Our Challenge towards Signal Therapy of Non-infectious Diseases and AIDS

Like FDR and JFK, Barack Obama, a young Harvard Law School graduate, is trying hard to change this world for the better by taking an unconventional bold political approach to unite the people, instead of dividing them. Similarly, we have been taking a fresh approach to cure a variety of non-infectious but formidable diseases such as cancers as many as possible, under an unified principle called "signal therapy" (ST), that is to signal the disordered body back to the normal. Though it might sound as if it were a new cult or religion, the ST is surely a new solid modern medical approach based on the outcome of our cutting-edge scientific research.

The best known among this approach is a chemical drug called "Gleevec". Gleevec (also called "STI-571", STI for signal transducer inhibitor) is an inhibitor of a group of enzymes or STs called ABL, KIT, and PDGFR, Tyr-kinases, which are responsible for the development of rare cancers such as CML (chronic myeloid leukemia) and GIST (gastrointestinal stromal tumor). In these cancer cells, these enzymes/STs are abnormally activated, due to either genetic mutations or a few other changes, and stimulate the growth of normal cells in an un-controlled manner. STIs such as Gleevec block or tame these "malignant" enzymes so that they regain their normal "controlled" function. In other words these STIs (or signal therapeutics) signal cancer cells back to the normal.

However, CML and GIST represent only a very minor population of cancers, and Gleevec cannot cure the remaining majority of cancers. Thus, a group of molecular oncologists started looking for the key enzyme or ST which is essential for the growth of the majority of cancers such as breast and prostate cancers or so-called RAS cancers, which are caused by RAS mutations, and represent more than 30% of human cancers such as pancreatic and colon cancers.

Around the turn of this century, it was found that an enzyme called PAK, a Ser/Thr kinase, which is abnormally activated by oncogenic RAS mutants, is required for the growth of these RAS cancers. Thus, a series of anti-PAK drugs have been developed or identified by a few groups including us. Using these drugs that selectively block the oncogenic PAK signaling, we and others found that more than 70% of human cancers including breast and prostate cancers require PAK for their growth, but not the normal cell growth. Thus, anti-PAK drugs would be potentially far more useful for the treatment of these PAK-dependent (and Gleevec-resistant) cancers in the future. Among these anti-PAK drugs, so far a ring peptide called FK228 is the most potent, and is currently in clinical trials (phase 2) for CTCL (cutaneous T-cell lymphoma).

It would be of great interest to note that another enzyme/kinase called AMPK (AMP-dependent kinase) is a tumor suppressor, and this kinase activates another protein called FOXO, a tumor suppressing transcription factor, which is required for the longevity. Thus, recently a series of AMPK activators have been developed or identified for the treatment of cancers and a few other metabolic diseases/disorders such as diabetes (type 2) and obesity. For AMKP activates a glucose transporter called GLUT-4 as well, which is responsible for up-taking glucose from blood stream into cells.

We recently found that PAK suppresses the FOXO at least in a tiny nematode called C. elegans somehow. Thus, it is possible that both anti-PAK drugs and AMPK activators can be used for signal therapy of the majority of cancers and improving our QOL (quality of life) to expand our life span, by simply activating the FOXO.

To be continued