Weaponizing EGF-containing fibulin-like extracellular matrix protein 1 to treat malignant gliomas
Glioblastoma multiforme, or GBM, is the most common and, unfortunately, the most aggressive form of primary brain tumors. Despite best available current multi-modality therapies, 90% of GBM patients live less than 2 years. Current therapies, such as surgical resection, radiation therapy and standard chemotherapies, do succeed in killing a large portion of existing tumor cells. Unfortunately they fail to kill them all, and recent studies have shown that a small subpopulation of tumor stem cells are relatively resistant to current therapies, and serve as a pool of cells to allow tumor repopulation and recurrence once standard therapies have completed. More effective ways of killing an even larger proportion of existing tumor cells as well as a means of preventing tumor stem cells from re-populating the tumor after therapy are both desperately needed.
We have identified a very promising extra-cellular matrix protein EFEMP1 with the ability to aid tumor cell killing through a novel anti-angiogenic effect preventing formation of a tumor blood supply, as well as the ability to prevent tumor cell recurrence or re-population by suppressing tumor stem cell activation as well as its anti-angiogenic effect. As a protein normally produced by normal glial cells, and normally present in non-tumor brain tissue, this protein is likely to have minimal toxicity if utilized as a therapeutic agent.
This project is designed to (1) prove the therapeutic potential of EFEMP1 in appropriate animal brain tumor models using human-derived GBM cells that contain tumor stem cells, (2) identify the best form of the protein to utilize for maximizing therapeutic potential, (3) identify the best initial dose of EFEMP1 for testing in GBM patients, (4) identify the best method for protein delivery, and (5) ultimately test EFEMP1 for both effectiveness and potential toxicity in GBM patients. If successful, this study has the potential to significantly improve the quality of life as well as survival potential for patients suffering with GBM.
Glioblastoma multiforme (GBM) is the most common form of primary brain tumor seen in humans. Unfortunately, it is not only the most aggressive and malignant form of brain tumor, it is the most aggressive and malignant tumor arising from any human organ system. In the United States in 2009, 12,920 people died of GBM. With 12% of the US populations, this translates into ~1,550 California citizens dying from GBM. GBM not only has significant impact on patient survival, it has devastating effects on the brain itself throughout the course of the disease. As the master organ controlling all other body functions, brain function has a dominant impact on California citizen quality of life, productivity in the work place, and functional independence. As they can no longer work, they often lose employer health insurance coverage and often have to rely on State and County medical support programs. More than 50% of GBM patients become divorced within a year of clinical diagnosis. As they lose functional independence, and their family social support networks fragment and disintegrate, they come to require extensive support service resources investments.
A new, safe, and low toxicity therapy based on this novel extracellular matrix protein has strong potential for not only increasing the effectiveness of current multimodality treatments such as surgical resection, radiation therapy, and chemotherapy, but also preventing tumor recurrence/repopulation after completion of conventional therapies through a suppressive effect on GBM tumor stem cells. As such, there is enormous potential for improving, both, patient survival, as well as quality of life and functional independence for California GBM patients.