Exponential Growth in Anti-angiogenic Research

Today marks the third annual ASH/ASCO Joint Symposium (9:45 a.m. - 11:30 a.m.) which will be co-chaired by Dr. Ronald Hoffman, president of ASH, and Dr. Margaret Tempero, president of the American Society of Clinical Oncology (ASCO). This year 's topic, New Anti-Angiogenic Strategies for Cancer Therapy, will provide hematologists and oncologists with the highlights of the basic mechansims in angiogenesis, anti-angiogenic targets, and the challenges of designing clinical anti-angiogenic studies.

Dr. Kari Alitalo, from the University of Helsinki, will begin the symposium with a discussion of the Basic Mechanisms of Angiogenesis. In his talk, Dr. Alitalo will address the importance of understanding how tumors produce new blood vessels and the subsequent metastatic spread through lymphatic vascular regulation. Dr. Alitalo will discuss the "balance between angiogenic stimulators and inhibitors" and outline the current data on the vascular endothelial growth factor receptors (VEGFRs) that mediate angiogenic stimuli through tyrosine kinase activity. Increasing the basic knowledge of the "processes and regulatory mechanisms" involved in angiogenesis and lymphangiogenesis will aid researchers in developing specific anti-angiogenic targets.

Dr. Doug Hanahan, from the University of California-San Francisco, will then discuss Potential Therapeutic Targets. He will expand on the basic understanding of angiogenesis and will present intriguing results of studies evaluating receptor tyrosine kinase inhibitors (RTKIs) in the RIP1Tag2 transgenic mouse lineage. These mice develop islet carcinomas in a multistep pathway with characteristic lesions appearing when the vasculature is still quiescent, followed by distinct changes in the early-stage and late-stage of angiogenic lesions. Dr. Hanahan will discuss how this mouse model was used to design trials to evaluate the effect of blocking, early-stage, and late-stage angiogenic effects of two different RTKIs (SU5416 and SU6668) by comparing the immunohistological effects of the treatments. He will also enlighten the mem- bers of ASH on a new observation that perivascular cells associated with their tumor model expressed platelet-derived growth factor receptors (PDGFRs) important in maintaining tumor blood vessels. Dr. Hanahan will present further encouraging results of testing the combinations of RTKIs that target differ- ent angiogenic receptors (VEGFRs in endothelial cells and PDGFRs in perivascular cells). The finding of new potential targets for anti-angiogenic treatment and the concept of "muliplex receptor-targeting strat- egies" will be important for designing future clinical trial strategies.

The final speaker will be Dr. Gail Eckhart from the University of Colorado. Dr. Eckhart will update the audience on the Challenges and Opportunities for Clinical Evaluation of New Agents. Dr. Echart will use examples of "real" clinical trials using anti-angiogenic therapies to take a critical look at what clinical re- searchers have learned and to outline strategies for future trials.

In a related talk given yesterday (and offered again today from 7:00 a.m. - 9:15 a.m.) in the Scientific Committee Session on Thrombosis and Vascular Biology Targeting the Endothelium for Good and Bad, Dr. Rob- ert Kerbel spoke on the "Challenges for Clinical Translation of Angiogenesis Inhibitors." Dr. Kerbel points out that there were five negative phase III clinical trials using angiogenesis inhibitors prior to the finding of prolonged survival using bevacizumab (humanized anti-VEGF antibody) as first line therapy of meta- static colorectal cancer. Some of the problems involve (1) determining the optimal biologic dose (OBD) with therapy that may not cause an objective response such as rapid tumor regression, (2) monitoring anti- tumor activity if no objective response, (3) how to combine anti-angiogenic and chemotherapy agents, and (4) minimizing toxicity especially with combination therapies.