Glioblastoma multiforme is the most prevalent and aggressive type of brain tumor, and devastating to any patient unfortunate enough to receive its diagnosis. As one of the most populous states in the nation, more Californians are diagnosed with glioblastoma multiforme than nearly every other state. Over the past 20 years surgery, radiation therapy and chemotherapy have been utilized with frustrating results. Surgery is very risky and radiation and chemotherapy kill both cancer and healthy cells. Today, even with the most advanced treatments available, survival rates have improved by an average of only 9 months – from 3 months without treatment to 12 months with treatment.
Our proposed research focuses on a new theory that brain tumor cells are initiated and maintained by a small fraction of cells with stem cell properties. This “cancer stem cell” hypothesis states that if this small subset of cancer stem cells could be inactivated, the tumor would cease to grow. Therefore, we reasoned that cancer-specific genetic alterations in a glioblastoma tumor could be a potential marker for cancer stem cells and zeroing in on these cells could result in targeted therapeutics. What we have already done is to develop an antibody that recognizes two known potential cancer stem cell markers, CD133 and a tumor-specific variant of the epidermal growth factor receptor, or EGFRvIII. CD133 is a marker for normal neural and hematopoietic stem cells and EGFRvlll is a receptor that is genetically altered in glioblastoma tumors. Although CD133 is found in normal cells and the EGFRvIII is found in cancer cells (and rarely present in normal tissues), they are both tightly associated in glioblastoma tumors. We have now shown that tumors that express both CD133 and EGFRvIII grow much more quickly. We have already developed a “bispecific” antibody that recognizes both of these markers and we have shown that this antibody selectively kills the cancer cells in glioblastoma tumors that express both CD133 and EGFRvIII, but not normal stem cells. When we injected glioblastoma cells pre-treated with BsAb into mice, tumor formation was severely inhibited. These results are very promising.
To move this research forward we plan to identify high yield methods for BsAb production for use in animal testing. We will establish the most effective dose and route of delivery that reproducibly results in tumor regression. Once determined, we will evaluate any side-effects of the treatment. One goal of this treatment is to increase treatment specificity, so that the tumor cells are eradicated but not at the expense of healthy cells. Our goal is to ready this antibody for the investigational new drug phase and to ultimately generate a human therapeutic effective against glioblastoma multiforme.
Statement of Benefit to California:
Glioblastoma is a devastating diagnosis. The most common and malignant form of brain cancer, the most aggressive treatments available yield an average survival of only 12-14 months. As the most populous state in the nation, more Californians are diagnosed with glioblastoma each year than any other state, with a consequent significant economic toll to the state as well as its emotional toll.
As the leader in cutting edge biomedical research, California through CIRM has recognized the unmet need to provide a roadmap for the translation of stem cell research to clinical applications. Through CIRM there is an unparalleled opportunity to foster clearly-defined discovery that will not only benefit Californians with glioblastomas, but potentially those with many other cancers, and ultimately all Californians, through healthier citizens, increased employment opportunities, and reduced economic burdens.
We have previously shown that two markers of cancer stem cells, CD133 and EGFRvIII, are tightly associated in glioblastoma tumors. We created a recombinant bispecific antibody (BsAb) selectively targeting CD133 and EGFRvIII. This antibody selectively kills glioblastoma tumor cells but not healthy cells. When glioblastoma cells pre-treated with BsAb were injected into mice, tumor formation was significantly reduced, strongly suggesting that targeting of the EGFRvIII/CD133 cancer stem cell population can inhibit glioblastoma formation.
The key objective of our project is to identify efficient and high yield methods for BsAb production, identify an effective dose and route of delivery for the treatment of brain tumors, and evaluate any potential effects on cells/tissues that express CD133. Our goal is to ready the BsAb for investigational new drug-related development.
Californians will benefit from this research project in several significant ways.
1) Most importantly, this research has the promise to dramatically extend the long-term survival rates for Californians with glioblastomas, with potential applications to multiple other human cancers.
2) The research will take place in California with direct benefit to the California economy through the hiring of employees and purchase of supplies and reagents.
3) With successful completion of the proposed project, an investigational new drug application will be the direct next step, requiring employing a local contract research organization to generate clinical grade antibody, requiring additional employees along with associated expenditures.
4) If the therapeutic BsAb generated is commercialized, profits derived from the production of the BsAbs by CIRM policy will result in improved treatments to insured patients and lower cost treatments to the uninsured, thus ultimately benefiting all Californians.
5) Finally, funding this research will help raise awareness of California’s prominence as a national and international leader in stem cell research with the potential to benefit all glioblastoma patients.