Innovation Pharmaceuticals Inc (IPIX)

[biodoc]

I believe the complexity of the p53/p21 relationship was discussed late last year. My understanding is that p21 can be expressed through both p53 dependent and p53 independent mechanisms. In an environment where the genome is damaged (cancer), increased p21 correlates with increased apoptosis (cell death) which is a good thing. There was a review article that I looked at late last year that showed that increased p21 can be both anti-tumor and oncogenic (pro-tumor). There are so many ridiculously complex feedback loops and pathways that it's very difficult to know how much of an increase in p21 is significant, how much is good, and if more is better. We hope that there is a positive correlation between Kevetrin dose, p21 expression, and tumor response but bottom line is that we want to see tumor shrinkage and increased survival with optimally dosed Kevetrin. It would be very cool to see that correlated with increased p21 expression.

Since we know Kevetrin induces activation of p53 and we know there is a p53 dependent activation pathway for p21, it makes sense to look for increasing p21 in Kevetrin treated patients. However, the percentage increase of p21 may not tell a complete and accurate story as the relationships are too complex. We know that Kevetrin increased p21 by more than 10% in some patients at fairly low doses and I think this is intended more as a statement that Kevetrin actually increases p21. Perhaps 10% was a number where there was a high level of confidence that the change in p21 was real. Intuitively, more seems better but I've yet to see anyone quantify a relationship that may be more qualitative in nature.