Molecular Determinants of [18F] FACBC PET Imaging in Brain Tumors

Andrew Lassman, M.D.

Memorial Sloan-Kettering Cancer Center

Department of Neurology
Funded in June, 2009: $200000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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PET imaging may aid early assessment of brain tumor progression and response to treatment

This study will help to determine the validity and reliability of a new PET imaging tracer for assessing deadly brain tumor progression and the efficacy of anti-tumor agents in killing the tumor or slowing or preventing its growth.

Malignant brain tumors usually result in death within a few years. Treatment is challenging because the brain’s blood-brain-barrier (BBB) limits drug delivery to the tumor, and tumor cell abnormalities differ from patient to patient, requiring highly individualized therapies. Clinicians currently assess anti-tumor therapy effectiveness through MR imaging. This approach has major limitations, however. MRI does not completely reveal the extent to which the glioma cells have infiltrated normal brain tissue, and enlarging tumor may not be visible for several months.

Now another approach, using new type of PET imaging, may be possible. The investigators have developed a new PET imaging tracer, called FACBC-PET.  Transport of FACBC into tumor cells may depend on a signaling molecule in the tumor, called AKT. The investigators hypothesize that the FACBC-PET tracer can indicate whether the tumor’s AKT molecule is active or has been deactivated by a therapeutic agent.  They will perform FACBC-PET scans on patients with glioma and compare imaging results to analysis of patients’ surgically resected tumor tissues.  They will determine whether the PET images reflect AKT activity in tumor tissue evaluations. They will also determine whether FACBC-PET scanning can determine whether “smart” drugs have turned off AKT molecule signaling. Finally, they will determine whether “early” imaging with FACBC after only a few weeks of treatment can predict the effectiveness of a treatment, earlier than traditional MRI scans after a few months.  In this way, future patients may be able to determine that a treatment is ineffective for them earlier than currently possible, so they may discontinue it and consider alterantives.

ABSTRACT

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Molecular Determinants of [18F] FACBC PET Imaging in Brain Tumors

Current evaluation of GBM response to therapy involves assessment of contrast enhanced MRI.  However, this imaging modality does not adequately address the extent of infiltration of glioma cells into surrounding normal brain.  In addition, low grade gliomas generally do not demonstrate contrast enhancement.  [18F]-FACBC is a non-metabolized amino acid that depends on the L-type amino acid transporter (LAT1) for entry across the blood-brain and blood-tumor barriers.  The PI3K/AKT/mTOR cascade, activated in the majority of GBMs and a major focus of translational glioma research, regulates LAT1 activity. We hypothesize that [18F]-FACBC-PET imaging will identify areas of high and low PI3K/AKT/mTOR signaling, and that this will be a non-invasive assay for inhibition of PI3K during therapy for high grade gliomas.

We first aim to identify molecular determinants of [18F]FACBC uptake in patients with gliomas.  Such molecular profiling of tumor tissue may allow identification of a subset of tumors sensitive to a particular therapy.  The availability of a non-invasive imaging technique that could guide therapy would represent a major advance in glioma translational research.  To correlate imaging with molecular abnormalities, we will analyze tissue from tumor biopsies targeting regions of high and low tracer uptake.

We next aim to determine the effects of PI3K/AKT/mTOR pathway inhibition on [18F]FACBC PET imaging.  A subset of patients will receive a PI3K/AKT/mTOR inhibitor before a planned tumor resection and undergo FACBC-PET imaging at baseline (pre-treatment) and again immediately before surgery (i.e., during therapy).  We will assess changes in FACBC uptake during treatment in comparison with the molecular analyses of corresponding tissue samples.  If FACBC-PET imaging changes correspond with inhibition of PI3K/AKT/mTOR, this will demonstrate that FACBC-PET can serve as a surrogate marker of pathway inhibition.  If effective, FACBC-PET can serve as important clinical tool in both the assessment and treatment of brain tumors.  Our proposal aims to generate a bridge between tissue analysis and PET imaging.

Finally, we will determine the utility of early FACBC-PET as a predictor of clinical outcome.  Patients will undergo FACBC-PET imaging of the brain both at baseline and after 2 weeks of treatment with a PI3K/AKT/mTOR inhibitor.  We hypothesize that a reduction in FACBC uptake at this “early” time point will predict radiographic response as measured by MRI at a later time, and that increased or unchanged uptake will predict tumor progression.  Such a finding would be highly significant because it would allow discontinuation of an experimental drug after only a few weeks of therapy, sparing patients prolonged therapy with an ineffective and potentially toxic regimen.

INVESTIGATOR BIOGRAPHIES

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Andrew Lassman, M.D.

Dr. Lassman received his Bachelor’s degree and Master’s in Science from Yale University in 1992, graduating summa cum laude from a specialized 4 year program in Molecular Biophysics & Biochemistry that allows students to obtain both degrees.  He received his MD from Columbia University College of Physicians and Surgeons in 1997 where he also spent an additional year doing full time laboratory research.  He completed his Neurology residency also at Columbia, and then enrolled in the Neuro-Oncology Fellowship at Memorial Sloan-Kettering Cancer Center in 2001.  During his fellowship, he worked in Eric Holland’s laboratory where he developed an in depth knowledge of the molecular biology of gliomas.  Since joining the faculty at Memorial Sloan-Kettering in 2003, he used that knowledge to design innovative trials for patients with gliomas, translating discoveries in the laboratory to patient care.  He is also the Director of the Neuro-Oncology Fellowship at Memorial where he also serves on a Molecular Pathology Clinical Testing Advisory Board and Ethics Committee for the hospital.  Dr. Lassman has published multiple book chapters and manuscripts related to brain tumors.  He is the principal investigator for numerous brain tumor clinical trials and projects, applying his interest in translational research and knowledge of molecular biology to patient care.