I strongly recommend you read this article (even if you have to struggle a bit)
 

http://www.plosone.org/article/info%...l.pone.0039626

incredible advance in understanding and fabulous results even in Stage IV even with brain mets or leptomeningeal mets, whether ER+ or ER-

Hope this speeds up drug development and testing and leads to both cure/prevention!


Open Access
RESEARCH ARTICLE
Multiorgan Metastasis of Human HER-2+ Breast Cancer in Rag2−/−;Il2rg−/− Mice and Treatment with PI3K Inhibitor



Patrizia Nanni1, Giordano Nicoletti2, Arianna Palladini1, Stefania Croci1, Annalisa Murgo1, Marianna L. Ianzano1, Valentina Grosso1, Valeria Stivani1, Agnese Antognoli1, Alessia Lamolinara3, Lorena Landuzzi2, Emmanuelle di Tomaso4, Manuela Iezzi3, Carla De Giovanni1*, Pier-Luigi Lollini5
1 Section of Cancer Research, Department of Experimental Pathology, University of Bologna, Bologna, Italy, 2 Rizzoli Orthopedic Institute, Bologna, Italy, 3 Aging Research Centre, “G. D'Annunzio” University, Chieti, Italy, 4 Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts, United States of America, 5 Department of Hematology and Oncological Sciences, University of Bologna, Bologna, Italy
Abstract
In vivo studies of the metastatic process are severely hampered by the fact that most human tumor cell lines derived from highly metastatic tumors fail to consistently metastasize in immunodeficient mice like nude mice. We describe a model system based on a highly immunodeficient double knockout mouse, Rag2−/−;Il2rg−/−, which lacks T, B and NK cell activity. In this model human metastatic HER-2+ breast cancer cells displayed their full multiorgan metastatic potential, without the need for selections or additional manipulations of the system. Human HER-2+ breast cancer cell lines MDA-MB-453 and BT-474 injected into Rag2−/−;Il2rg−/− mice faithfully reproduced human cancer dissemination, with multiple metastatic sites that included lungs, bones, brain, liver, ovaries, and others. Multiorgan metastatic spread was obtained both from local tumors, growing orthotopically or subcutaneously, and from cells injected intravenously. The problem of brain recurrencies is acutely felt in HER-2+ breast cancer, because monoclonal antibodies against HER-2 penetrate poorly the blood-brain barrier. We studied whether a novel oral small molecule inhibitor of downstream PI3K, selected for its penetration of the blood-brain barrier, could affect multiorgan metastatic spread in Rag2−/−; Il2rg−/− mice. NVP-BKM120 effectively controlled metastatic growth in multiple organs, and resulted in a significant proportion of mice free from brain and bone metastases. Human HER-2+ human breast cancer cells in Rag2−/−;Il2rg−/− mice faithfully reproduced the multiorgan metastatic pattern observed in patients, thus allowing the investigation of metastatic mechanisms and the preclinical study of novel antimetastatic agents.

Re: I strongly recommend you read this article (even if you have to struggle a bit)
 

Hi Lani
Once again many thanks for the info. I have struggled through it a couple of times to try to grasp fully the implications. Does this mean they already have a drug that works very very well and could progress to human trials soon? Does this mean that it would be effective equally against hormone positive and negative tumours? Is there a realistic chance that this is our cure!
Thanks
Ellie

Re: I strongly recommend you read this article (even if you have to struggle a bit)
 

No, we don't even know if this drug is safe and effective in humans yet.

But the great news is for the first time they have what seems like a reasonable model of metastatic her2+ breast cancer--it is the metastases that kill, not the primary tumor. And they have a drug which crosses the blood brain barrier.

They may find they have to combine say herceptin, TDM-1 and/or pertuzumab with a PI3K inhibitor (as it is the PI3K pathway which often is responsible for antiher2 therapy resistance). For some it may end up being herceptin, TDM-1 and/or pertuzumab plus a Hsp90 inhibitor or plus an mTor inhibitor. But we have drugs in all these classes either in Stage II/III trials or already approved and now a way to see in real time and using human tumors (and in some cases the patients own immune system transplanted into the same mice) what works in what cases.

Again, I still feel serial bone marrow will also be helpful in this pursuit, but
this is a great leap forward in finding out how her2+ breast cancer develops (perhaps it takes both mutations AND loss/loss of function of B,T, and NK cells), how to best treat each of its subtypes, how to block its usual modes of escape and how to correctly dose and how long to treat with these agents.

This is really different from the NodSCID mice they have used before and the her2 transfected cell lines (extremely artificial constructs which may in no way behave like the real thing).

I expect it will speed things up remarkably--at least I hope so!

Re: I strongly recommend you read this article (even if you have to struggle a bit)
 

Thanks Lani for your very comprehensive reply.It is encouraging that we may already have these drugs so we don't need to 'reinvent the wheel'. Hopefully some drug consortium will now view this as a very good investment and pursue it's development
Ellie

Re: I strongly recommend you read this article (even if you have to struggle a bit)
 

I agree with Lani that this model will allow the pharmaceutical industry to have a map to test drugs. This is like having a map where there never was one before; a English/foreign language dictionary; or a pH meter to test for acidity. Without a good diagnostic system it is a guessing game. This is an extremely important break through. Hopefully this will shorten time to development of new treatments.

Re: I strongly recommend you read this article (even if you have to struggle a bit)
 

Thanks Lani!

It's exciting to see developments like this.

Re: I strongly recommend you read this article (even if you have to struggle a bit)
 

Lani,

Thanks so much for this and for all the research that you've brought to this group. I appreciate you a lot!

Idelle

Re: I strongly recommend you read this article (even if you have to struggle a bit)
 

Dear Lani,

Thank you so much for the info.

Re: I strongly recommend you read this article (even if you have to struggle a bit)
 

NVP-BKM120 was used at 50 mg/kg for the mice. For a 132 pound (60 kg) woman, this would scale to 3 gm per dose, four dose per week. I hope this is not too expensive and does not have any side effects at these doses. Also, it might be some time before it gets to clinical trials. TDM-1 and Pertuzumab are available for now, and these are good front line systems. If the new drug can be brought to market and is less expensive and has fewer side effects, this will be a great step forward. The mere fact that both a test model and a drug have made this progress should be inspirational for the people on this web, both the women with HER+, their family members, and their friends.

Re: I strongly recommend you read this article (even if you have to struggle a bit)
 

Once again / Lani YOU Rock! Feels like
you r an angel!

Thanks - Kim

Re: I strongly recommend you read this article (even if you have to struggle a bit)
 

Thanks so much, Lani!!! You are amazing! I printed this so I can read it later, with my companion dictionary!!!

Re: I strongly recommend you read this article (even if you have to struggle a bit)
 

Hi,

I just want to cry this disease has me confused. Right now I have 6 rounds of TCH with Herceptin as well as Herceptin every week between the TCH. Triple Positive, 1 cm tumor no node envolvement. Should I be taking the TCH? What is the prognosis of this early stage? I just don't know.

Thanks,

Mary Jo