KYPROLIS or CARFILZOMIB, A NEW DOOR FOR RESEARCH AT CRBCM!

KYPROLIS, a proteasome inhibitor indicated for refractory Multiple Myeloma after failure of Velcade and an immunomodulator, has opened a new can of worm in research.  We have said that proteasome inhibitors are the most powerful class of drug in this disease in which the cancer cell rely on autocrine growth factors.  Lack of destruction of used proteins by impairing ubiquitination or eliminating ubiquitinated proteins, has a strong inhibitory effect.  This inhibitory effect is as strong as destroying the Nuclear content by an Alkylating agent.  This is why Velcade has been the strongest medication against Myeloma and should be included in any serious initial Therapy.  Kyprolis success is not a surprise, the Velcade story has led the fight!

Any proteasome inhibitor has also a profound disruption of cell division. It disrupts profoundly check point function and initiation of DNA replication.  In fact, this would be of interest, and probably is another major way to check proteasome inhibitor efficacy.  We propose that activity of this new drug be checked by quantitatively measuring Ki 67, ORC and Cdc6 or Cdc28 for that matter.  

This discussion brings up the fact that since we have gotten so good at genome study, we should have by now identified differences in Origin Recognition Complexes between cancer cells Vs normal cell. Because if we do, this could be a major way to electively stop cancer progression by shutting down cell division.

The story of the Silent Information Regulator (Yeast), its relation to Origin Recognition Complex, its now described inhibition of NFkB signaling by a Vanderbilt Team, and its role on the Osteoclastogenesis, put the inhibitor of proteasome center to the treatment of Myeloma and beyond!

QUESTION AT CRBCM?

what is the DRIVER mechanism in Myeloma? This post suggests:

1. Inhibition of Growth factor ubiquitination
2. Inhibition of ubiquitination of  proteins involved with initiation of Replication at check points or interphases.
3. Inhibition of survival pathways or NFkB signaling

You tell me!  We are working hard at CRBCM!
and should Ki 67 and Cdc6 be a way to monitor efficacy of Anti-Proteasome, will speak with the NCI (CPRIT being paralyzed and all!)