Gene Profiling Predicts Resistance To Breast Cancer Drug Herceptin
 

http://www.medicalnewstoday.com/medi...p?newsid=63485

The below is a copy paste from Wikipedia...INTERESTING:

"Inhibitors of IGF-1R
Due to the similarity of the structures of IGF-1R and the insulin receptor, especially in the regions of the ATP binding site and tyrosine kinase regions, synthesising selective inhibitors of IGF-1R is difficult. Prominent in current research are two main classes of inhibitor: 1) Tyrphostins such as AG538 and AG1024. These are in early pre-clinical testing. They are not thought to be ATP-competitive, although they are when used in EGFR as described in QSAR studies. These show some selectivity towards IGF-1R over IR. 2) Pyrrolo[2,3-d]-pyrimidine derivatives such as NVP-AEW541, which show far greater (100 fold) selectivity towards IFG-1R over IR."



Rhonda

Thanks for all parts of your post, Rhonda.

Is the comment at the beginning of the article true?

"Using gene chips to profile tumors before treatment, researchers at Harvard and Yale Universities found markers that identified breast cancer subtypes resistant to Herceptin, the primary treatment for HER2-positive breast cancer."

The article says the samples they used were exposed to both trastuzumab and another chemo. So would the result be the same if they had only used trastuzumab and not the other chemo? In other words, do the markers geuinely ID the subtypes that are resistant to Herceptin, PERIOD, or do they ID the subtypes that are resistant if the tissue is exposed to the other chemo or the other chemo plus trastuzumab?

AlaskaAngel

just read this today--lapatinib tends to work on EGFR, IGFR simultaneously
 

and reverse herceptin resistance. It was done on SKBr3 (her2+er-) but in its discussion opined that triple positive bc would probably need treatment with an her2inhibitor, IGFR inhibitor and ER inhibitor(?lapatinib+AIor faslodex?):


http://mct.aacrjournals.org/cgi/content/full/6/2/667


Lapatinib induces apoptosis in
trastuzumab-resistant breast cancer
cells: effects on insulin-like growth
factor I signaling

Rita Nahta, F. Esteva, et al

Abstract
The majority of breast cancer patients who achieve an initial therapeutic response to the HER2-targeted
antibody trastuzumab will show disease progression within 1 year. Thus, the identification of novel agents
that effectively inhibit survival of cancer cells that have progressed on trastuzumab is critical. In the current
study, we show that the dual epidermal growth factor receptor (EGFR)/human EGFR-2 (HER2) kinase
inhibitor lapatinib induces apoptosis in trastuzumab-resistant cells derived from the HER2-overexpressing
SKBR3 breast cancer line. Lapatinib inhibited EGFR and HER2 signaling in resistant cells, blocking
activation of downstream Akt, mitogen-activated protein kinase, and S6 kinases and inducing expression of
p27kip1. Importantly, lapatinib also inhibited insulin-like growth factor I (IGF-I) signaling and growth-
promoting effects in parental and resistant cells, and the cytotoxic effects of lapatinib were further enhanced
by the IGF-I receptor–blocking antibody IR3. As increased IGF-I receptor signaling has been implicated in
trastuzumab resistance, our data strongly support further study of lapatinib as a potential therapeutic in
breast cancers that have progressed on trastuzumab. [Mol Cancer Ther 2007;6(2):667–74]

Herceptin after progression
 

A section of the article reported by Rhonda appears to give support to some of the oncs who favor continuing Herceptin treatment after resistance develops:

They also discovered that resistant tumors continue to over-express the HER2 growth factor protein -- an important finding given that many scientists had thought that loss of HER2 was likely responsible for Herceptin resistance.

"Herceptin has revolutionized the care of HER2-positive breast cancer for many patients, but unfortunately, not for some. This work demonstrates that digging deeper into the molecular subtypes of these tumors helps us understand why some tumors are resistant and may point to ways to remedy that," said the study's lead author, Lyndsay Harris, M.D., associate professor and Director of the Breast Cancer Disease Unit at Yale University Medical Center.

If additional studies validate these findings, it may be possible to select those patients that will be resistant to Herceptin and treat them with additional drugs to restore Herceptin sensitivity, according to Harris. "Our goal is to see what the tumor tells us before any treatment starts and tailor therapy accordingly," she said.

A little off the main topic here
 

but this same article also contains the following information:

"Although the study was not designed to look at outcome, the researchers determined that 42 of 48 patients had a clinical response (16 complete responses and 26 partial responses) from the neoadjuvant treatment, and five patients experienced cardiotoxicity."

The chemo used in the study was Navelbine, which was chosen "because we found it has few side effects," according to the researchers.

I point this out only because I believe the cardiotoxicity associated with Herceptin is much higher than we are led to believe, and it is interesting to see that demonstrated here.

Hopeful

hot-off-the press: her2+ breast cancer recurrence after vaccination
 

with her2 vaccines in rats seems to be due to "survival of the fittest" of clonogenic group of cells which have epigenetically silenced her2 (methylation of gene which essentially hides it from being transcribed and made into the gene product). Thus her2 doesn't have to be lost to be "invisible" to herceptin or her2vaccines

1: Eur J Immunol. 2007 Feb 16; [Epub ahead of print] Links
HER-2/neu antigen loss and relapse of mammary carcinoma are actively induced by T cell-mediated anti-tumor immune responses.

Kmieciak M,
Knutson KL,
Dumur CI,
Manjili MH.
Department of Microbiology & Immunology , VCU School of Medicine, Massey Cancer Center, Richmond, VA.
Induction of tumor-specific immune responses results in the inhibition of tumor development. However, tumors recur because of the tumor immunoediting process that facilitates development of escape mechanisms in tumors. It is not known whether tumor escape is an active process whereby anti-tumor immune responses induce loss or downregulation of the target antigen in the antigen-positive clones. To address this question, we used rat neu-overexpressing mouse mammary carcinoma (MMC) and its relapsed neu antigen-negative variant (ANV). ANV emerged from MMC under pressure from neu-specific T cell responses in vivo. We then cloned residual neu antigen-negative cells from MMC and residual neu antigen-positive cells from ANV. We found marked differences between these neu-negative clones and ANV, demonstrating that the residual neu-negative clones are probably not the origin of ANV. Since initial rejection of MMC was associated with the presence of IFN-gamma-secreting T cells, we treated MMC with IFN-gamma and showed that IFN-gamma could induce downregulation of neu expression in MMC. This appears to be due to methylation of the neu promoter. Together, these data suggest that neu antigen loss is an active process that occurs in primary tumors due to the neu-targeted anti-tumor immune responses.
PMID: 17304628 [PubMed - as supplied by publisher]

Hopeful,
You are quite right about the risk of cardiotoxicity of Herceptin which was probably under reported in the phase 3 clinical trials published in 2005 (as a result of the preselection of patients without cardiovascular problems at baseline).
However some patients,among them some members of this forum, have been on Herceptin for up to 8 years.
So if the drug can be tolerated by some, they may even continue taking it after progression if it shows they can still benefit from it as found possible in these links I posted in an other thread dealing with the pros & cons:

The links below relate to the medical argumentation for or against continued Herceptin treatment after progression. It should be noted that the commentaries were made at different dates. So it is possible some of their authors might have changed their mind to some extent with advancing knowledge.
FOR:
http://www.abstracts2view.com/sabcs...S06L_1099&terms=
[2064] Favourable effect of continued trastuzumab treatment in metastatic breast cancer patients: results from the French Hermine cohort study. SABCS Dec 2006

http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_docsum
Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression
J Clin Oncol. 2004 Mar 15
One of the researchers of this paper is no other than DJ Slamon the inventor of Herceptin.

AGAINST:
http://www.jco.org/cgi/content/full/23/12/2868
CORRESPONDENCE In Reply: Gabriel N. Hortobagyi
Journal of Clinical Oncology, Vol 23, No 12 (April 20), 2005
The author is one of the Herceptin clinical trial investigators

http://theoncologist.alphamedpress....t/full/11/4/318 april 2006
Outcome of Patients with HER2-Positive Advanced Breast Cancer Progressing During Trastuzumab-Based Therapy

Wow! Thanks for the research
 

heblaj01,

It is terrific having all this information in one place. Thank you very much.

Hopeful

Inhibiting the IGR, one of the components that cause Herceptin resistance...
 

Wow, what a bad player the IGR is--researchers need to develop drugs against it. In the meantime, we must all limit our carbohydrate intake and exercise in order to help decrease the IGR naturally.

Rhonda, do you have any natural IGR inhibitor suggestions?

Robin...
 

I did stumble across a few, but right now have a bad cold (this has only happened to me once before since dx when my fruit and veg intake was down due to traveling and Tony and I JUST got back from 4 days at Disney so, diet hasn't been the best and I just bottomed out...I'm not kidding, I can tell JUST by my intake and output how I am going to feel) and don't feel like researching, will get back to you later. Take care and God bless.

Rhonda

Stumbled Across this
 

Thought it might add to the discussion:

http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum

Hopeful

Turmeric
 

Turmeric inhibits IGF-1R

http://www.leaonline.com/doi/abs/10....27914nc5502_10

Rhonda

Also Genistein (isoflavones) inhibits IGF-1R
 

http://www.ihop-net.org/UniPub/iHOP/bng/121908.html

http://en.wikipedia.org/wiki/Genistein

Rhonda

Hmm...
 

http://www.ncbi.nlm.nih.gov/entrez/q...&dopt=Abstract

Rhonda