Renal cell carcinoma (RCC) is the fourth most lethal cancer in the world. Of the estimated 49,000 patients diagnosed with RCC each year in the United States alone, approximately 11,000 will die from the disease. Worldwide, RCC results in more than 100,000 deaths every year.

RCC tends to metastasize to bone, giving patients a mean survival rate of only 12 months. Behind this poor prognosis is the fact that RCC is resistant to conventional radiation and chemotherapy, and its robust vascularity often makes surgery impossible. Successfully treating RCC will require new and innovative approaches.

Proteins in tumor growth
Dr. Tyler and her team are measuring the growth of cancer cells using nude mice injected with cancer cells and an enzyme that can be detected by bioluminescence imaging. After 14 days, the injected mice are tested to see if the cancer cells have begun to grow. Tumor cells grow in the mice about 50 percent to 60 percent of the time. Dr. Tyler’s experiments focus on those mice with growing tumors.

Backed by the OREF grant, Dr. Tyler is investigating two proteins in particular: angiopoietin 1 and angiopoietin 2. These two proteins have been associated with vasculogenesis and angiogenesis, the processes by which blood vessels grow, branch, and reproduce under both normal and abnormal conditions.

When the mouse tumors reach a certain size, Dr. Tyler injects an antibody called AMG386 that specifically targets these two proteins. She can then compare any subsequent changes in tumor size and cancer cells with tumors in control mice that received either a saline solution or current renal cancer treatment agents.

Hope for stopping tumor growth
Results so far have been good. “We’ve had some successes and some failures,” Dr. Tyler said. “The angiopoietin—particularly angiopoietin 1—seems to play a role in the growth and development of these tumors. So, it has a potential to act as a target.” By contrast, she noted that angiopoietin 2 has not responded as well, but she chalks that up to a “live and learn” moment. Knowing that angiopoietin 2 is a less effective target, Dr. Tyler and her team are exploring whether different antibodies can successfully block other newer proteins.

The question now is whether angiopoietin 1 or other proteins could serve as effective targets in clinical trials. “It’s a little early, and we’re still analyzing some of the data,” said Dr. Tyler, “but we’ve had good progress.” She hopes that in the next few years this study will lead to applying for an investigational new drug to test in humans.

Support from others makes more possible
For Dr. Tyler, OREF funding has been invaluable. “Without this type of grant support,” she said, “young researchers like myself are not going to be able to do the research, and if we’re not able to do the research, the field of orthopaedics doesn’t move forward.”

The grant confers not only financial support, but external validation as well. “There’s an emotional side to it. Getting the grant and having somebody say to you, ‘your research is valuable and important, and we want you to do it’ is so rewarding,” said Dr. Tyler.

Dr. Tyler never loses sight of the ultimate goal—improving and extending the lives of RCC patients. She sees patients each day with metastatic RCC, and she knows that it is a difficult cancer to treat. Yet Dr. Tyler remains hopeful, stating that the ultimate reward of her research will be that “in the very near future we may have an agent that can treat these patients and turn what is a fatal disease into a chronic disease that they can live with for the next 15 or 20 years.”

Dr. Tyler’s interest in research began during her time in medical school and, since she earned her master’s degree in public health, has leaned toward investigations with high impact and broad reach. Today, Dr. Tyler is an orthopaedic surgical oncologist and assistant professor at the University of Rochester Medical Center (URMC) in Rochester, N.Y., with special interests in bone tumors and metastatic cancer.

Dr. Tyler gratefully acknowledges the support she has received from mentors throughout her career. At URMC, Dr. Tyler has benefited from the support of Randy Rosier, MD, PhD, and Regis J. O’Keefe, MD, PhD, while Edward M. Schwarz, PhD, has been providing helpful guidance as a regular mentor. Dr. Tyler also thanks her colleague in the laboratory with whom she shares this project, Chao Xie, BM.

Sherri Damlo is a contributing writer for OREF. She can be reached at communications@oref.org