin, recurrent glioblastoma, mTOR inhibition, neoadjuvant therapy, anticancer activity, Akt activation, PI3K signaling, drug resistance, dose escalation, time to progression, Ki-67 proliferation index
MeSH terms
Adult, Aged, Antineoplastic Agents, Brain Neoplasms, Cell Division, Combined Modality Therapy, Female, Glioblastoma, Humans, Male, Middle Aged, Neoplasm Proteins, Neoplasm Recurrence, Local, Protein Kinases, Signal Transduction, Salvage Therapy, Disease Progression, Sirolimus, Neoadjuvant Therapy, Feedback, Physiological, Ribosomal Protein S6, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, TOR Serine-Threonine Kinases

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