Tykerb/Herceptin

[Lani]

I was told the article is to come out soon in ONCOGENE


Home > Abstracts & Virtual Meeting > Abstracts > 2008 ASCO Annual Meeting

Effect of lapatinib on accumulation of inactive HER2 at the cell membrane and on antibody-dependent cellular cytotoxicity (ADCC) mediated by trastuzumab: A novel mechanism for the enhanced effects of combined anti-HER2 therapy.
Sub-category:
Tyrosine Kinase Inhibitors
Category:
Developmental Therapeutics: Molecular Therapeutics
Meeting:
2008 ASCO Annual Meeting

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Abstract No:
3594
Citation:
J Clin Oncol 26: 2008 (May 20 suppl; abstr 3594)
Author(s):
M. Scaltriti, C. Verma, M. Guzman, J. Jimenez, J. Parra, K. Pedersen, S. Landolfi, S. Ramon y Cajal, J. Arribas, J. Baselga
Abstract:
Background: Lapatinib is a HER2 tyrosine kinase inhibitor that has clinical activity in HER2 overexpressing (HER2+) breast cancer. In vitro and clinical studies have shown that lapatinib enhances the effects of the monoclonal antibody trastuzumab suggesting partially non-overlapping mechanisms of action. In order to dissect the differential mechanims of these agents, we have studied the effects of lapatinib and trastuzumab on receptor expression and signaling and have explored a new potential mechanism underlying the profound antitumor activity of the combination. Methods: HER2+ breast cancer cells SKBR3 and MCF7-HER2 were treated with lapatinib, trastuzumab or both. Assays of receptor expression, phosphorylation, signalling and tumor growth were performed. Trastuzumab-dependent cellular cytotoxicity was measured with different levels of HER2 expression and doses of lapatinib. Results: Lapatinib treatment of HER2+ breast cancer cells inhibited HER2 phosphorylation, prevented ubiquitination and resulted in a marked accumulation of inactive receptors at the cell surface. By contrast, trastuzumab caused enhanced HER2 phosphorylation, ubiquitination and degradation of the receptor. By immunoprecipitation and computational protein modelling techniques we further demonstrated that the lapatinib-induced accumulation of HER2 lead to stabilization of inactive HER2 homo- and hetero-dimers. Accumulation of HER2 induced by lapatinib and downregulation of HER2 mediated by trastuzumab were also observed in vivo, where the combination of the two agents triggered complete tumor remission in all cases after 10 days of treatment. Lapatinib-induced accumulation of HER2 at the cell surface markedly enhanced trastuzumab-mediated ADCC. Conclusions: Lapatinib results in a marked accumulation of inactive HER2 receptors at the cell surface both in vitro and in vivo. This increase in receptors number at the cell surface enhances ADCC by trastuzumab. We propose that this is a novel mechanism that may be clinically relevant and exploitable in the therapy of patients with HER2+ tumors

Best of luck and Let us know how you do!

[Adriana Mangus]

Oncogene? Anyone knows the website, please. Thank you.

[runtolive]

adriana

here is a link to the old tras-dm1 study. click on the 40 site locations.. for one near you.. ucsf should be reopening with the newer trials shortly.. or call michele fernandez at genentech..

ucsf is not listed but we know they treat patients there..

http://www.clinicaltrials.gov/ct2/sh...ow_locs=Y#locn

run to live

[chrisy]

I was already on a trial at UCSF (tykerb + avastin) and progressed while on that trial...just as they were about to open the Trastuzumab-MCC-DM1 trial there. So for me it was a case of being in the right place at the right time. I will say that what has helped me most is I had a "regular" follow up with my 2nd opinion guru (Dr. Rugo at UCSF) so when I needed it, I had pretty good access. That was how I came to be under her care for the tykerb/avastin trial and now the DM1 trial.

If I remember, you are in Southern California, right? I know that other DM1 trials are getting ready to open, but I don't know where.
There is also some talk about trying to reopen the one I'm in (but I don't know what the status is on that, or if it's just a rumor).

If you have a good onc in your area, ask about the trials or as runtolive suggests, contact Genentech. Do not rely on the "list of locations" because it is NOT accurate - the trial I'm in has never updated the original 40 sites even after new sites were opened.

There is a lot of interest in this new drug - so there is a good chance there may be a study near you if you should need to make a change.

And by the way, DELIGHTED to see you are "still kicking"!

[SoCalGal]

Hi Esther-

I'm on Tykerb-herceptin and avastin. Dr Glasby at UCLA told me not to stop tykerb when I had progression on tykerb xeloda but to add in herceptin. He used the analogy of a road block - if some "cars" are getting by add to the road block don't remove it entirely. I'm hoping that sometime soon I can stop the avastin and just stay on herceptin-tykerb. (Or I would take a cure - either one).
xo Flori

[Believe51]

Trying to get my ammo ready because I do think we are going to try this combo next. We gamma-knifed 10 spots that are dying right now. We just found another brain met, tumor markers rising again.....think we have bone progression. Will know more after further testing.

What are your opinions for adding a chemotherapy element to this combo?? Flori, your opinion will be appreciated if you have a moment, as well as all responders. Thanks>>Believe51