TY - JOUR
T1 - Phase 0 clinical trial of everolimus in patients with vestibular schwannoma or meningioma
AU - Karajannis, Matthias A.
AU - Mauguen, Audrey
AU - Maloku, Ekrem
AU - Xu, Qingwen
AU - Dunbar, Erin M.
AU - Plotkin, Scott R.
AU - Yaffee, Anna
AU - Wang, Shiyang
AU - Roland, J. Thomas
AU - Sen, Chandranath
AU - Placantonakis, Dimitris G.
AU - Golfinos, John G.
AU - Allen, Jeffrey C.
AU - Vitanza, Nicholas A.
AU - Chiriboga, Luis A.
AU - Schneider, Robert J.
AU - Deng, Jingjing
AU - Neubert, Thomas A.
AU - Goldberg, Judith D.
AU - Zagzag, David
AU - Giancotti, Filippo G.
AU - Blakeley, Jaishri O.
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research
PY - 2021/9
Y1 - 2021/9
N2 - Inhibition of mTORC1 signaling has been shown to diminish growth of meningiomas and schwannomas in preclinical studies, and clinical data suggest that everolimus, an orally administered mTORC1 inhibitor, may slow tumor progression in a subset of patients with neurofibromatosis type 2 (NF2) with vestibular schwannoma. To assess the pharmacokinetics, pharmacodynamics, and potential mechanisms of treatment resistance, we performed a presurgical (phase 0) clinical trial of everolimus in patients undergoing elective surgery for vestibular schwannoma or meningiomas. Eligible patients with meningioma or vestibular schwannoma requiring tumor resection enrolled on study received everolimus 10 mg daily for 10 days immediately prior to surgery. Everolimus blood levels were determined immediately before and after surgery. Tumor samples were collected intraoperatively. Ten patients completed protocol therapy. Median pre- and postoperative blood levels of everolimus were found to be in a high therapeutic range (17.4 ng/mL and 9.4 ng/mL, respectively). Median tumor tissue drug concentration determined by mass spectrometry was 24.3 pg/mg (range, 9.2-169.2). We observed only partial inhibition of phospho-S6 in the treated tumors, indicating incomplete target inhibition compared with control tissues from untreated patients (P = 0.025). Everolimus led to incomplete inhibition of mTORC1 and downstream signaling. These data may explain the limited antitumor effect of everolimus observed in clinical studies for patients with NF2 and will inform the design of future preclinical and clinical studies targeting mTORC1 in meningiomas and schwannomas.
AB - Inhibition of mTORC1 signaling has been shown to diminish growth of meningiomas and schwannomas in preclinical studies, and clinical data suggest that everolimus, an orally administered mTORC1 inhibitor, may slow tumor progression in a subset of patients with neurofibromatosis type 2 (NF2) with vestibular schwannoma. To assess the pharmacokinetics, pharmacodynamics, and potential mechanisms of treatment resistance, we performed a presurgical (phase 0) clinical trial of everolimus in patients undergoing elective surgery for vestibular schwannoma or meningiomas. Eligible patients with meningioma or vestibular schwannoma requiring tumor resection enrolled on study received everolimus 10 mg daily for 10 days immediately prior to surgery. Everolimus blood levels were determined immediately before and after surgery. Tumor samples were collected intraoperatively. Ten patients completed protocol therapy. Median pre- and postoperative blood levels of everolimus were found to be in a high therapeutic range (17.4 ng/mL and 9.4 ng/mL, respectively). Median tumor tissue drug concentration determined by mass spectrometry was 24.3 pg/mg (range, 9.2-169.2). We observed only partial inhibition of phospho-S6 in the treated tumors, indicating incomplete target inhibition compared with control tissues from untreated patients (P = 0.025). Everolimus led to incomplete inhibition of mTORC1 and downstream signaling. These data may explain the limited antitumor effect of everolimus observed in clinical studies for patients with NF2 and will inform the design of future preclinical and clinical studies targeting mTORC1 in meningiomas and schwannomas.
UR - http://www.scopus.com/inward/record.url?scp=85114235848&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85114235848&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-21-0143
DO - 10.1158/1535-7163.MCT-21-0143
M3 - Article
C2 - 34224367
AN - SCOPUS:85114235848
SN - 1535-7163
VL - 20
SP - 1584
EP - 1591
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 9
ER -