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Rini, who is a professor at the Cleveland Clinic Lerner College of Medicine in addition to holding several posts at the Case Comprehensive Cancer Center, discussed broad issues in antiangiogenic research in this interview with OncologyLive.
Brian Rini, MD
Brian I. Rini, MD, focuses on antiangiogenic therapy and immunotherapy for the treatment of renal cell carcinoma (RCC) and prostate cancer. He has been involved in the initial and ongoing development of targeted agents for metastatic RCC and in the clinical development of several agents that are now FDA approved. Rini, who is a professor at the Cleveland Clinic Lerner College of Medicine in addition to holding several posts at the Case Comprehensive Cancer Center, discussed broad issues in antiangiogenic research in this interview with OncologyLive.
Why does targeting angiogenesis make an attractive strategy for anticancer therapy?
All solid tumors to some degree rely on angiogenesis for continued growth and progression of cancer cells. In addition, targeting new blood vessel formation should be relatively specific for tumors versus normal cells. Thus, this has emerged over the last decade as a viable strategy.
It has become clear, however, that not all solid tumors are equally susceptible to antiangiogenic therapy. For instance, my specialty of RCC appears especially suitable given that the underlying biology of RCC (von Hippel-Lindau gene mutation) leads to an addition to the vascular endothelial growth factor (VEGF) pathway. Other solid tumors no doubt have alternative mechanism( s) and thus inhibiting blood vessels has minimal to no effect.
In what cancer types has antiangiogenic therapy proved most beneficial?
As noted above, RCC is among the tumors with proven benefit for antiangiogenic strategies as single agents. Others include glioblastoma multiforme (although with some controversy), pancreatic neuroendocrine tumors, and hepatocellular cancer (although that is only with sorafenib, which has many other targets). Other solid tumors have benefited only in combination with standard chemotherapy (eg, lung, colon) and thus the precise mechanism of benefit is not clear to me.
In your opinion, what are the most promising antiangiogenic agents?
Agents targeting VEGF and its receptor have the most clinical activity proven to date. A myriad of other agents targeting molecules such as angiopoietin, fibroblast growth factor (FGF), and others are in clinical development and are promising but as yet largely unproven.
What has the clinical development of antiangiogenic therapy taught us about the mechanisms of cancer development and the role of angiogenesis?
I believe one lesson is that some (but not all) tumors rely heavily on angiogenesis for growth and progression. We are still ignorant about mechanisms of escape from inhibiting angiogenesis, which limits the clinical application of these drugs tremendously.
What are currently the most significant limitations to the successful development of antiangiogenic therapies?
The biggest limitation is a precise understanding of how each drug works in each specific disease, how to optimize that effect through better targeting of a given pathway (eg, VEGF), better drug delivery (eg, dose titration of individual drugs), and, most importantly, mechanism(s) of resistance.