I don't expect any big scientific revelations on cabo's MOA from Dr. Debono. Known MOA of cabo account for disrupting interaction of metastatic cancer cells with stromal cells in bone microenvironment without invoking a new mechanism of selective cytotoxicity of tumor cells. Cancer cells die without the nutrient, gas-exchange, etc., support provided by adequate blood supply and other growth factors from stromal cells. This is the basis for targeting endothelial cell growth envisioned by Judah Folkman, the Father of antiangiogenesis as a cancer therapeutic.
It would be a different story if one could show cabo selectively induces apoptosis in metastatic cancer cells. But this is extremely difficult to prove in-vivo because dead and dying cells are rapidly removed/degraded by immunocytes such as macrophages. Cabo MAY be selectively cytotoxic to metastatic cancer cells but it will be difficult to prove with existing models and damn near impossible in patients. Therapeutic effect of dual inhibition of cMet and VEGFR2 is certainly more complicated than simply shutting off nutrient supply and probably involves disrupting the interaction of normal and cancer cells. It will be difficult (if not impossible) to tease apart the magnitude of these relative, individual effects and will probably vary amongst patients.
Joe, as always, your analysis is clear and understandable. Do we really need to know why there is a "therapeutic effect of dual inhibition of cMet and VEGFR2" as long as it is a therapeutic effect?
Sentiment: Strong Buy
Understanding MOA at the cellular and molecular level is critical for any therapeutic. You would get nowhere with the FDA if you wanted to start a clinical trial based on a "positive therapeutic effect" without a MOA. Preclinical data supporting theoretical MOA is required before any clinical trials can be initiated. I work on the preclinical side of this equation and we spend a lot of time/effort/money to "prove" the drug/biological we are working with is doing what it's supposed to do AND nothing else. As such, we spend a lot of time looking at issues of differential cytotoxicity and/or antiproliferative activity in the biological systems we have available - cell lines and animal models. Problem is, the cell lines and animal models will never reveal what actually occurs in human patients. "Bony mets" are especially difficult to model and to show cabo-induced cytotoxicity is due to a direct, selective effect on the tumor cells and not some secondary effect mediated by the endothelial or other stromal cells in the bone microenvironment.
The main point I was trying to make with this thread was the decrease in "bony mets" is almost certainly due to tumor cells dying for reasons that are within the scope of cabo's known MOA. I would be very surprised if Debono provides data showing cabo selectively kills tumor cells by a mechanism other than cMet/VEGFR inhibition.
post was primarily directed at you wild - intended to be helpful and teaching . tried/meant to post on this long ago when you originally brought it up. Debono's headline is an eye-catcher but proving this sort of stuff is what I do for a living.
thanks for all your posts.