DR. CARROLL: Questions? How would you see integrating some of these agents with a backbone of chemotherapy? Phase I trials, but what would be your protocol to launch these with chemo?

DR. ANDREEFF: Well, starting with BCL2, that is a no brainer, because most chemotherapy, of course, goes through that pathway.

In my opinion, one has to first determine the apoptogenic potential of these drugs by themselves, not in combination.

My general idea is our results would indicate that we would get more bang from combining inhibition of several pathways with small molecule inhibitors than combining these inhibitors with chemotherapy.

At least in vitro, adding chemotherapy does not add that much. Of course, it is what everybody expects and we want to tie it into existing regimens, but I would rather see a completely separate plan for developing these agents by determining what is critical for cell survival, not just what is activated, but what is activated for cell survival, and targeting that.

That may not be popular in a chemotherapy context, but that would be my first priority. In reality, I think, we will always add chemotherapy, and we may or may not be disappointed at what comes out.

DR. GAYNON: Isn't there a danger in an assumption that a target must be over-activated to be a target? You may have high activation of some pathway that a modest reduction makes little effect, but in another case, a small expression might be very vulnerable to repression?

DR. ANDREEFF: I don't think I excluded that. Over-expression is a very relative term. Everybody uses over-expression. If you are looking at our cure rates in leukemias, if you have a universal resistance factor, it just has to be present, and it is not necessary to be over-expressed.

Pathways, I think, have to be activated, obviously, but all these pathways are activated, MAP kinase, PI3 kinase, BCL2, all these things are real in primary cells.

In ALL, there are really not enough good studies done. AML is much better investigated. We still have to learn a lot about ALL and subtypes of ALLs.

PARTICIPANT: Are there small molecule inhibitors of BCL2, for example, are they in phase I trials now? Are the heading there?

DR. ANDREEFF: There are two small molecule inhibitors. One is HA14, published in 2000 in PNAS. The concentration needed is 10 micromole, and I thought that wasn't so attractive until Dr. Plunkett told me that it was used at that level, and is still the best drug in leukemia. So, we are finally doing the small toxicology and PK studies now.

There is a second class of inhibitors from a pharm company now that is active in sub-micromolar levels, and that is being investigated right now in preclinical models right now. Nothing is in phase I so far.

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