An important new paper from the laboratory of Dr. Jeffrey Greenfield, co-director of the Children’s Brain Tumor Project at Weill Cornell Medicine, details how it may be possible to stop the progression of a low-grade, survivable glioma into a high-grade, fatal malignancy. The paper was accepted by the journal Clinical Cancer Research (a high-impact publication of the American Association for Cancer Research), and has been published electronically ahead of its appearance in the printed journal.
In addition to Dr. Greenfield, the paper’s senior authors include Dr. David Lyden, professor of Pediatrics and Cell and Developmental Biology at Weill Cornell Medicine and pediatric neuro-oncologist at Memorial Sloan Kettering Cancer Center, and Dr. Jacqueline Bromberg, medical oncologist and researcher at Memorial Sloan Kettering Cancer Center. Substantial support for the project that led to this publication was provided by the families of the Children’s Brain Tumor Project.
The paper, “Malignant astrocytic tumor progression potentiated by JAK-mediated recruitment of myeloid cells,” details how a specific population of cells that are made in the bone marrow are recruited to the brain to facilitate brain tumor progression; more importantly it shows that inhibiting this process may act as a remote control of sorts to stop tumor progression. JAK inhibitors are compounds that are known to modulate immune responses in other disease states and interrupt signaling pathways involving proteins that have been implicated in cancer.
Dr. Prajwal Rajappa, a fellow from the Greenfield lab, is the lead author on the study, which demonstrated that important key cells could be detected within the blood of glioma patients confirming data uncovered in the animal models of brain tumors. These cells, CD11b+ myeloid cells, are found in significantly increased levels in patients with advanced (Stage IV) glioblastoma multiforme (GBM) when compared with levels taken from patients with low-grade (Stage II) glioma. Using a JAK 1/2 inhibitor in mouse models, levels of CD11b+ myeloid cells were reduced in the bone marrow and bloodstream of these animals, which correlated with impaired tumor progression and significantly extended the overall survival in treated animals by preventing the low-grade tumor from transforming into a higher-grade malignancy.
The data from this paper suggests that specific cells within the body’s bone marrow, far from a tumor site, support the tumor’s progression. The tumor signals the bone marrow to increase production of CD 11b+ myeloid cells and enter the bloodstream, recruiting them to the tumor site. Interrupting this process has the potential to arrest progression of the tumor – stopping it before it becomes incurable, such as occurs in high-grade gliomas like glioblastoma multiforme (GBM).
GBM is a devastating tumor with an extremely poor prognosis. In recent years, GBM has claimed the lives of Senator Edward Kennedy, baseball player Gary Carter, and former Vice President Joe Biden’s son Beau. An estimated 35% of these deadly tumors originate as low-grade gliomas that transform into their high-grade and mostly fatal counterparts. With a simple blood test, patients with elevated CD11b+ myeloid cells could be stratified into clinical trials designed to arrest malignant progression before tumors progress.
This important finding, which has been shown to work in mouse models, will likely be translated into a clinical trial and may someday offer new targeted immunomodulation for children and adults diagnosed with a low-grade glioma. FDA-approved JAK 1/2 inhibitor compounds are being used in current clinical practice for various myeloproliferative disorders, and this study suggests that these agents may be appropriate to test in select low-grade glioma patient populations.
Malignant astrocytic tumor progression potentiated by JAK-mediated recruitment of myeloid cells.
