Targeting the PI3K/mTOR Axis, Alone and in Combination with Autophagy Blockade, for the Treatment of Malignant Peripheral Nerve Sheath Tumors

There is a critical need for efficacious therapeutic strategies to improve the outcome of patients afflicted by malignant peripheral nerve sheath tumors (MPNST). Multiple lines of evidence suggest a role for deregulated phosphoinositide 3-kinase (PI3K)/mTOR signaling in MPNST, making this axis an attractive target for therapeutic manipulation. On the basis of previous observations obtained from in vitro experimentation, here we aimed to assess the effects of PI3K/mTOR blockade on MPNST growth in vivo. The anti-MPNST impact of XL765, a dual PI3K/mTOR inhibitor currently being evaluated in human cancer clinical trials, was tested in two human MPNST xenograft models (STS26T and MPNST724) and an experimental model of pulmonary metastasis (STS26T). XL765 abrogated human MPNST local and metastatic growth in severe combined immunodeficient mice. Notably, this therapeutic approach failed to induce apoptosis in MPNST cells but rather resulted in marked productive autophagy. Importantly, genetic and pharmacologic autophagy blockade reversed apoptotic resistance and resulted in significant PI3K/mTOR inhibition-induced MPNST cell death. The addition of the autophagy inhibitor, chloroquine, to the therapeutic regimen of MPNST xenografts after pretreatment with XL765 resulted in superior antitumor effects as compared with either agent alone. Together, preclinical studies described here expand our previous findings and suggest that PI3K/mTOR inhibition alone and (most importantly) in combination with autophagy blockade may comprise a novel and efficacious therapy for patients harboring MPNST. Mol Cancer Ther; 11(8); 1758–69. ©2012 AACR.

[1]  Robert Clarke,et al.  Guidelines for the use and interpretation of assays for monitoring autophagy , 2012 .

[2]  K. Leslie,et al.  A Mechanism for Synergy with Combined mTOR and PI3 Kinase Inhibitors , 2011, PloS one.

[3]  F. Khuri,et al.  Augmentation of NVP-BEZ235's anticancer activity against human lung cancer cells by blockage of autophagy , 2011, Cancer biology & therapy.

[4]  Kai Huang,et al.  Expression of ‘drugable’ tyrosine kinase receptors in malignant peripheral nerve sheath tumour: potential molecular therapeutic targets for a chemoresistant cancer , 2011, Histopathology.

[5]  K. Shokat,et al.  Autophagy suppression promotes apoptotic cell death in response to inhibition of the PI3K—mTOR pathway in pancreatic adenocarcinoma , 2011, Journal of Molecular Medicine.

[6]  Jun Liu,et al.  Activated MET Is a Molecular Prognosticator and Potential Therapeutic Target for Malignant Peripheral Nerve Sheath Tumors , 2011, Clinical Cancer Research.

[7]  Mitchel S. Berger,et al.  Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide. , 2011, Neuro-oncology.

[8]  J. Debnath,et al.  Autophagy and Tumorigenesis , 2010, Seminars in Immunopathology.

[9]  Kai Huang,et al.  Vimentin Is a Novel Anti-Cancer Therapeutic Target; Insights from In Vitro and In Vivo Mice Xenograft Studies , 2010, PloS one.

[10]  Hoyun Lee,et al.  Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies. , 2009, European journal of pharmacology.

[11]  S. Dry,et al.  PTEN dosage is essential for neurofibroma development and malignant transformation , 2009, Proceedings of the National Academy of Sciences.

[12]  A. Lazar,et al.  Malignant peripheral nerve sheath tumour (MPNST): the clinical implications of cellular signalling pathways , 2009, Expert Reviews in Molecular Medicine.

[13]  Dexin Kong,et al.  Advances in development of phosphatidylinositol 3-kinase inhibitors. , 2009, Current medicinal chemistry.

[14]  Wei-Lien Wang,et al.  Clinical, Pathological, and Molecular Variables Predictive of Malignant Peripheral Nerve Sheath Tumor Outcome , 2009, Annals of surgery.

[15]  E. Heath,et al.  A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics of XL765, a PI3K/TORC1/TORC2 inhibitor administered orally to patients (pts) with advanced solid tumors. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  G. Mills,et al.  Dual targeting of AKT and mammalian target of rapamycin: A potential therapeutic approach for malignant peripheral nerve sheath tumor , 2009, Molecular Cancer Therapeutics.

[17]  R. Lothe,et al.  Germline and somatic NF1 mutations in sporadic and NF1‐associated malignant peripheral nerve sheath tumours , 2009, The Journal of pathology.

[18]  C. Jung,et al.  ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. , 2009, Molecular biology of the cell.

[19]  L. Siu,et al.  First-in-class, first-in-human phase I results of targeted agents: Highlights of the 2008 American Society of Clinical Oncology meeting , 2008, Journal of hematology & oncology.

[20]  A. Lazar,et al.  Midkine Enhances Soft-Tissue Sarcoma Growth: A Possible Novel Therapeutic Target , 2008, Clinical Cancer Research.

[21]  H. Lane,et al.  Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors , 2008, Molecular Cancer Therapeutics.

[22]  G. Mills,et al.  Soft tissue sarcoma cells are highly sensitive to AKT blockade: a role for p53-independent up-regulation of GADD45 alpha. , 2008, Cancer research.

[23]  John L Cleveland,et al.  Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes , 2008, Autophagy.

[24]  A. Goldberg,et al.  Coordinate activation of autophagy and the proteasome pathway by FoxO transcription factor , 2008, Autophagy.

[25]  Yoshihiro Kakeji,et al.  Deregulation of the Akt pathway in human cancer. , 2008, Current cancer drug targets.

[26]  D. Durden,et al.  Mechanisms of Disease: the PI3K–Akt–PTEN signaling node—an intercept point for the control of angiogenesis in brain tumors , 2007, Nature Clinical Practice Neurology.

[27]  G. Mills,et al.  Akt inhibitor shows anticancer and radiosensitizing effects in malignant glioma cells by inducing autophagy. , 2007, International journal of oncology.

[28]  Guido Kroemer,et al.  Self-eating and self-killing: crosstalk between autophagy and apoptosis , 2007, Nature Reviews Molecular Cell Biology.

[29]  K. Shokat,et al.  A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma. , 2007, Cancer research.

[30]  L. Helman,et al.  Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism , 2007, Oncogene.

[31]  N. Leslie.  The redox regulation of PI 3-kinase-dependent signaling. , 2006, Antioxidants & redox signaling.

[32]  D. Sabatini.  mTOR and cancer: insights into a complex relationship , 2006, Nature Reviews Cancer.

[33]  C. Mussi,et al.  Malignant peripheral nerve sheath tumors , 2006, Cancer.

[34]  William A Weiss,et al.  A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. , 2006, Cancer cell.

[35]  M. Watson,et al.  Large-scale molecular comparison of human schwann cells to malignant peripheral nerve sheath tumor cell lines and tissues. , 2006, Cancer research.

[36]  Y. Tsujimoto,et al.  Another way to die: autophagic programmed cell death , 2005, Cell Death and Differentiation.

[37]  Raymond Sawaya,et al.  The role of autophagy in cancer development and response to therapy , 2005, Nature Reviews Cancer.

[38]  F. Khuri,et al.  Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. , 2005, Cancer research.

[39]  J. Zeller,et al.  Association between benign and malignant peripheral nerve sheath tumors in NF1 , 2005, Neurology.

[40]  C. Johannessen,et al.  The NF1 tumor suppressor critically regulates TSC2 and mTOR. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[41]  G. Mills,et al.  Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. , 2005, Cancer research.

[42]  L. Cantley,et al.  Targeting the PI3K-Akt pathway in human cancer: rationale and promise. , 2003, Cancer cell.

[43]  C. Sawyers,et al.  The phosphatidylinositol 3-Kinase–AKT pathway in human cancer , 2002, Nature Reviews Cancer.

[44]  D. Evans,et al.  Malignant peripheral nerve sheath tumours in neurofibromatosis 1 , 2002, Journal of medical genetics.

[45]  S. Emr,et al.  Autophagy as a regulated pathway of cellular degradation. , 2000, Science.

[46]  B. Scheithauer,et al.  Malignant peripheral nerve sheath tumor: analysis of treatment outcome. , 1998, International journal of radiation oncology, biology, physics.

[47]  D H Leung,et al.  Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[48]  A. Lazar,et al.  Autophagic survival in resistance to histone deacetylase inhibitors: novel strategies to treat malignant peripheral nerve sheath tumors. , 2011, Cancer research.

[49]  H. Wakimoto,et al.  A dual PI3K/mTOR inhibitor, PI-103, cooperates with stem cell-delivered TRAIL in experimental glioma models. , 2011, Cancer research.

[50]  D. Rubinsztein,et al.  Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies , 2009, Cell Death and Differentiation.

[51]  Yiling Lu,et al.  Soft Tissue Sarcoma Cells Are Highly Sensitive to AKT Blockade: A Role for p53-Independent Up-regulation of GADD45A , 2008 .

[52]  Hu Shih,et al.  Development of Methodology , 1980 .