A new paper by the Children’s Brain Tumor Project team addresses one of the many vexing aspects of diffuse intrinsic pontine glioma (DIPG), the incurable brain stem tumor that primarily attacks very young children. The paper, “Biomarker Based PET Imaging of Diffuse Intrinsic Pontine Glioma in Mouse Models,” describes a successful new way to measure and monitor tumor volume in patients with DIPG. It is one of the many initiatives that have developed from Dr. Mark Souweidane’s clinical trial testing convection-enhanced delivery (CED) of drugs to the tumor site in DIPG patients.
DIPG, which claims the lives of 150 to 200 American children each year, is so infiltrative and amorphous that it’s nearly impossible to measure. The inability to accurately determine the volume of a tumor makes it especially difficult to monitor its progression — or its response to a treatment being tested. Developing a reliable means of measuring the volume of a DIPG tumor is a significant advance that will greatly aid in the assessment of potential new treatments.
The key to this new imaging technique is the enzyme Poly [ADP-ribose] polymerase 1 (referred to as PARP-1). PARP-1 expression is known to be abundant in certain cancers, including breast, ovarian, oral, and colorectal cancers. What was unknown was whether PARP-1 was a reliable biomarker for DIPG, and, if so, whether and how imaging it could produce a valid measurement of the tumor. Although MRI scans have been effective in imaging for diagnostic purposes, DIPG tumors don’t absorb contrast agents well, making them nearly impossible to see on scans. The result is that the entire tumor cannot be accurately imaged with MRI, its growth cannot be measured as it progresses, and researchers have had no means of evaluating the effects of new treatments being tested in clinical trials.
At left, an MRI scan of a DIPG tumor in a mouse model. The orange arrow points to contrast agent signal accumulation, not tumor. The tumor appears below that, much less clearly (white arrow). At center is a PET scan of the same mouse brain, created after injection with the fluorescent agent. In this image the tumor is clearly delineated (bright orange areas). At right is a microscopic histology image of a slice of that same mouse brain, confirming the extent and location of the tumor.In this study, the PARP-1 enzyme was targeted by an injected fluorescent agent that attaches to it, making it visible on a positron-emission tomography (PET) scan. The researchers first confirmed that the level of PARP-1 expression is a reliable indicator of tumor volume in DIPG; they then showed that the injected fluorescent agent can find its target and appear on PET scans; finally, they showed that the fluorescent images accurately traces the proliferation of a tumor as it infiltrates regions of the brain beyond the pons.
These results hold great promise not only for future clinical trials of DIPG, but for other brain tumors and conditions as well, including radiation-induced necrosis. Researchers in this trial found the potential for using this technique for diagnosing other brain tumors or tumor progression, using quantities of contrast agent so small as to be safe even for patients undergoing a treatment regimen.
The research was done as a collaboration among investigators from multiple departments at Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center as well as from the Department of Chemistry at Hunter College and the PhD Program in Chemistry at the Graduate Center of the City University of New York. The paper has been accepted by Cancer Research,a journal of the American Association for Cancer Research, and will appear in a future issue of the publication. It is available now electronically ahead of publication.
Biomarker based PET Imaging of Diffuse Intrinsic Pontine Glioma in Mouse Models.
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