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

Abstract

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 PI3K/mTOR signaling in MPNST, making this axis an attractive target for therapeutic manipulation. Based on 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 SCID 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 pre-treatment with XL765 resulted in superior anti-tumor effects as compared to either agent alone. Together, pre-clinical 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.

Autophagy Inhibition for Chemosensitization and Radiosensitization in Cancer: Do the Preclinical Data Support This Therapeutic Strategy?

“…In recent studies by Ghadimi et al (2012), chloroquine clearly enhanced sensitivity to a dual PI3K/mTOR inhibitor in a xenograft model of malignant peripheral nerve sheath tumors. In contrast, Mirzoeva et al (2011) demonstrated minimal sensitization to an agent with a similar mechanism of action in a xenograft model of pancreatic cancer.…”

“…as indicated: (a) 25 mg/kg CQ (chloroquine), (b) 50 mg/kg CQ, (c) 100 mg/kg CQ, or (d) phosphate-buffered saline. The CQ doses chosen were based on the available literature, where studies have generally been performed using CQ at 50-60 mg/kg (Fu et al, 2009;Carew et al, 2010;Jiang et al, 2010;Wu et al, 2010;Ding et al, 2011;Lopez et al, 2011;Mirzoeva et al, 2011;Pan et al, 2011;Shi et al, 2011;Xu et al, 2011;Ghadimi et al, 2012;Godbole et al, 2012;Guo et al, 2012;Hu et al, 2012;Liang et al, 2012;Loehberg et al, 2012;Rao et al, 2012;Sasaki et al, 2012). Additional experiments were conducted where the mice were exposed to g-irradiation using a 137 Cs irradiator as indicated: (e) 5 Gy IR (ionizing radiation), (f) 10 Gy IR, (g) 15 Gy IR, (h) 10Gy IR 1 14 days CQ i.p.…”

“…An extensive number of studies in cell culture (for example, among many others, Paglin et al, 2001;Kanzawa et al, 2004;Boya et al, 2005;Zhao et al, 2005;Amaravadi et al, 2007;Apel et al, 2008;Qadir et al, 2008;Livesey et al, 2009;Solomon and Lee, 2009;Ma et al, 2011;Wilson et al, 2011;Bristol et al, 2012), as well as a limited number of studies in animal models (Fu et al, 2009;Carew et al, 2010;Jiang et al, 2010;Wu et al, 2010;Ding et al, 2011;Lopez et al, 2011;Mirzoeva et al, 2011;Pan et al, 2011;Shi et al, 2011;Xu et al, 2011;Ghadimi et al, 2012;Godbole et al, 2012;Guo et al, 2012;Hu et al, 2012;Liang et al, 2012;Loehberg et al, 2012;Rao et al, 2012;Sasaki et al, 2012), have been performed combining chloroquine or hydroxychloroquine with chemotherapeutic drugs or radiation. Furthermore, a number of clinical trials have been initiated to test this premise in patients (Sotelo et al, 2006;Solomon and Lee, 2009).…”

Radiation-induced intradural malignant peripheral nerve sheath tumor of the cauda equina with diffuse leptomeningeal metastasis

“…5 Chemotherapy has not proven to be effective in the treatment of MPNST 6 but can be used in cases without alternatives for disseminated metastatic disease. 13 The expanding scientific literature suggests that MPNST can be treated more effectively with the addition of agents that target and inhibit specific pathways and/or cellular processes: PI3K/mTOR pathway with XL765, 12 autophagy with chloroquine, 12 and plateletderived growth factor receptor with sunitinib. 35 The reported 5-year survival rate for patients diagnosed with MPNST is poor, ranging from 16% to 52%.…”

Increased drug resistance is associated with reduced glucose levels and an enhanced glycolysis phenotype

“…The combination of BEZ235, the dual PI3K/mTOR inhibitor, with temsirolimus resulted in cell death due to autophagy (Yang et al, 2011). Inhibition of autophagy has also enhanced the effect of PI3K/mTOR inhibition in neurological tumours (Ghadimi et al, 2012) and lung cancer (Xu et al, 2011).…”