First-in-Human Trial of 4-18F-(2S,4R)-Fluoroglutamine Positron Emission Tomography

A PET imaging tracer may accelerate brain tumor treatment progress

Mark Dunphy, D.O.

Memorial Sloan Kettering Cancer Center

Funded in September, 2015: $200000 for 3 years
LAY SUMMARY . ABSTRACT .

LAY SUMMARY

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A PET imaging tracer may accelerate brain tumor treatment progress

A new non-invasive PET imaging tracer is showing promise for improving the ability to differentiate indolent brain tumors from those that are aggressively growing, and for assessing the aggressive tumor’s response to therapy, faster and more reliably than currently available methods. This study will provide preliminary validation of this technique by expanding the number of participating patients.

Standard structural MRI imaging has been the primary radiologic technique used to determine whether a brain tumor is a low grade indolent glioma that can be safely monitored or a high grade aggressive tumor that must be treated immediately. MRI is also the primary imaging technique used to assess the tumors’ post-treatment responses. Does residual tumor remain? Does the tumor recur? Does a low grade indolent tumor transform into a high grade glioma? Unfortunately, though, MRI has a limited capacity to reveal answers to these critical questions rapidly and accurately, essential when patients’ lifetimes are measured in months.  

MRI’s speed and accuracy are limited by several key factors. First, certain characteristics of low grade and high grade gliomas overlap, making it difficult to differentiate the two using MRI. Second, ironically, if a specific treatment is effective in killing off the cancerous and surrounding cells, this process results in inflammation and edema. The swelling produced, though, often mimics tumor growth as seen on MRI. So physicians typically need to wait for an additional month or two for follow-up scans to confirm whether the treatment is working or the tumor is truly progressing and requires a change in treatment.    

Now a metabolic PET tracer (F-18 Fluoroglutamine) may provide a faster and more reliable alternative. Since tumors rely on exogenous glucose for fuel, the tracer is based on the premise that tumor cells will take up (consume) the metabolic glutamine tracer and this will be evident on PET scans. To date, this PET tracer has been tested in nine glioma patients (four with low grade and five with high grade tumor). Initial findings show that the PET tracer differentiates aggressive tumors from indolent ones: Only the high grade gliomas consume an abnormally high amount of the PET tracer. Moreover, inflammation does not take up the tracer. So, treatments that produce inflammation by killing cancer cells can be differentiated from actual tumor progression and spread.  

The investigators hypothesize, therefore, that the PET tracer will provide definitive assessment of treatment efficacy within one month of treatment initiation compared to two or more months needed for accurate MRI assessment. They will test this hypothesis in an additional 18 patients. These patients will undergo MRI and PET scans before glioma treatment and a month following treatment, when MRI scans are unreliable in differentiating inflammation from tumor progression. The investigators then will re-image patients over the following few months with MRI, when its reliability is greater.

Next, they will compare PET findings of treatment efficacy at one month to the MRI treatment efficacy results obtained over several additional months of treatment. If the later MRI results confirm the earlier PET results, the study will provide validation that the PET tracer yields rapid definitive results of treatment efficacy. Physicians then can assess whether to continue with the current treatment or change to a new one. The investigators also will analyze surgically removed tumor tissue to study genes and proteins that may reveal why consumption of the PET tracer differs among low grade tumors, and whether relatively higher consumption by some compared to others is a biomarker indicating imminent conversion from low to high grade glioma.

Significance :   If validated, this PET tracer will enable clinicians to rapidly differentiate low from high grade tumors and assess treatment efficacy, and will expedite clinical testing of experimental glioma therapies.    

ABSTRACT

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Hypothesis: F-18 Fluoroglutamine, a new first-of-kind fluorinated glutamine positron emission tomography (PET) radiotracer, improves non-invasive neuroradiologic diagnosis of high-grade glioma (HGG): distinguishing aggressive HGG from indolent low-grade glioma (LGG); and distinguishing favorable HGG response to treatment, including treatment-induced inflammation/pseudo-progression, from true tumor progression. Relevance: Glioma specialists urgently need new, more reliable neuroradiologic HGG biomarkers for tumor detection and evaluation of therapeutic response, to optimize individual glioma patient care and glioma therapy trial pharmacometrics. Standard structural brain MRI has limited accuracy for diagnosis of residual/recurrent HGG, post-therapy, and of suspected high-grade transformation of LGG, because the radiologic phenotypes (MRI structural and tissue enhancement characteristics) of HGG and non-HGG brain lesions overlap. Notoriously, therapeutic induction of glioma necrosis (prognostically-favorable) is associated with tissue inflammation and edema that frequently (~50% of cases, in some reports) mimics tumor growth on conventional MRI --tumor pseudo-progression. In these frequent cases, standard MRI yields false or ‘non-diagnostic’ results that delay or potentially mislead optimal therapeutic decision-making. Seeking a reliable non-invasive HGG biomarker, glioma specialists supplement standard structural MRI with adjunctive diagnostic imaging of tissue biology: functional MR approaches (fMRI, PW-MRI, MRS, DW-MRI) and positron emission tomography (PET), with the pre-eminent radiotracers being F-18 fluorodeoxyglucose (FDG), in North America, and F-18 Fluoroethyltyrosine (FET), in Europe. To-date, these diagnostic adjuvants overall potentially improve diagnostic accuracy compared to standard MRI alone, but the combined accuracy of the improvement remains insufficiently reliable – again because of overlapping radiologic phenotypes. Aims & Methods: The objective of this proposal is to expand the glioma cohort of our first in human trial of F-18 Fluoroglutamine PET (NCT01697930, Dr. Dunphy, P.I.) The expansion recruits 18 new glioma patients with pathology-proven LGG (n=6) and HGG (n=12) tumors, evident on MRI; with our first aim of evaluating whether Fluoroglutamine PET distinguishes HGG as Fluoroglutamine-avid tumors and LGG as non-avid tumors. Brain PET/CT scans obtained pre-/off-treatment; at 0, 80, and 160 minutes after IV microdose of F-18 Fluoroglutamine (275 MBq; μg dose; minimal toxicity-risk); with serial blood sampling for clearance and metabolite radioassays. Patient-specific ex vivo tumor gene profiling and protein expression data including MSK-IMPACT, a panel of 341 oncogenes and tumor suppressors including several key regulators of glutamine flux and metabolism; EGFR-FISH; and additional assay of key glutamine flux and metabolism biomarkers (GLS, GLUL, GLUD, GPT) will explore how molecular biology differs between Fluoroglutamine-avid tumors versus non-avid tumors. Our second aim is examine whether Fluoroglutamine PET distinguishes tumor response better than MRI, at the 1 month post¬treatment time-point when MRI pseudoprogression is most prevalent. Patients having Fluoroglutamine¬avid tumors, on the pre-/off-treatment PET (n≤20) will repeat Fluoroglutamine PET imaging 1 month after starting standard chemoradiation or other treatment, with first tumor response MRI assessment. We will quantify and compare the relative Fluoroglutamine-avidity, at 1 month, of responsive-tumors, pseudo-progressive tumors, and true progressive tumors. Tumor response/pseudoprogression confirmed by standard clinical and MRI (RANO) follow-up, with adjuvant confirmation by standard brain FDG PET and/or biopsy if indicated per oncologist judgment.

KEYWORDS


Conditions: Brain tumors
Technology: MRI
PET