The mTORC1 inhibitor everolimus has antitumor activity in vitro and produces tumor responses in patients with relapsed T-cell lymphoma.
Everolimus is an oral agent that targets the mammalian target of rapamycin (mTOR) pathway. This study investigated mTOR pathway activation in T-cell lymphoma (TCL) cell lines and assessed antitumor activity in patients with relapsed/refractory TCL in a phase 2 trial. The mTOR pathway was activated in all 6 TCL cell lines tested and everolimus strongly inhibited malignant T-cell proliferation with minimal cytotoxic effects. Everolimus completely inhibited phosphorylation of ribosomal S6, a raptor/mTOR complex 1 (mTORC1) target, without a compensatory activation of the rictor/mTORC2 target Akt (S475). In the clinical trial, 16 patients with relapsed TCL were enrolled and received everolimus 10 mg by mouth daily. Seven patients (44%) had cutaneous (all mycosis fungoides); 4 (25%) had peripheral T cell not otherwise specified; 2 (13%) had anaplastic large cell; and 1 each had extranodal natural killer/T cell, angioimmunoblastic, and precursor T-lymphoblastic leukemia/lymphoma types. The overall response rate was 44% (7/16; 95% confidence interval [CI]: 20% to 70%). The median progression-free survival was 4.1 months (95% CI, 1.5-6.5) and the median overall survival was 10.2 months (95% CI, 2.6-44.3). The median duration of response for the 7 responders was 8.5 months (95% CI, 1.0 to not reached). These studies indicate that everolimus has antitumor activity and provide proof-of-concept that targeting the mTORC1 pathway in TCL is clinically relevant. This trial was registered at www.clinicaltrials.gov as #NCT00436618.
Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, MN;
Thomas E
http://orcid.org/0000-0002-4215-6500
TE
Witzig
Division of Hematology, Department of Medicine, Mayo Clinic Scottsdale, Scottsdale, AZ;
Craig
C
Reeder
Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, MN;
Jing Jing
JJ
Han
Division of Biomedical Statistics and Bioinformatics, Department of Health Sciences Research, Mayo Clinic Rochester, Rochester, MN;
Betsy
B
LaPlant
Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, MN;
Mary
M
Stenson
Division of Hematology, Department of Medicine, Mayo Clinic Jacksonville, Jacksonville, FL; and.
Han W
HW
Tun
Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, MN.
William
W
Macon
Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, MN;
Stephen M
SM
Ansell
Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, MN;
Thomas M
TM
Habermann
Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, MN;
David J
DJ
Inwards
Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, MN;
Ivana N
IN
Micallef
Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, MN;
Patrick B
PB
Johnston
Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, MN;
Luis F
LF
Porrata
Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, MN;
Joseph P
JP
Colgan
Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, MN;
Svetomir
S
Markovic
Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, MN;
Grzegorz S
GS
Nowakowski
Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, MN;
Mamta
M
Gupta
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D000068338:Everolimus; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D010766:Phosphorylation; D011379:Prognosis; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D016207:Cytokines; D007166:Immunosuppressive Agents; D046912:Multiprotein Complexes; D000068338:Everolimus; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus