I found an interesting study published in November 2017:
https://www.ncbi.nlm.nih.gov/pubmed/29348854
http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=22637&path[]=71521
"The standard glioblastoma chemotherapy agent, temozolomide, had minimal GSC-targeted effects at comparable or even higher concentrations (IC50 > 750 μM against GSCs). ASAH1 is identified as a de novo glioblastoma drug target, and ASAH1 inhibitors, such as carmofur, are shown to be highly effective and to specifically target glioblastoma GSCs. Carmofur is an ASAH1 inhibitor that crosses the blood-brain barrier, a major bottleneck in glioblastoma treatment. It has been approved in Japan since 1981 for colorectal cancer therapy. Therefore, it is poised for repurposing and translation to glioblastoma clinical trials."
"ASAH1 inhibitors are highly more potent than temozolomide in killing GSCs and U87MG cells. Due to its high level of expression in GSCs, ASAH1 inhibition is proposed as a new anti-glioblastoma therapy that specifically targets GSCs."
2017 https://www.ncbi.nlm.nih.gov/pubmed/28765947
"inhibition of ASAH1 and Sph-1P, either with humanized monoclonal antibodies, small molecule drugs (i.e. carmofur), or a combination of both, led to suppression of GBM cell growth. These results suggest that ASAH1 and Sph-1P may be excellent targets for the treatment of new GBMs and recurrent GBMs, especially since the latter overexpresses ASAH1."
https://www.drugs.com/international/carmofur.html
Unfortunately, I did not find any trials with carmofur (or mifurol) at https://clinicaltrials.gov
https://en.wikipedia.org/wiki/Carmofur
"Carmofur has also been used as adjuvant chemotherapy for curatively resected colorectal cancer patients in China, Japan, and Finland for many years. Trials and meta-analyses have confirmed that the drug is effective on patients with this cancer type, extending their survival.
A clinical trial for small hepatocellular carcinoma was stopped prematurely because 56% of the treated patients had unacceptable side effects. Moreover, the treatment had no survival advantage for stage 1 and 2 cancer patients. This may be a reason why carmofur was never pursued for FDA-approval in the US."
Maybe there are more modern and safe ASAH1 inhibitors crossing the blood-brain barrier?
https://www.ncbi.nlm.nih.gov/pubmed/29348854
http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=22637&path[]=71521
"The standard glioblastoma chemotherapy agent, temozolomide, had minimal GSC-targeted effects at comparable or even higher concentrations (IC50 > 750 μM against GSCs). ASAH1 is identified as a de novo glioblastoma drug target, and ASAH1 inhibitors, such as carmofur, are shown to be highly effective and to specifically target glioblastoma GSCs. Carmofur is an ASAH1 inhibitor that crosses the blood-brain barrier, a major bottleneck in glioblastoma treatment. It has been approved in Japan since 1981 for colorectal cancer therapy. Therefore, it is poised for repurposing and translation to glioblastoma clinical trials."
"ASAH1 inhibitors are highly more potent than temozolomide in killing GSCs and U87MG cells. Due to its high level of expression in GSCs, ASAH1 inhibition is proposed as a new anti-glioblastoma therapy that specifically targets GSCs."
2017 https://www.ncbi.nlm.nih.gov/pubmed/28765947
"inhibition of ASAH1 and Sph-1P, either with humanized monoclonal antibodies, small molecule drugs (i.e. carmofur), or a combination of both, led to suppression of GBM cell growth. These results suggest that ASAH1 and Sph-1P may be excellent targets for the treatment of new GBMs and recurrent GBMs, especially since the latter overexpresses ASAH1."
https://www.drugs.com/international/carmofur.html
Unfortunately, I did not find any trials with carmofur (or mifurol) at https://clinicaltrials.gov
https://en.wikipedia.org/wiki/Carmofur
"Carmofur has also been used as adjuvant chemotherapy for curatively resected colorectal cancer patients in China, Japan, and Finland for many years. Trials and meta-analyses have confirmed that the drug is effective on patients with this cancer type, extending their survival.
A clinical trial for small hepatocellular carcinoma was stopped prematurely because 56% of the treated patients had unacceptable side effects. Moreover, the treatment had no survival advantage for stage 1 and 2 cancer patients. This may be a reason why carmofur was never pursued for FDA-approval in the US."
Maybe there are more modern and safe ASAH1 inhibitors crossing the blood-brain barrier?
Temozolomide is a prodrug that gets converted into the active metabolite under physiological conditions in the body. In the artificial conditions of the lab, much higher concentrations of TMZ are required to kill cancer cells than are achieved in the body. Almost any directly acting agent is more potent than TMZ in vitro at equimolar concentrations. What is true in vitro is very often not true in real life, for many reasons.
ReplyDeleteYes carmofur may cross the blood-brain barrier, but we know this because of the brain toxicity it has caused, for example leukoencephalopathy. https://www.ncbi.nlm.nih.gov/pubmed/3379758
Carmofur, in addition to being an acid ceramidase inhibitor is also a prodrug of 5-fluorouracil, which probably accounts for the toxic side-effects as observed in the link above.
In this study:
https://www.nature.com/articles/srep01035.pdf
they use carmofur as a scaffold to create modified molecules with potent acid cermidase inhibition, but unable to release 5-FU. But it doesn't appear these molecules have made it into clinical trials.
With carmofur trials in other cancers being stopped because of unacceptable side effects, and not having any data from brain tumor trials, it seems to me that carmofur (presuming you could even get access to it) would be quite a gamble - with risk of toxic side effects in the brain being high and therapeutic value for GBM being unknown beyond the most preliminary in vitro data.
ASAH1 is definitely an interesting target for drug development. It's too bad these carmofur derivatives with better safety profiles haven't made it to the clinic yet (as far as I can tell from my limited research).
DeleteThank you once again for such a detailed analysis!
ReplyDelete