Rapamycin Holds Promise for the Treatment of Gliomas
Abstract & Commentary
By Andrew Lassman, MD, Assistant Attending, Department of Neurology, Memorial Sloan-Kettering Cancer Center. Dr. Lassman reports no financial relationships relevant to this field of study.
Synopsis: Rapamycin was effective in the treatment of low-grade gliomas in patients with tuberous sclerosis complex, and may be effective in other types of gliomas.
Source: Franz DN, et al. Rapamycin Causes Regression of Astrocytomas in Tuberous Sclerosis Complex. Ann Neurol. 2006;59:490-498.
Brain tumors occur in children and young adults with the autosomal dominant disorder, tuberous sclerosis complex (TSC). The most common brain tumor in these patients, the subependymal giant cell astrocytoma (SEGA), grows slowly and is considered to be grade I (World Health Organization), indicating a benign course. However, SEGAs are often located adjacent to the foramen of Monro, and may cause obstructive hydrocephalus with increased intracranial pressure. Symptomatic therapy involves CSF diverting procedures and antiepileptic medications for patients with seizures. These tumors are typically refractory to radiotherapy (RT) and current chemotherapies (CTX). Moreover, patients with TSC are predisposed to second malignancies from the DNA damaging effects of RT and CTX, because they have a germ cell line abnormality that inactivates tumor suppressors TSC1 (hamartin) or TSC2 (tubulin). Therefore, definitive treatment for patients with SEGA or pilocytic astrocytoma (another low grade glioma that occurs in patients with TSC) consists of repeated surgical resections.
To avoid surgical morbidity and the risks of second malignancies from RT and CTX, Franz and colleagues treated 5 patients with rapamycin for TSC-associated SEGA (n = 4) or pilocytic astrocytoma (n = 1). They observed radiographic responses in all patients, including one patient who responded initially and then again upon re-treatment, after a pause in therapy was associated with tumor growth.
Commentary
Rapamycin is an immune suppressant that has most commonly been used in the renal transplant population. However, it functions by inhibiting the mammalian target of rapamycin (mTOR), which is an oncogene implicated in numerous malignancies. Normally, TSC1 and TSC2 inhibit mTOR activity through an intermediary protein. In patients with TSC, inactivating mutations of TSC1 or TSC2 leads to constitutive activation of mTOR. Rapamycin functionally reverses this process, providing the inhibitory influence on mTOR normally provided by wild type TSC1/2. The favorable responses to rapamycin observed in TSC-associated astrocytomas further support the importance of mTOR activation as the key molecular abnormality driving such tumors. It should be noted that higher rapamycin doses are required to achieve therapeutic serum levels in patients co-administered anticonvulsants (eg, phenytoin, carbamazepine, oxcarbazepine, phenobarbital, primidone, ethosuximide) that induce the hepatic p450 enzyme system, resulting in increased rapamycin metabolism. Rapamycin and other mTOR inhibitors are generally well tolerated, and a prospective study in patients with TSC is warranted. Rapamycin and other mTOR inhibitors have also been used in clinical trials for patients without TSC but with sporadic high grade gliomas, including anaplastic astrocytoma (WHO grade 3) and glioblastoma multiforme (GBM, WHO grade IV). Success in treating such tumors with mTOR inhibitors monotherapy is extremely limited, with transient efficacy in only a small minority of patients.1,2 The likely explanation is that, while mTOR activation is the key molecular abnormality causing TSC-associated astrocytomas, multiple oncogenic abnormalities induce sporadic GBMs. Therefore, although activation of the AKT signal transduction cascade (of which mTOR is a key effector) has been observed in up to 70% of sporadic GBMs,3 inhibition of AKT/mTOR alone is insufficient to treat the majority of such tumors. Trials of mTOR inhibitors in combination with other small molecular inhibitors and with traditional chemotherapies are under way for patients with high grade gliomas.
References
1. Galanis E, et al. Phase II Trial of Temsirolimus (CCI-779) in Recurrent Glioblastoma Multiforme: A North Central Cancer Treatment Group Study. J Clin Oncol. 2005;23:5294-5304.
2. Chang SM, et al. Phase II Study of CCI-779 in Patients with Recurrent Glioblastoma Multiforme. Invest New Drugs. 2005;23:357-361.
3. Choe G, et al. Analysis of the Phosphatidylinositol 3'-Kinase Signaling Pathway in Glioblastoma Patients In Vivo. Cancer Res. 2003;63:2742-2746.
Rapamycin was effective in the treatment of low-grade gliomas in patients with tuberous sclerosis complex, and may be effective in other types of gliomas.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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