| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Cancer Therapy: Clinical |
Authors' Affiliations: Departments of 1 Leukemia and 2 Blood and Marrow Transplantation, University of Texas M.D. Anderson Cancer Center, Houston, Texas
Requests for reprints: Francis J. Giles, Department of Leukemia, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 428, Houston, TX 77030. Phone: 713-792-8217; Fax: 713-794-4297; E-mail: frankgiles{at}aol.com.
Purpose: Everolimus (RAD001, Novartis), an oral derivative of rapamycin, inhibits the mammalian target of rapamycin (mTOR), which regulates many aspects of cell growth and division. A phase I/II study was done to determine safety and efficacy of everolimus in patients with relapsed or refractory hematologic malignancies.
Experimental Design: Two dose levels (5 and 10 mg orally once daily continuously) were evaluated in the phase I portion of this study to determine the maximum tolerated dose of everolimus to be used in the phase II study.
Results: Twenty-seven patients (9 acute myelogenous leukemia, 5 myelodysplastic syndrome, 6 B-chronic lymphocytic leukemia, 4 mantle cell lymphoma, 1 myelofibrosis, 1 natural killer cell/T-cell leukemia, and 1 T-cell prolymphocytic leukemia) received everolimus. No dose-limiting toxicities were observed. Grade 3 potentially drug-related toxicities included hyperglycemia (22%), hypophosphatemia (7%), fatigue (7%), anorexia (4%), and diarrhea (4%). One patient developed a cutaneous leukocytoclastic vasculitis requiring a skin graft. One patient with refractory anemia with excess blasts achieved a major platelet response of over 3-month duration. A second patient with refractory anemia with excess blasts showed a minor platelet response of 25-day duration. Phosphorylation of downstream targets of mTOR, eukaryotic initiation factor 4E-binding protein 1, and/or, p70 S6 kinase, was inhibited in six of nine patient samples, including those from the patient with a major platelet response.
Conclusions: Everolimus is well tolerated at a daily dose of 10 mg daily and may have activity in patients with myelodysplastic syndrome. Studies of everolimus in combination with therapeutic agents directed against other components of the phosphatidylinositol 3-kinase/Akt/mTOR pathway are warranted.
This article has been cited by other articles:
|
|
 |
|
  F. Meric-Bernstam and A. M. Gonzalez-Angulo Targeting the mTOR Signaling Network for Cancer Therapy J. Clin. Oncol., May 1, 2009; 27(13): 2278 - 2287. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Crazzolara, A. Cisterne, M. Thien, J. Hewson, R. Baraz, K. F. Bradstock, and L. J. Bendall Potentiating effects of RAD001 (Everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia Blood, April 2, 2009; 113(14): 3297 - 3306. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Breuleux, M. Klopfenstein, C. Stephan, C. A. Doughty, L. Barys, S.-M. Maira, D. Kwiatkowski, and H. A. Lane Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition Mol. Cancer Ther., April 1, 2009; 8(4): 742 - 753. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. W. Ma and A. A. Adjei Novel Agents on the Horizon for Cancer Therapy CA Cancer J Clin, March 1, 2009; 59(2): 111 - 137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Ruan, K. Hajjar, S. Rafii, and J. P. Leonard Angiogenesis and antiangiogenic therapy in non-Hodgkin's lymphoma Ann. Onc., March 1, 2009; 20(3): 413 - 424. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Wall, G. Poortinga, K. M. Hannan, R. B. Pearson, R. D. Hannan, and G. A. McArthur Translational control of c-MYC by rapamycin promotes terminal myeloid differentiation Blood, September 15, 2008; 112(6): 2305 - 2317. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Garcia and D. Danielpour Mammalian target of rapamycin inhibition as a therapeutic strategy in the management of urologic malignancies Mol. Cancer Ther., June 1, 2008; 7(6): 1347 - 1354. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. M.W. Verheul, B. Salumbides, K. Van Erp, H. Hammers, D. Z. Qian, T. Sanni, P. Atadja, and R. Pili Combination Strategy Targeting the Hypoxia Inducible Factor-1{alpha} with Mammalian Target of Rapamycin and Histone Deacetylase Inhibitors Clin. Cancer Res., June 1, 2008; 14(11): 3589 - 3597. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Rizzieri, E. Feldman, J. F. DiPersio, N. Gabrail, W. Stock, R. Strair, V. M. Rivera, M. Albitar, C. L. Bedrosian, and F. J. Giles A Phase 2 Clinical Trial of Deforolimus (AP23573, MK-8669), a Novel Mammalian Target of Rapamycin Inhibitor, in Patients with Relapsed or Refractory Hematologic Malignancies Clin. Cancer Res., May 1, 2008; 14(9): 2756 - 2762. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A Dennis Targeting Akt in Cancer: Promise, Progress, and Potential Pitfalls Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 25 - 35. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Chumsri, W. Matsui, and A. M Burger Therapeutic Implications of Leukemic Stem Cell Pathways Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 397 - 406. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Chumsri, W. Matsui, and A. M. Burger Therapeutic Implications of Leukemic Stem Cell Pathways Clin. Cancer Res., November 15, 2007; 13(22): 6549 - 6554. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fouladi, F. Laningham, J. Wu, M. A. O'Shaughnessy, K. Molina, A. Broniscer, S. L. Spunt, I. Luckett, C. F. Stewart, P. J. Houghton, et al. Phase I Study of Everolimus in Pediatric Patients With Refractory Solid Tumors J. Clin. Oncol., October 20, 2007; 25(30): 4806 - 4812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. E. Johnson, D. Jackman, and P. A. Janne Rationale for a Phase I Trial of Erlotinib and the Mammalian Target of Rapamycin Inhibitor Everolimus (RAD001) for Patients with Relapsed Non Small Cell Lung Cancer Clin. Cancer Res., August 1, 2007; 13(15): 4628s - 4631s. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Y. Follo, S. Mongiorgi, C. Bosi, A. Cappellini, C. Finelli, F. Chiarini, V. Papa, M. Libra, G. Martinelli, L. Cocco, et al. The Akt/Mammalian Target of Rapamycin Signal Transduction Pathway Is Activated in High-Risk Myelodysplastic Syndromes and Influences Cell Survival and Proliferation Cancer Res., May 1, 2007; 67(9): 4287 - 4294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Zeng, D. D. Sarbassov, I. J. Samudio, K. W. L. Yee, M. F. Munsell, C. Ellen Jackson, F. J. Giles, D. M. Sabatini, M. Andreeff, and M. Konopleva Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML Blood, April 15, 2007; 109(8): 3509 - 3512. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. J. Giles Syk-driven mTOR in lymphoma-complimentary targets? Blood, December 15, 2006; 108(13): 3957 - 3958. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
