The Pediatric Neuro-Oncology Program (PNOP) at UT Southwestern/Children’s Medical Center is a multidisciplinary program, consisting of pediatric neuro-oncologists, neurosurgeons, radiation oncologists, neuro-imaging and neuropathology, and this team provides clinical care to children with cancer of the brain and spine. Approximately 80 children with newly diagnosed brain tumor are evaluated and treated by the Program each year, including 30-40 children who are treated with vincristine.

The Program is actively engaged in clinical research through its membership in the Children’s Oncology Group and several other consortia. With current therapies, only approximately 70% of children with brain tumors are expected to be long-term survivors.

Despite its widespread use in pediatric brain tumor therapy, vincristine does not penetrate across the blood-brain barrier (BBB) and blood-tumor barrier (BTB). Drug penetration across BBB and BTB are among the most important problems associated with the use of chemotherapy for childhood brain tumors. Variability in intra-tumor blood supply, oxygenation, and acidosis likely influences the distribution and penetration of chemotherapy agents into brain tumors.

For example, vincristine is incorporated into the current treatment regimens for low-grade gliomas, anaplastic oligodendrogliomas, and medulloblastomas, despite scant evidence that vincristine actually penetrates across the BBB and has activity against these tumors, but it is associated with drug-related side effects. Animal studies demonstrate very little penetration into brain tumor xenograft models, possibly as a result of p-Glycoprotein in the vascular endothelium of normal brain and tumor cells. Furthermore, accidental intrathecal injection of vincristine has been noted to result in rapid and progressive ascending chemical meningoencephalitis leading to coma and death.

These observations have led to questions regarding whether vincristine has any penetration into the central nervous system and a re-examination of the inclusion of vincristine in treatment regimen – and this question can be answered by the CRCFPO.

Osteosarcoma represents another major childhood sarcoma where better, functional imaging may have a clinical impact. Currently, the best marker of long-term survival is the degree of necrosis within the primary tumor and when measured after about 12 weeks of chemotherapy. Unfortunately, recognizing those with less necrosis at that late stage is not helpful. That is, altering therapy in those with a poor response at 12 weeks does not alter the grim prognosis.

With funding from CPRIT, Dr. Patrick Leavey is testing the hypothesis that high-resolution MRI signal changes – when performed just three weeks following the first course of chemotherapy for children with osteosarcoma – can correlate with the degree of necrosis at 12 weeks. With the availability of the CRCFPO services on campus, we have the opportunity to also evaluate more functional probes, like [¹⁸F]FDG-PET, [¹⁸F]MISO, [¹¹C]acetate, or [¹¹C]choline in combination of bone scans with [¹⁸F]NaF in this pilot clinical trial. Conducting this trial in parallel to the MRI study opens the possibility for co-registration of the MR and PET imaging as well as histological/molecular analyses because all of these tumor specimens will be surgically removed.

The CRCFPO is interacting with this User Group to identify their needs for PET and radiotracers. In the case of vincristine, the CRCFPO is providing radiochemical procedures for the possible labeling of vincristine with ¹¹C or ¹⁸F (left – radiolabel indicated by red) on the basis of the established radiochemistry capability of the CRP. Despite the fact that the ex vivo pharmacokinetics, metabolism, and excretion profiles of vincristine were reported in patients in 1977 by using of [³H]labeled vincristine, the in vivo BBB and BTB penetration data of vincristine are still lacking.

Noninvasive and quantitative PET imaging with ¹¹C or ¹⁸F-labeled vincristine is able to provide the desired in vivo measure of the biological profiles of vincristine in patients. Undoubtedly, the in vivo information obtained will be of great value to the pediatric patients with newly-diagnosed brain tumor. They can be therefore stratified for chemotherapy with or without vincristine. The treatment response of vincristine in the children with brain tumor is being noninvasively evaluated by [¹¹C]-methionine and other radiotracers reported for PET of brain tumor. The Regulatory Component of CRCFPO is working with the PNOP to file the corresponding IND to U.S.-FDA and IRB application.