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Pilomyxoid Astrocytoma

Pilomyxoid astrocytoma (PMA) is a newly discovered type of brain tumor. In the past, this neoplasm was grouped together with pilocytic astrocytoma (PA), a slow-growing and benign tumor. Recently, however, it has been shown that PMA demonstrates unique histological features that allow it to be differentiated from PA. Furthermore, PMA tends to behave aggressively and carry a poor prognosis, with significantly shorter survival than typical PA, as well as a high rate of metastasis throughout the nervous system.

PMA has not yet been studied on the genetic level. We seek to identify the mutations present in PMA. This new information may prove not only beneficial in the treatment of this childhood tumor, but also in the development of diagnostic and therapeutic modalities related to other aggressive pediatric neoplasms. Our specific aims are as follows: 1) To identify germline and somatic mutations, as well as polymorphisms in PMA. This will be done by scanning tumor suppressor genes and oncogenes known to be mutated in other astrocytomas and related neoplasms. 2) To delineate patterns of gene expression within PMA for subsets of genes displaying promoter mutations, as well as downstream genes regulated by oncogenes and tumor suppressor regions. Furthermore, we plan to evaluate the radiographic characteristics in the hopes of aiding diagnosis of this new entity.

Pilocytic astrocytoma (PA) is the most common central nervous system tumor in the pediatric population. PA is typically benign, indolent, and slow growing. In a small subset of patients, however, this tumor exhibits aggressive growth and carries a poor prognosis. We previously characterized these unique tumors, both clinically and histologically. This neoplasm has been termed pilomyxoid astrocytoma (PMA) based on its microscopic appearance. While tumors have traditionally been categorized on the basis of their histology, the unique pattern of cancer cells under the microscope is insufficient to reflect the complex molecular events that drive the neoplastic process. Therefore, a critical challenge facing neuro-oncology is the development of tumor classifications that reflect the underlying molecular and genetic abnormalities. This protocol, termed molecular profiling, holds tremendous potential for the future treatment of cancer. The development of inhibitors targeted to specific genetic mutations or pathways represents an important new approach to cancer therapy. Advances in molecular profiling of tumors can help pinpoint new targets for drug development and identify subsets of individuals that will maximally benefit from specific treatments.

Our expected results are twofold. First, by investigating mutations that are known to occur in PA as well as those that tend to occur in more aggressive neoplasms, we expect to find genetic differences between PA and PMA as well as genetic similarities between PMA and more aggressive neoplasms. This specific pattern of genetic alterations seen in PMA should further elucidate the aggressive biologic behavior exhibited by PMA. Second, upon identifying genetic mutations unique to PMA we aim to investigate alterations in both gene and protein expression. This would help identify products of the downstream pathway that may be involved in the cell cycle, apoptosis, and the ability of cancerous cells to metastasize.


Through collaborations with world-renowned researchers at Columbia University, the Gabriele Bartoli Brain Tumor Research Laboratory is investigating how the immune system interacts with childhood brain tumors. Primary brain tumors are the most common solid cancer among children, and medulloblastomas (MEDs) are the most frequent malignant brain tumor in pediatric patients. In the last decade there have been significant advances in the use of chemotherapy to treat childhood brain tumors, with 5-year survival rates for pediatric MEDs of greater than 70%. Nonetheless, early recurrence of disease and adverse effects of prior treatment are commonplace.

One approach aims at understanding the fundamental developmental processes that go wrong and lead to childhood brain tumors in the first place. Tumors in children frequently occur in the cerebellum, and by studying its development, researchers hope to shed light on the mechanisms of tumor formation and strategies to stop their progression. CXCR4 is a molecule that plays an integral role in the developing cerebellum and it is also associated with glioblastoma multiforme (the most common malignant brain tumor in adults), breast cancer metastasis, and von Hippel-Lindau syndrome. Without CXCR4, immature cells in the cerebellum continue to migrate and divide – mimicking a precancerous state. Therefore, derangements in molecular pathways involving CXCR4 could turn normal cells into cancerous cells, leading to tumors like medulloblastoma. By studying basic developmental genes such as CXCR4, the research aims to provide new and more specific therapeutic targets in fighting children’s brain tumors.

Accordingly, neurosurgeons at Columbia University believe that the discovery and use of an appropriate immunotherapeutic strategy for MEDs, in conjunction with current chemotherapies, could significantly improve the current treatment of this disease. Recent data have demonstrated that cells of the immune system (including T cells, B cells, and monocytes/macrophages) frequently infiltrate pediatric MEDs, suggesting that immunity could impact tumor survival/proliferation in vivo. Our neurosurgeons hypothesize that pediatric MEDs avoid immune attack by up-regulation of non-functional “decoy” receptors against death receptor ligands and cytokines that would lead to growth arrest or killing. Therefore they are seeking a better understanding of the role of these receptors in the malignancy and survival of pediatric MEDs, which could lead to novel immunotherapeutic strategies.

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Columbia University Medical Center

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