Also published in the literature is inhibition of Met upregulates p38MAPK. Negative feedback loops are a pain in the rectum.
I have wondered about the prostate and in an effort to look for a model for predicting success, I have some speculation on potential pH partition.
Cabo is subject to enterohepatic recirculation and is recovered as compound and metabolites at ~70% via feces and ~24% urine (documented for FDA). I suspect the compound is actively kept out of certain compartments though the plasma levels show good levels.
With no biopsy data and only plasma levels..... Renal pH is lower than 6, Large intestines 5.5-7, small intestines 6-7.4, body 6.5-7.5, and prostrate 6.1-6.7, liver 7. If you consider the pKa of Cabo is 6.2 and protonation inhibits penetration, the lack of elimination renally and preference of the liver/bile/body avoiding the large intestines until metabolized might be evidence of pH partition. The prostate is slightly acidic to begin with and normal levels might be unfavorable at pH 6.1 on the low end but add that one can expect tissue acidosis from cancer related ischemia, the surrounding tissues can preferentially drop to a pH of 6.0 (published data) which would be unfavorable pH aside from the general ischemia potentially preventing delivery of the compound by restricting blood flow.
I'm looking for a model that works here. So far this is my best idea with failure and successes in the right places where the thyroid is body pH (6.5-7.5).
Do you have better information? I'm looking for success in hepatic cancer and I'm not hopeful for the others. Studies in Rats is one thing especially when it's graphed but human is a different beast.
You can find the list of Cobimetinib trials. There is one with Bevacizumab (P2), Onartuzumab (completed P1, October 2014), MPDL3280A (P1b), PII Melanoma Brain Metastases, ....
List goes on..
It only gets it approve perhaps 6 months earlier. Yes, it's a good thing but it's not a game changer. Perhaps they get to take advantage of 6 more months on the patent life or before some company gets a better combo.
Despite unnecessary obfuscatory reference to some document that may exist, I found it:
It does indeed say "Fast-track designation in US" on page 35. If that means that the FDA as approved the application, then we could expect results as early as mid-year. Good deal. I'm trying to confirm this on the FDA site.
Can yo please provide a cut and paste of the exact address. Contextually, your directions lead nowhere once at the Roche website.
I did find a 12 page document and on page 6, it mentioned CoBrim but it said the results were expected later in 2014. No mention of fast track.
Please be precise.
I believe I did at one point say that something was better than a kick in the caboose. I don't remember the context. I believe I know who it is; but someone on this board did spoof my name and tried to misrepresent me.
Preliminary data in metastatic castration-resistant prostate cancer (mCRPC) suggested a benefit of the oral tyrosine kinase inhibitor cabozantinib to pain palliation. Prospective evaluation of cabozantinib's benefits on pain and narcotic use in mCRPC. This was a nonrandomized expansion (NRE) cohort (n = 144) of a phase 2 randomized discontinuation trial in docetaxel-refractory mCRPC patients. Pain and interference of symptoms with sleep and general activity were electronically self-reported daily for 7-d intervals at baseline and regularly scheduled throughout the study. Mean per-patient scores were calcd. for each interval. Narcotic use was recorded daily during the same intervals. Open-label cabozantinib (100 mg or 40 mg). The following stringent response definition was used: clin. meaningful pain redn. (≥30% improvement in mean scores from baseline) confirmed at a later interval without concomitant increases in narcotics. Only patients with moderate or severe baseline pain were analyzed. Sixty-five patients with moderate or severe baseline pain were evaluable. Of these, 27 (42%) experienced pain palliation according to the stringent response definition. Thirty-seven patients (57%) had clin. meaningful pain relief at two consecutive intervals, reported ≥6 wk apart in the majority. Forty-four patients (68%) had palliation at one or more intervals; 36 (55%) decreased narcotics use during one or more intervals. Clin. meaningful pain redn. was assocd. with significant (p ≤ 0.001) improvements in sleep quality and general activity. A limitation of this study was its open-label design. Cabozantinib demonstrated clin. meaningful pain palliation, reduced or eliminated patients' narcotic use, and improved patient functioning, thus meriting prospective validation in phase 3 studies. We evaluated the potential of cabozantinib to improve symptoms in patients with metastatic prostate cancer
I've not heard of "reverse endocinology" before but having now looked it up, I wouldn't call it voodoo medicine but less applicable. Perhaps an academic study would be more appropriate first. I'll be looking more into this. It's interesting.
I see. What I found since (very little) indicated they were buying patents more than anything to shut others out (perhaps) to remove competition for companies they were already dealing with.
You can get information from
They have projected "completion dates" that may vary.
Out of context.... a p-value of 1 is bad by the way.
Did you intend a decimal point?
Just remember they're investing other peoples money plus that is a fraction of a percent for them. If you want to follow their model, invest 0.01% of your investments in Exel.