CP #5: F-18 Imaging for Early Therapy Response Assessment in Glioblastoma

F-18 Imaging for Early Therapy Response Assessment in Glioblastoma

Significance:

Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor found in humans. Even with standard treatment of radiotherapy and chemotherapy, the median survival time is 15 months [1]. With such an aggressive type of cancer, it is imperative to determine the efficacy of treatment by monitoring early response, not only to facilitate drug development but also to improve clinical management. Currently, treatment response is evaluated by World Health Organization (WHO) or RECIST criteria [2]. However, size reduction in tumors is a late indication of successful cancer therapy and cannot detect initial responses. The limitations of the size criteria are quite apparent when treating GBM because patients often experience pseudoprogression at the beginning of postoperative cancer therapy [3]. Patients with tumors demonstrating MGMT promoter methylation silencing have a higher incidence of pseudoprogression [4], suggesting that the early radiologic change relate to radiosensitizing effects of the temozolomide, but the mechanism and exact pathophysiology underlying pseudoprogression remain uncertain.

Aims:

In this study, we will utilize the quantitative PET imaging biomarkers F-18ML-10 (apoptosis imaging agent), and F-18 FLT (proliferation tracer) to develop predictive methodologies for early assessment of response to cancer therapy in GBM patients. With the development of these predictive methodologies, we will also be able to distinguish pseudoprogression from progression in patients with GBM undergoing external beam radiotherapy and concomitant low dose temozolomide therapy.

Approach:

​A cohort of 20 patients with at least 1 cm (shortest dimension) tumor size undergoing external beam radiotherapy and low dose temozolomide will receive PET quantitative imaging at baseline and on post-therapy days 8±2 and 72±7. Another group of 20 patients will receive the VEGF inhibitor afibercept, given at 14 day intervals beginning 14 days after the start external beam radiation therapy. This group will undergo PET quantitative imaging at the same time intervals as the first group. Modeling will be performed with PMOD software (PMOD Technolo¬gies Ltd., Zurich, Switzerland). For analysis of the F-18 ML-10 data, we will use the time dependent voxel change index (VCI, Figure 1). Differ-ences in tumor dimension between baseline intratreatment scans will be measured according to the RECIST criteria [2] and on volume rendering. All subjects will have tissue biomarker correlation on tumor specimens, including MGMT promoter methylation analysis (shown to be predictive of response to certain chemoradiation regimens [5]), plasma angiogenic peptide determinations, basement membrane coverage (Collagen IV [Dako]), microvascular density (CD31 and CD105), pericyte coverage (anti-PECAM and alpha-SMA), tumor cell proliferation (MIB-1), apoptosis (TUNEL), methylguanine methyltransferase activity, MGMT protein levels by immunohistochemistry, and a diverse panel of genetic and chromosomal analysis.

Push-Pull Interaction with TR&D Projects 1, 2 & 3:

TR&D#1: This project relies on concurrent MRI and PET imaging to address the role of tissue biomarkers on assessing the therapeutic response of brain gliomas. Some of the MRI measures rely on rapid, motion-robust, image acquisition. These measures will, therefore, benefit greatly from the developments of TR&D #1.

TR&D#2: As noted by reviewers, low-attenuation RF coils will benefit PET performance in the MR-PET setting.

TR&D#3: The PET acquisition techniques originally proposed for this project will be subject to substantial improvements as a result of the developments of TR&D #3. Specifically, this CP will leverage and test the efficacy of joint tracer kinetic modeling approaches for isolating the effect of functional tissue parameters (such as perfusion) on the observed uptake values, and for improving the specificity of the proposed biomarkers. The collaborative project PI has a history of working with TR&D#3 co-PI Dr. Boada, who was integrally involved in the procurement of a Siemens MR-PET scanner at UPMC. The availability of a common MR-PET platform will also allow this collaborative project to serve as a key offsite test bed for MR-based PET correction and joint reconstruction techniques developed in TR&D #3.

Principal Investigator: 

Sponsors

Latest Updates

10/31/2017 - 11:54
10/31/2017 - 11:37

Philanthropic Support

We gratefully acknowledge generous support for radiology research at NYU Langone Medical Center from:
 
• The Big George Foundation
• Raymond and Beverly Sackler
• Bernard and Irene Schwartz

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