Glioblastoma is the most common and aggressive type of brain cancer in adults. Its treatment presents particular challenges—surgery to remove the tumor can cause collateral damage to healthy brain structures, the tumor often quickly re-grows after radiation and chemotherapy, and it tends to become resistant to treatment despite aggressive management. Standard therapies, which typically include a combination of surgery, radiation and chemotherapy often result in serious side effects and are ineffective long term. Unfortunately, most patients with glioblastoma survive an average of 14 months once diagnosed.
Our research has the potential to dramatically extend the long-term survival rates of patients with this type of tumor using a highly targeted yet systemic and safe approach. It focuses on an exciting new theory that brain cancer cells begin and are maintained by a small fraction of all tumor cells with stem cell properties. The theory proposes that if this small subset of cancer stem cells could be inactivated, the tumor would stop growing.
In our studies, we reasoned that cancer-specific gene alterations in glioblastoma could be a potential marker for cancer stem cells and zeroing in on these cells could result in targeted therapies. We discovered a tumor-specific marker of epidermal growth factor receptor (EGFR) called EGFRvIII and found that EGFRvIII often occurred in glioblastoma tumor cells with another marker found on normal stem cells called CD133.
We then developed a “bispecific” antibody (BsAb) that recognizes both of these markers and we showed that BsAb selectively kills cancer stem cells in glioblastoma tumors that express both CD133 and EGFRvIII, but not normal stem cells. When glioblastoma cells treated with BsAb were injected into mice, tumor formation was severely inhibited and significantly more animals survived after treatment with it.
To advance this discovery to the clinic, we have assembled a world-class and highly experienced multi-disciplinary team of experts who have carefully considered the pharmacology, toxicology and manufacturing issues that may occur during the development of BsAb for clinical use. As a result, we are ideally positioned to accomplish our immediate goal, which is to complete the necessary work to file an investigational new drug application with the Food and Drug Administration to study the safety of BsAb in a Phase 1 human clinical trial.
Our ultimate goal is to generate a safer and far more effective treatment for patients with glioblastoma that significantly improves their quality of life and long-term survival. If successful, this will be the first antibody therapeutic that is specifically designed to attack cancer stem cells, and it could be applied to other types of cancers.
Statement of Benefit to California:
According to the Central Brain Tumor Registry of the United States (CBTRUS), approximately 22,340 new cases of malignant brain tumors were diagnosed the United States in 2011 with associated healthcare costs in the billions of dollars. Glioblastoma is the most common and most aggressive form of malignant brain tumor, and more Californians are diagnosed with glioblastoma each year than any other state in the nation. There is a consequent significant economic toll not only to Californians suffering from glioblastoma but also to taxpayers who bear some of the financial burden due to uninsured healthcare costs and costs related to lost job productivity, not to mention the tremendous emotional toll this disease has on patients, their families and their communities. Therapies to improve both the quality and length of life are desperately needed for glioblastoma patients who live on average a dismal 14 months once diagnosed.
In our research, we have shown that two markers of cancer stem cells, CD133 and EGFRvIII, are tightly associated in glioblastoma tumors. We have created a recombinant bispecific antibody (BsAb) to selectively target CD133 and EGFRvIII. This highly targeted approach kills glioblastoma tumor cells but not normal cells. Our primary objective for this study is to file the investigational new drug (IND) application necessary to advance the BsAb to a Phase 1 clinical trial for use in glioblastoma patients.
Californians will experience tangible benefits from this research project in several significant ways:
1) Most important, this research has the promise to dramatically extend the long-term survival rates for Californians with glioblastoma and to improve their quality of life. This will result in healthier citizens, increased employment, and reduced economic burden to the state. In addition, this therapy is potentially applicable to multiple other human cancers with high rates of occurrence in California, such as colon, lung, breast, prostate, ovary and head and neck cancers.
2) Filing the IND application will result in employment and increased knowledge of California-based companies and consultants in such areas as contract manufacturing, analytical, clinical and preclinical research and development organizations necessary to generate clinical grade antibody, develop and interpret requisite assays, conduct preclinical development programs and prepare for clinical research efforts.
3) If the therapeutic BsAb generated is commercialized, profits derived from the production of the BsAb by CIRM policy will result in improved treatments to insured patients and lower-cost treatments to the uninsured, thus ultimately benefiting all Californians.
4) Funding this research will help raise awareness of California’s prominence as a national and international leader in translational stem cell research and could potentially benefit glioblastoma patients world-wide.