[al from Canada]

Hey Lani,

I think you are on the right track. I have to apologize and admit that I only skimmed the abstracts as I'm very tight on time these days due to Linda's tx.

Most of the stuff in the articles talks about the down-regulation of HER2.
Let me postulate 4 scenarios:

1. Let's assume herceptin is working but not optimally; I agree that you can downregulate HER2 say with oleic acids therefore weakening the HER2 receptors thus increasing suseptability to herceptin

2. The HER2/AKT/PI3K.....by down-regulating PI3K and upregulating PTEN which sensitizes the HER2 tumor cells to apoptosis.

3. Transciption: the dimerization of HER2 and EGFR (HER1) of HER3. In this case adding lapatinib or pertuzumab would be effective preventing transcription.

4. herceptin resistance: like any drug, herceptin will cause cells to develop resistance or habituate to the drug. It has been shown that herceptin resistant HER2 tumor cells can be re-sensitized to herceptin by adding an EGFR inhibitor such as lapatinib, iressa, centuximan or tarceva.

Here's my take: do molecular profiling on the tumor cells and target the therapy accordingly, (this doesn't sound like rocket science), ie. test for HER1 - 3, VEGF, PI3K, PTEN, ER, or........lets do a trial on active mets with herceptin + pertuzumab + avastin + lucentis (which attacks VEGF in a different way) + LY294002 + say a friendly chemo drug like Xeloda. If I personally, had stage 4 cancer; I would volunteer as what's the worst that will happen, I'll die young?? After that, maintainence with herceptin + lapatinib + Avastin (+ faslodex if ER+).

Diclaimer: don't believe me because I'm only a care-giver.

Al