Innovation Pharmaceuticals Inc (IPIX)

[KMBJN]

Re: p21 activation and is 10% significant?

From their 2011 AACR poster "Importantly, we identified the levels of p21 as a potential biomarker in our upcoming clinical trial for Kevetrin. Based on the mechanism studies, levels of p21 were measured by qPCR in peripheral blood lymphocytes from mice treated with Kevetrin. Kevetrin significantly enhanced p21 levels compared to control which correlated with anti-tumor activity of Kevetrin."

No mention of what amount is "significant."

They are not checking for p21 activation in tumor cells, but in circulating, healthy white blood cells exposed to kevetrin. I'm not sure we'd like kevetrin to have any effect on healthy cells, especially if those effects could be harmful.

In general, p21 activation would show that p53 was activated, since p21 is a transcriptionally activated via p53, and thus most view p21 increases as a positive - as a biomarker for (wild-type / non-mutated) p53 activation, which hopefully would correlate with tumor suppression.

However, there is some evidence that p21 impedes apoptosis, and so could be tumor promoting.

http://www.ncbi.nlm.nih.gov/pubmed/21815189

"On the one hand, p21(Cip1/Waf1) acts as a tumor suppressor; on the other hand it prevents apoptosis and acts as an oncogene."

The conclusion of the above recent paper discussing p21 in cancer:

"p21Cip1/Waf1 protein plays an important role in tumor initiation. On one hand it works as a tumor suppressor. It was proved, using mice models, that mice without p21Cip1/Waf1 protein are more sensitive to tumorigenesis [Caballero et al., 2001]. The absence of p21Cip1/Waf1 protein enables the proliferation of cells with damaged DNA and it promotes tumor progression [Gartel, 2009]. On the other hand p21Cip1/Waf1 protein acts in an anti-apoptotic way and can behave as an oncogene. Increased expression of p21Cip1/Waf1 protein was proved in human prostate cancer, cervical cancer, breast cancer, and in many cases upregulation of p21Cip1/Waf1 protein correlated with the invasiveness and aggressivity of the cancer [Abbas and Dutta, 2009].

Treatment of cancer cells with different drugs often induces p21Cip1/Waf1 and cellular senescence, which helps the cells to escape drug-induced apoptosis. It was found that in breast cancer, lung cancer or colon cancer treated by doxorubicine, the tumor cells were more susceptible to the treatment after the p21Cip1/Waf1 protein inhibition and died [Gartel, 2009]. Better understanding of the role of p21Cip1/Waf1 protein in cells under various conditions would help to increase efficiency of treatment of many types of cancer."

So I'm not so sure increase of p21 is necessarily a desirable outcome in cancer treatment.

More on targeting p21 in cancer:

http://www.ncbi.nlm.nih.gov/pubmed/22165965

Apparently p21 increases are good in the nucleus, but not in the cytoplasm:

http://www.ncbi.nlm.nih.gov/pubmed/22817456

I don't think we are distinguishing where p21 protein may be increased. In fact, we are just measuring p21 mRNA via qPCR. What happens to p21 mRNA is very complex:

http://nar.oxfordjournals.org/content/early/2010/09/03/nar.gkq778.full

In any event, other drugs increased p21 mRNA up to 100x in cell lines:

http://www.ncbi.nlm.nih.gov/pubmed/16733561

10% doesn't sound that great, but it would be nice to know what they found in their mouse studies, in terms of percentage increase, and how it correlated with tumor suppression in mice.