her2+ bc cured in mice with gamma secretase inhibitor(already developed vs Alzheimers

[Lani]

Oncogene. 2011 Jun 13. doi: 10.1038/onc.2011.212. [Epub ahead of print]
Gamma-secretase inhibitors target tumor-initiating cells in a mouse model of ERBB2 breast cancer.
Kondratyev M, Kreso A, Hallett RM, Girgis-Gabardo A, Barcelon ME, Ilieva D, Ware C, Majumder PK, Hassell JA.
Source
Center for Functional Genomics, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Abstract
Human breast tumors comprise a minor sub-population of tumor-initiating cells (TICs), commonly termed cancer stem cells. TICs are thought to sustain tumor growth and to confer resistance to current anticancer therapies. Hence, targeting TIC may be essential to achieving durable cancer cures. To identify molecular targets in breast TIC, we employed a transgenic mouse model of ERBB2 breast cancer; tumors arising in this model comprise a very high frequency of TIC, which is maintained in tumor cell populations propagated in vitro as non-adherent tumorspheres. The Notch pathway is dysregulated in human breast tumors and overexpression of constitutively active Notch proteins induces mammary tumors in mice. The Notch pathway has also been implicated in stem cell processes including those of mammary epithelial stem cells. Hence, we investigated the potential that the Notch pathway is required for TIC activity. We found that an antagonist of Notch signaling, a gamma (γ)-secretase inhibitor termed MRK-003, inhibited the survival of tumorsphere-derived cells in vitro and eliminated TIC as assessed by cell transplantation into syngeneic mice. Whereas MRK-003 also inhibited the self-renewal and/or proliferation of mammosphere-resident cells, this effect of the inhibitor was reversible thus suggesting that it did not compromise the survival of these cells. MRK-003 administration to tumor-bearing mice eliminated tumor-resident TIC and resulted in rapid and durable tumor regression. MRK-003 inhibited the proliferation of tumor cells, and induced their apoptosis and differentiation. These findings suggest that MRK-003 targets breast TIC and illustrate that eradicating these cells in breast tumors ensures long-term, recurrence-free survival.Oncogene advance online publication, 13 June 2011; doi:10.1038/onc.2011.212.

PMID: 21666715

[Rich66]

You mean it's being prescribed or in trials for Alzheimers?

[Ellie F]

This trial was specific to her 2 breast cancer and targets stem cells Is it possible it may also work with other types of bc?

Hopefully it will work in humans not just our furry friends.

Next question is where can I get it!!!

Thanks for posting. We LOVE good news especially when it mentions 'CURE'

Ellie

[Lani]

It didn't mention cure and it said the effect was reversible, but it also described long-term recurrence-free survival.

The gamma-secretase inhibitors are only in AD trials, and in one neoadjuvant her2+ bc trials.

A new paper by Dr. Yarden of Israel seems to imply a combination of herceptin and a gamma secretase inhibitor could stop ADH from progressing to DCIS and to her2+ bc.

More to come.

[Lani]

Oncogene. 2011 Jul 11. doi: 10.1038/onc.2011.279. [Epub ahead of print]
Modeling ductal carcinoma in situ: a HER2-Notch3 collaboration enables luminal filling.
Pradeep CR, Köstler WJ, Lauriola M, Granit RZ, Zhang F, Jacob-Hirsch J, Rechavi G, Nair HB, Hennessy BT, Gonzalez-Angulo AM, Tekmal RR, Ben-Porath I, Mills GB, Domany E, Yarden Y.
Source
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
Abstract
A large fraction of ductal carcinoma in situ (DCIS), a non-invasive precursor lesion of invasive breast cancer, overexpresses the HER2/neu oncogene. The ducts of DCIS are abnormally filled with cells that evade apoptosis, but the underlying mechanisms remain incompletely understood. We overexpressed HER2 in mammary epithelial cells and observed growth factor-independent proliferation. When grown in extracellular matrix as three-dimensional spheroids, control cells developed a hollow lumen, but HER2-overexpressing cells populated the lumen by evading apoptosis. We demonstrate that HER2 overexpression in this cellular model of DCIS drives transcriptional upregulation of multiple components of the Notch survival pathway. Importantly, luminal filling required upregulation of a signaling pathway comprising Notch3, its cleaved intracellular domain and the transcriptional regulator HES1, resulting in elevated levels of c-MYC and cyclin D1. In line with HER2-Notch3 collaboration, drugs intercepting either arm reverted the DCIS-like phenotype. In addition, we report upregulation of Notch3 in hyperplastic lesions of HER2 transgenic animals, as well as an association between HER2 levels and expression levels of components of the Notch pathway in tumor specimens of breast cancer patients. Therefore, it is conceivable that the integration of the Notch and HER2 signaling pathways contributes to the e pathophysiology of DCIS