Clinical and biological relevance of PI3K/AKT/mTOR

Administrator

Clinical and biological relevance of PI3K/AKT/mTOR

pathway activation in pilocytic astrocytoma

Fausto J. Rodriguez M.D., Johns Hopkins School of Medicine

(Report from funding, 2011-2012)

This study has been published in two journals.

 

Pilocytic astrocytomas (PA) are low grade neoplasms that represent the most frequent gliomas in children and your adults. Most of these tumors have an excellent outcome after gross total resection. However a subset progress clinically despite standard treatments, particularly those that arise in anatomic locations where a complete resection is not possible. Therefore, a basic understanding of the molecular mechanisms responsible for PA biology is needed in order to provide novel curative treatments.

 

The most frequent, consistent molecular abnormality in PA is activation of the MAPK pathway, usually as a result of activation of BRAF. However, several lines of evidence    suggest that other signaling pathways may also play a role in the biology of these tumors. One such pathway is PI3K/AKT/mTOR which contributes to cellular proliferation and growth, and may be targeted with currently available drugs. In the past year, with the support of CBTF, we have tested numerous components of the mTOR pathway using tissue microarrays of surgically obtained PA tissue (n=114). Our data suggests that mTOR is active in a significant subset of these tumors, based on moderate to strong pS6 immunostaining in up to approximately 60% of tumors tested.

 

We currently know that mTOR in the cell exists in association with other proteins in two   different complexes: mTORC1 and mTORC2. One of our preliminary observations is that   Raptor (a component of mTORC1) is increased to a greater extent than Rictor (a component of mTORC2) in sporadic PA, while the converse was noticed in diffuse and high grade gliomas. In follow-up studies, we are analyzing the prevalence of these alterations by clinicopathologic subgroups, including tumors arising in different parts of the brain.  Additionally we are studying the mechanisms responsible for mTOR activation in pediatric low grade gliomas, and the effect of pharmacologic inhibition of the pathway on tumor growth in model systems. 

 

We are grateful to the CBTF and Tennis for Tumors for their kind support for these studies.                                             CBTF thanks Dr. Rodriguez for his very informative progress report.

 

 

Clinical and biological relevance of PI3K/AKT/mTOR pathway activation

 in pilocytic astrocytomas

 (new 2011-2012, one-year)

PI:  Fausto J. Rodriguez M.D., Johns Hopkins Medical Institute

 

Patients with pilocytic astrocytoma (PA) generally have favorable outcomes following surgical intervention, although a subset may cause significant morbidity or mortality, despite lack of atypical histologic features. Unlike diffuse gliomas, increased proliferation, invasive growth pattern, and/or necrosis do not always predict aggressive behavior in PA, although we have previously shown that frank anaplastic histologic change in the form of brisk mitotic activity with or without necrosis may portend a worse survival. Insight into the molecular alterations and pathways underlying aggressive behavior in pediatric low grade gliomas is needed, to decrease the morbidity and mortality associated with these tumors and conventional therapies. The importance of the PI3K/AKT/mTOR signaling axis has been highlighted in diffuse and high grade gliomas, and there is increasing interest in pharmacological targeting of this pathway in the pediatric setting, given recent successes reported with some low grade gliomas such as subependymal giant cell astrocytoma.    However, little is known about the role of AKT/mTOR signaling in PA, the most common primary glioma in children. Some studies have highlighted a role for mTOR activation in NF1-associated PA, and we have also reported preliminary data suggesting that it mediates phenotypic variations in NF1-associated low grade gliomas with unusual morphologies.  In addition, we have recently documented an association with phospho-AKT (ser473) and specific aggressive PA subtypes, but its clinical significance, in particular relationship to outcome, remains to be tested in a formal manner to justify specific therapeutic approaches. The goal of this proposal is to examine the role of PI3K/AKT/mTOR signaling in PA to determine if therapies targeting this pathway should be tested in children.

We are grateful to the CBTF and Tennis for Tumors for their kind

support of this grant.

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