for those of you running out of options

[Lani]

this is still in mice and not yet approved, but may lead way to screen for similar compounds which are already approved


Clin Cancer Res. 2013 Apr 25. [Epub ahead of print]

Monoclonal antibody against the ectodomain of E-cadherin (DECMA-1) suppresses breast carcinogenesis: Involvement of the HER/PI3K/Akt/mTOR and IAP pathways.

Brouxhon SM, Kyrkanides S, Teng X, Raja V, O'Banion MK, Clark R, Byers SW, Silberfeld A, Tornos C, Ma L.
Source
Department of Emergency Medicine, Stony Brook University
.
Abstract
PURPOSE:
Although targeted therapies against HER2 have been one of the most successful therapeutic strategies for breast cancer, patients eventually developed acquired resistance from compensatory upregulation of alternate HERs and MAPK-PI3K/Akt/mTOR signaling. As, we and others, have shown that the soluble ectodomain fragment of E-cadherin (sEcad) exerts pro-oncogenic effects via HER1/2-mediated binding and activation of downstream pro-survival pathways, we explored whether targeting this ectodomain (DECMA-1 mAb) was effective in the treatment of HER2-positive breast cancers.
EXPERIMENTAL DESIGN:
MMTV-PyMT transgenic mice and HER2+/E-cadherin-positive MCF-7 and BT474 Trastuzumab-resistant (TtzmR) cells were treated with the DECMA-1 mAb. Antitumor responses were assessed by BrdU incorporation, apoptosis and necrosis. The underlying intracellular pro-oncogenic pathways were explored using subcellular fractionation, immunoprecipitation, fluorescence microscopy and immunoblotting.
RESULTS:
Treatment with DECMA-1 mAb significantly delayed tumor onset and attenuated tumor burden in MMTV-PyMT mice by reducing tumor cell proliferation and inducing apoptosis without any detectable cytotoxicity to mice or end-organs. In vitro, treatment of MCF-7 and BT474 TtzmR cells reduced proliferation and induced cancer cell apoptosis. Importantly, this inhibition of breast tumorigenesis was due to concomitant down-regulation, via ubiquitin-mediated degradation through the lysosome and proteasome pathways, of all HER family members, components of downstream PI3K/Akt/mTOR pro-survival signaling and suppression of IAPs.
CONCLUSIONS:
Our results establish that the E-cadherin ectodomain-specific mAb DECMA-1 inhibits Ecad+/HER2+ breast cancers by hindering tumor growth and inducing apoptosis via down-regulation of key oncogenic pathways involved in Trastuzumab resistance, thereby establishing a novel therapeutic platform for the treatment of HER2+ breast cancers.
PMID: 23620408 [PubMed - as supplied by publisher]

[CoolBreeze]

Doesn't it take years to get to humans? Maybe for those of us running out of options shouldn't be included in this? Because once we run out, we don't usually have long....

[Lani]

Most recently, once they find the pathway affected they develop a monoclonal antibody (which takes years to get tested and approved) but also they do a screen of all compounds every developed by drug companies (whether they worked for the problem they were developed against or not as well as other
compounds (from fruits, vegetables, fungi) in a system that screens thousands upon thousands of compounds quickly. It is not unusual it seems for them to find a drug/other compound which has already been approved that has a similar action.

That is what I am hoping for here. If you don't know the pathway you don't know what to look for.

[NEDenise]

And...if you don't know Lani...you don't even know these things are out there!!
Thanks for keeping us all in the loop, my friend!

Can't tell you how much I appreciate your sifting through all thats out there to find what we need. You rock!

Denise

[dearjilly]

and I! Thank you Lani! xoxo
oh and the mice, thanks mice.