High grade malignant gliomas are characterized by widely dispersed neoplastic disease in the brain. Current therapeutic modalities are incapable of adequately targeting these multiple tumor foci, resulting in bleak outcomes for patients with this disease. The development of a viable treatment strategy, therefore, depends on the identification of an approach that is capable of seeking out and eliminating the infiltrative intracranial tumor burden associated with gliomas. In this context, we and others have previously described the marked ability of neural precursor cells (NPC) to migrate towards, and therapeutically target, disseminated glioma in the brain. However, despite the robust tumor tropism exhibited by NPC, their migratory behavior is non-uniform with a notable portion of cells failing to demonstrate any significant translocation towards tumor. On this basis, we hypothesized that the tumor tropic sub-portion of NPC was likely characterized by a particular phenotype that enabled NPC to respond to tumor elaborated chemotactic cue(s). The delineation of these cues will be fundamental to the development of optimized NPC therapies for glioma. In this proposal, we now seek to definitively identify fundamentalmechanisms underlying the ability of tumor tropic NPCto migrate towards disseminated glioma in the brain. Specifically, we will investigate the contribution of four chemokine ligands (CXCL1, CXCL8, CXCL12, and CCL21) and their corresponding receptors (CXCR1, CXCR2, CXCR4, and CCR7) in governing the migratory capacity of NPC. Furthermore, we will assess whether NPC that have initiated differentiation towards a glial fate (glial precursors) demonstrate enhanced tumor tropic activity as compared to heterogeneous NPC. Ultimately, after identifying chemotropic and differentiation related cues that affect the ability of NPC to migrate towards intracranial tumor, we will validate the therapeutic viability of these findings in a rodent glioma treatment model. It is our expectation that, by establishing a mechanistic foundation, the proposed studies will enhance the translational relevance of NPC based treatments for malignant glioma.
TO PUBLIC HEALTH: Approximately 15-20,000 Americans are diagnosed annually with an aggressive variant of brain cancer (high grade glioma). Currently employed therapies make only a minimal impact on the prognosis of these patients. The studies outlined in this proposal are geared towards validating a promising treatment strategy for this disease involving the use of neural precursor cells. It is our expectation that the knowledge gained from our work will ultimately facilitate the use of this therapy in a clinical setting.
| Ehtesham, Moneeb; Thompson, Reid C (2012) CXCR4-Expressing Glial Precursor Cells Demonstrate Enhanced Migratory Tropism for Glioma. J Cancer Ther 3:1086-1091 |
| Ehtesham, Moneeb; Mapara, Khubaib Y; Stevenson, Charles B et al. (2009) CXCR4 mediates the proliferation of glioblastoma progenitor cells. Cancer Lett 274:305-12 |
| Stevenson, Charles B; Ehtesham, Moneeb; McMillan, Kathryn M et al. (2008) CXCR4 expression is elevated in glioblastoma multiforme and correlates with an increase in intensity and extent of peritumoral T2-weighted magnetic resonance imaging signal abnormalities. Neurosurgery 63:560-9;discussion 569-70 |
| Ehtesham, M; Sarangi, A; Valadez, J G et al. (2007) Ligand-dependent activation of the hedgehog pathway in glioma progenitor cells. Oncogene 26:5752-61 |
| Ehtesham, M; Winston, J A; Kabos, P et al. (2006) CXCR4 expression mediates glioma cell invasiveness. Oncogene 25:2801-6 |
