Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET.
What does this line mean? Anyone interpret how VEGF inhibitors "increase lung tumor burden"?
Josh, there is a full text article that follows the abstract, read it.
I copy from there:
"Preclinical studies have found that while continuous VEGF pathway inhibition initially slows tumor growth and trims tumor vasculature, this is quickly followed by rapid revascularization and increased tumor invasiveness (13). These observations show that cancers have the capacity to develop resistance to VEGF pathway–targeted inhibition.
Tumor cell evasion of VEGF pathway–targeted inhibition may occur as a response to hypoxia. Under hypoxic conditions, hypoxia-inducible factor 1α is upregulated, resulting in increased expression of both VEGF and MET (14, 15). These responses apparently allow the tumor cells to compensate for the hypoxic environment through stimulation of angiogenesis or migration away from the hypoxic zone. Because VEGF pathway inhibition can result in induction of hypoxia, it may also trigger upregulation of MET expression, which may then stimulate tumor invasion. Indeed, Shojaei and colleagues recently determined that the MET pathway plays an important role in the development of resistance to VEGF pathway inhibition by sunitinib treatment (16). Recent studies have also showed that the use of VEGFR inhibitors, such as sunitinib, sorafenib, cediranib, or a VEGFR2-targeting antibody, can result in the development of an aggressive tumor phenotype characterized by increased invasiveness and metastasis and, in patients treated with cediranib, higher MET expression levels (17–19)."
they experimented with mice and the species treated with sunitinib (versus Cabozantinib versus placebo) had their metastases regrown and their lungs weighted more at the end of the experiment versus the beginning of the experiment.
This is what happens when resistance develops.
But you also have to note the following:
All the authors of this article work for the company producing Cabozantinib.
Not everything that is true in mice going to be true in human.
The experiment was very short and who knows what happened after the cut off time with the mice treated with Cabozantinib.
Experimental tumor was not ASPS. ASPS is a slower growing tumor and the dynamic might be different, i.e. untreated ASPS inoculated mice might survive longer if the resistance to Cabozantinib develops later in some other way.
There are already known RCC cases of the complete and durable few years off the treatment responses to TKI - but only single cases versus lots of resistant and progressing cases. Out of people that had a complete response and were taken off the drug half of them progressed again at some point, half stayed NED (no evidence of disease) for now.
Cabozantinib looks promising for the MET expressing tumors with ASPS being one of them, but unless the promise is confirmed by the clinical trial, it is just a promise. Watch for the clinical trials.
Thank you for this important shared information Josh and Olga. Cabozantinib sounds very promising and certainly should be closely followed by our ASPS Community. I Hope that Brian will post an update soon on MJ's Cabozantinib experience and results thus far, and Hopefully she is having a very successful response to it. As you said Olga, there is unfortunately not enough data available yet to make any kind of definitive conclusions about this promising new drug, but Hopefully Clinical Trial results will confirm its potential as an effective ASPS treatment.
With special caring thoughts and continued Hope,
Bonni