RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:Pre-Clinical only!I reread the three abstracts. Basically, what they established with that is the fact that on animal models, nude mice without an immune system, grafted (xenografts) with docetaxel resistant human cancer cells, and for the first time, mice with a working immune system grafted with mice cancer cells (allografts of murine cancer cells) TH1902 works. They also tested TH1902 against cancer stem cells, and cancer cells with positive MDR against docetaxel. They also tested it on human cancer cells sensitive to docetaxel alone. All the results point to the fact that TH1902 works against resistance and in mice with an active immune system, while docetaxel alone does not or at a much lower level, while docetaxel works in SKOV-3 cancer cells that are not resistant to docetaxel. So with this data they have further proof that TH1902 allows to overcome resistance to docetaxel in specific lines of cells, with or without an active immune system in mice. And all that using equivalent dose of TH1902 to the MTD of docetaxel alone or less. So likely demonstrating a concentration effect inside cancer cells or to specific places inside cancer cells. Again, all that is great, but obviously, the key is to know if all these great results on animal models with grafted cancers can be seen when TH1902 is used on real advanced cancer patients. So they made their case stonger on mice, but it does not tell us anything about how it will translate on humans. That being said, why would they publish that at this time if what they see in phase Ia is a total failure of TH1902 on humans?
jfm1330 wrote: It all depend on which type of tumors you are testing it. You need also to remember that they graft selected cells lines that are genetically homogenous. So all the cells in the tumor will be the same, all resistant or not, to certain drugs. It's not that way in a real tumor that are genetically heterogenous. In one of the abstract Thera presented yesterday, I noticed that docetaxel was as efficacious as TH1902 on a particular cell line tumor they tested. This from the abstract:
In SKOV-3 xenografts, treatment with either drug both stopped tumor growth and induced similar tumor regressions. SKOV-3 is an ovarian cancer cell line
SKOV-3 is a human ovarian cancer cell line with epithelial-like morphology. These cells are resistant to tumor necrosis factor and to other cytotoxic drugs such as diphtheria toxin, cisplatin, and adriamycin. So they likely included it because it was resistant to cisplatin. On the othe hand, this article (see link), will tell you that SKOV-3 cancer cells are sensitive to docetaxel. So no surprise that in Thera's experiment, both docetaxel and TH1902 led to similar tumor regressions on tumors generated out of this cell line.
SKOV3 and HeyA8 cell lines were both sensitive to docetaxel (IC50 levels, 1-6.2 nmol/L), whereas the SKOV3-TR and HeyA8-MDR cells were resistant (IC50>or=250 nmol/L for both). Docetaxel induced high rates of apoptosis in SKOV3 and HeyA8 cells (84% and 66% apoptosis, respectively) but minimal apoptosis (5-8%) in SKOV3-TR and HeyA8-MDR cells. https://www.abstractsonline.com/pp8/#!/10517/presentation/12259
https://pubmed.ncbi.nlm.nih.gov/16361572/
SPCEO1 wrote: IS there any data out there easily findable that compares the results of Docetaxel in its original pre-clincial trials to the ultimate impact it had on actual tumpor in human testing? If so, could that be a good indicator of what to expect from TH-1902 in humans? Did the original Docetaxel tests inmice hold up roughly as well in humans or was there a fall-off in effectiveness?
jfm1330 wrote: Yes but this is the most important thing and the one about which we have zero data. To stay positive you say to yourself that they would not present these results at AACR if they would see absolutely nothing towards a proof of concept in the phase Ia. I mean by that at least stable disease and positive PK/PD data. In the latest articles, they are comparing TH1902 to docetaxel at the MTD of docetaxel alone and see efficacy. So it's hard to believe that patients that got 420 mg/m2 for at least two cycles had no efficacy signs if they were overexpressing sortilin. But again, real tumors in real humans is very different from tumors grafts on mice and you always wonder if docetaxel will be efficacious at higher intracellular concentrations on relapsed cancers with no effective treatment remaining.
LouisW wrote: All we need is the human efficacy data, then all the dots can be connected.