Replies to post #15390 on Innovation Pharmaceuticals Inc (IPIX)

[Gratefullife]

Karin,
Thank you for your specificity and the circumspect nature of your answer, your efforts educating people about CTIX are greatlly appreciated, and thank you for repeating yourself for the benefit my hard head!

Years in the stock market as well as my work around medical and health professions have taught me to be skeptical of far-reaching claims. Ruthless honesty about what could go wrong with ones investments is healthy.

Yet the more I read and re-read about what Cellceutix is trying to accomplish, the more I like.

Have a nice Christmas

GL

[KMBJN]

I'm excited about Kevetrin and the recent jump in CTIX price, but just because there may not be any competition to Kevetrin now, doesn't mean there won't be. The science is complex, is still being sorted out, and big pharma is putting lots of resources into p53 and related pathways in cancer drug development.

I mean, in 2008 Cellceutix thought that Kevetrin acted primarily as an AKT inhibitor. This is from their 2008 10-K:

"Kevetrin acts on multiple biological pathways as an alkylating agent, AKT inhibitor and LTB4 inhibitor with anti-angiogenic properties. Kevetrin has shown to have potent activity against various cancer cell lines both in-vitro and in-vivo. Since the compound works through MMOA..."

So when we hear that Kevetrin works through multiple mechanisms of action, we should probably take it to mean "we're still not sure exactly how it works, but we hope it works as well as before in animal models, and that nobody else has anything that could ever work as well."

To play the devil's advocate some more, I'm not convinced the whole story has been "put to rest" about how Kevetrin works, and that there are no other drugs in development that may work as well. I do agree that Kevetrin has a pretty good lead.

I'd love for someone with more of a basic science background and understanding of pre-clinical cancer research to explain things a little better. I haven't seen anything published on Kevetrin, just a few abstracts and press releases over the last 4 years. Below is my attempt to summarize some of the key findings from my limited understanding of how Kevetrin works.

The anti-angiogenic properties seem to be due to HDAC6 down-regulation/ inhibition by Kevetrin, causing acetylation of alpha-tubulin. Other HDAC6 inhibitors do the same.

For wild-type p53, Kevetrin somehow causes phosphorylation of p53 at serine 15, and mono-ubiquitination of p53 (probably via down-regulation / inhbition of HDAC6, causing acetylation and/or phosphorylation of (HDM2/MDM2) and affecting p53 through that interaction). So wild-type p53 is stabilized and re-activated. p53 may also be expressed in greater quantities directly because of p53 transcription (via HDAC down-regulation / inhibition).

Nutlins worked to stabilize / activate p53 via inhibition of (HDM2) MDM2-p53 binding. According to NYTimes article, nutlins failed because they "were not absorbed into the body." Others say they failed because they were genotoxic, and were not pursued further. There may be progress in developing new MDM2 inhibitors that are not genotoxic, developed at UMich and licensed to Ascenta:

http://www.cancer.med.umich.edu/news/drug-shrinks-cancer-in-animals-2011.shtml

Other drugs seem to be able to activate wild-type p53. Ascenta's HDM2 inhibitor does not seem to be in clinical trials.

I agree that Kevetrin acting on mutated p53 seems to be a unique feature not found in other compounds. In their 2012 AACR poster, they say that Kevetrin causes degradation of mutant p53, which may make cells more susceptible to chemotherapy. In their 2011 AACR poster, they say that Kevetrin may mono-ubiquinate and stabilize mutant p53, which still may have some interaction with pathways that lead to apoptosis. So I'm not sure if mutant p53 is activated or degraded by Kevetrin, or what makes Kevetrin unique. It worked well in animal models / mutant p53 cell lines, so let's hope it works in humans, where >50% of tumors have mutated p53.

Yes, I can't help speculating on the science. It's a fun way of learning.

I see CTIX came out with a nice press release responding to the p53 article and the state of competition:

http://cellceutix.com/cellceutix-comments-on-new-york-times-article-heralding-p53-drugs-as-the-new-age-in-cancer-research/

Gotta love this management team.