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Discussion
Dr Brian Untch (New York, NY): You mentioned that there have been some early phase clinical trials with these compounds already. Has any ACC patient been treated that you know of?
Dr Ton Wang: They have not done anything with Hsp90 in- hibitors in ACC yet. It has mostly been studied in breast cancer. That’s had the most promising results.
Dr Brian Untch (New York, NY): And what stopped the FDA approval? Was it toxicity or just lack of response in other diseases?
Dr Ton Wang: Toxicity is definitely a major issue, and it’s mostly due to the heat shock response, like I mentioned. Basi- cally, it’s a pro-survival mechanism, and so you have to keep using higher doses to keep killing the cancer cells, and then it eventually has toxic effects on normal tissue. Hepatotoxicity is a major issue.
Dr Emad Kandil (New Orleans, LA): How does this compare to beta-catenin inhibitors, Wnt pathways, and mTORs. There are other inhibitors. Did you look into this?
You mentioned in your conclusion that you plan to study this with siRNA. I wonder why you decided to do siRNA and not CRISPR techniques, for example.
Dr Ton Wang: We have not tested this against any beta-catenin inhibitors or mTOR inhibitors. This is a different type of drug. I think
that would be great next step to test this head to head against other types of inhibitors.
In terms of the next step, I think siRNA knockdown has previ- ously been shown specifically for GAS5 and has been successful in upregulation of the beta-catenin pathway. Since that’s previously been done successfully, that would be the next natural step in order to link all the conclusions together.
Dr Omair Shariq (Rochester, MN): Do you have a control cell line? How do you know that this substance isn’t just being toxic to all cells?
Dr Ton Wang: We use human fibroblast cell lines typically. MRC-5 and HMLE are the two fibroblasts we have tested in the past, and we use that as kind of the base-level screening.
We have actually done animal studies for KU758 already, and the mice had limited side effects. Probably the biggest one was weight loss, but they overcame that.
Dr Omair Shariq (Rochester, MN): You showed that it decreased proliferation. Did you look at apoptosis?
Dr Ton Wang: We have looked at apoptosis in two different ways. We have looked it with flow data and with annexin V array. I just didn’t show those data here. But we have looked at it, and we saw an increase in apoptosis.