FRESH SCIENCE for Clinicians

News about basic science of interest and relevance for cancer clinicians

Thursday, October 27, 2011

Restoring tumor suppressor proteins via antibody delivery

There are two kinds of cancer driver genes, tumor suppressors and oncogenes. Researchers have made progress targeting oncogenes (think BRAF inhibitors, for example), but tumor suppressors are a separate can of worms. They cause problems when they are absent from a cell, and current technology provides few options for restoring a deleted gene.


Now, researchers at Memorial Sloan-Kettering Cancer Center report in Cell today that anti-CD20 antibodies, such as rituximab, might be a viable delivery system for at least one tumor suppressor protein that appears to drive follicular lymphoma.


Working with a combination of cell and xenograft models, as well as human tumor samples, the team, led by Hans-Guido Wendel, MD, Assistant Member of the cancer biology/genetics program, establish a strong case for EPHA7’s role as a tumor suppressor in follicular lymphoma. 


But the most remarkable finding in their paper is that they can induce complete responses in xenograft animals by either injecting purified EPHA7 protein into the tumor or treating the animals with EPHA7 protein fused to rituximab.


Rituximab alone was as effective as the fusion protein, but only when given at a considerably higher dose, suggesting that the EPHA7 protein itself was having an anti-tumor effect.


The results suggest that using an anti-CD20 antibody to deliver EPHA7 to patient tumors might be a valuable therapeutic approach.


Of course there is a long way between these preclinical experiments and patient therapy, but Dr. Wendel says his team is looking for biotech collaborators to explore the possibility.


And from my point of view, I think the approach deserves some recognition simply for its novelty. Antibody-drug conjugates have become more popular again, after some initial setbacks in the field. But those agents tie small chemical drugs to the antibody, not proteins. And they aren’t aimed at restoring tumor suppressor function.


Given that there are nearly 10-fold more tumors suppressors than oncogenes (286 versus 33, according to Bert Vogelstein’s plenary talk at last year's AACR annual meeting), any new approach to restore tumor suppressor function deserves some attention.


Now we’ll just have to wait and see if that attention turns an interesting idea into therapy.