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Old 09-09-2012, 11:15 AM   #1
Lani
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and what have your HERs been up to? Scientist ID many more interactions of her1-4.

As I have previously intimated, her3 may hold the key to her2 resistance to anti-her2 agents
.
Dr. Ullrich of the Max Planck Institute who WAS the inventor of herceptin ( during his days at Genentech) was honored at AACR annual meeting five or so yrs ago in San Diego with lifetime achievement award (for the development work on herceptin, among other things) and his acceptance speech was all about how he thought her3 was the key to curing her2+ cancers

Who was the father of herceptin? It depends how you define that. Not to take glory away from Dr. Slamon, but without Dr Ullrich there would be no herceptin.

In any case, they have a new technology which has allowed them to find many more interactions of her1,2,3, and 4 and that should help find many more treatments for those for whom herceptin and/or lapatinib are not enough.

***

Study points to new target for cancers resistant to Iressa and Herceptin
[University of Chicago]

A more-sensitive method to analyze protein interactions has uncovered a new way that cancer cells may use the cell-surface molecule HER3 to drive tumor progression following treatment with HER1 and HER2 inhibitors.

The HER family of receptors has been linked to the development of a wide variety of human cancers. HER1 inhibitors such Iressa and HER2 inhibitors such as Herceptin are commonly used in the clinic for treatment of small cell lung carcinoma and breast cancer. A recent study suggests that HER3 levels can predict reduced breast cancer survival. However, HER3 inhibitors are not currently used in treatment.

Although the scientific basis for HER3's association with reduced patient survival was previously unclear, this study shows that HER3 could be up to 10 times more effective than HER2 in recruiting accessory proteins that drive the rapid proliferation, enhanced survival and distant spread of cancers, which are hallmarks of malignancy.

The finding, published Sept. 4 in the journal PLOS ONE, came from one of the largest-ever quantitative analyses of binary-protein interactions to date. Researchers from the University of Chicago identified more than 1,000 new interactions for the four members of the HER family of growth-factor receptors, with the largest number of new additions linked to HER3.

"Our high-throughput system for measuring interactions between proteins found nearly 1,200 completely new interactions," said study author Richard B. Jones, PhD, assistant professor in the Ben May Department for Cancer Research and the Institute for Genomics and Systems Biology at the University of Chicago. "Most of them were comparatively weak interactions relative to those previously known, but they were still bona fide, tested and confirmed biochemical interactions."

HER2 has long been a poster child for translational research, a laboratory discovery that led to the drug Herceptin (trastuzumab), which worked wonders in clinical trials. Herceptin increased survival for women with aggressive breast cancers by 33 percent. An editorial in the New England Journal of Medicine described the results as "simply stunning . not evolutionary but revolutionary."

Amplification, or over-expression, of HER2 occurs in approximately 30 percent of breast cancer cases. It is associated with more aggressive disease, worse prognosis and increased recurrence. Although Herceptin typically extends life considerably, many patients eventually develop resistance to the drug, so alternative treatments are needed, and HER3 may represent a prime target.

"HER2 overexpression results from an obvious chromosomal aberration that is easily appreciated by standard clinical methods," Jones said. "HER3's role is less blatant. But the sheer volume of newly uncovered connections and the function of the proteins with which it connects lead us to believe that it is likely to be an important driver of cancer when its cousins, the EGFR or HER2, get shut down by existing clinical therapies."

"HER3 is better than even HER2 at recruiting the accessory players in cancer, such as SRC, and breast tumor kinase," he said. "When cancer grows resistant to treatments such as Herceptin, we believe that HER3 has the potential to assume the new disease-promoting role by actively working with other cancer promoting players that are not affected by the therapy."

This study, relying on newer research tools, builds substantially on a 2006 report by Jones and his former colleagues at Harvard University. They had modified recently developed gene array technology, now standard for genomics, to apply it to protein-omics — a new subclass of the field of proteomics that seeks to leverage the tools of systems biology to place massive protein data sets into biological context.

"That protein microarray method worked really well for identifying the strongest interactors of the HER receptors," Jones said, "but over time we became increasingly aware that we were missing the majority of potentially important protein-protein interactions due to their weaker affinity for the receptors."

So they developed a new method that is 10 to 50 times more sensitive. This enabled them to pick up many interactions that the older system missed because they were too weak or short lived.

Some biological interactions "stick like glue," Jones said. "They need to hold on to their neighbors to make things happen."

Others are more fleeting. A protein finds its target, holds on long enough to attach a chemical group, which activates the protein, then sends it on its way. These turned-on proteins "go to the nucleus or other parts of the cell where they deliver instructions," Jones said. "In cancer, those instructions might be to grow aberrantly and autonomously from their neighbors."

"HER2 mostly plays tackle," Jones said. "HER3 plays touch, but it can touch a lot of other players that may substantially contribute to tumor progression and metastasis."

The new technique, which Jones' team labeled "comprehensive binary interaction mapping via florescence polarization," is far more sensitive and specific than protein microarrays: 83 percent of the 1,405 unique biological interactions identified for the four members of the HER group were completely novel, and 100 previously suspected interactions were ruled out. The results could trigger drastic systems-level revisions of the understanding of the roles of these important proteins.

Despite considerable automation, the process was neither simple nor quick. "This study required about six years," Jones said. "First we had to express about 100 proteins from humans in the context of bacteria, purify them in the lab, and then expose them in solution to the nearly 100 unique potential interaction modules of each of the HER family proteins."

At that point, the robot, an automated cell-screening device at the University of Chicago Cell Screening Center known affectionately as Dot, stepped in. In a series of 12-hour robotic pipetting runs, Dot completed "about a half million pipetting events and measured the large matrix of interactions," Jones said.

Because the technique was new, the team was eager to verify the results. They divided the 1,200 protein-peptide connections into strong, medium and weak interactions and then tested the ability of other proteins with stronger interactions to displace the connection.

"Typically, in the field of biochemistry, more credence has been given to tight interactions, which are easier to identify and verify," Jones said. "However, the gold standard for authenticity of true and specific interactions is a competition assay. If a protein is really interacting, you should be able to compete it away from its partner by adding a competitive protein, like a baseball in the pocket of a glove would block another ball from entering. We were able to validate a representative subset of the interactions this way."

"Many protein interactions with known biological consequences exist that interact at affinities lower than those that we measured in this assay," he said. "This bolsters our confidence in the potential relevance of these interactions to biology. We are excited to now begin to test their relevance in cancer cells."

The National Institutes of Health, the Cancer Research Foundation, and the Illinois Department of Public Health funded the study. Additional authors include Ronald Hause Jr., Kin Leung, John Barkinge and Mark F. Ciaccio of the University of Chicago, and Chih-pin Chuu, now at the National Health Research Institutes in Miaoli, Taiwan.

OPEN ACCESS: Comprehensive Binary Interaction Mapping of SH2 Domains via Fluorescence Polarization Reveals Novel Functional Diversification of ErbB Receptors
[Public Library of Science: One]

First-generation interaction maps of Src homology 2 (SH2) domains with receptor tyrosine kinase (RTK) phosphosites have previously been generated using protein microarray (PM) technologies. Here, we developed a large-scale fluorescence polarization (FP) methodology that was able to characterize interactions between SH2 domains and ErbB receptor phosphosites with higher fidelity and sensitivity than was previously achieved with PMs. We used the FP assay to query the interaction of synthetic phosphopeptides corresponding to 89 ErbB receptor intracellular tyrosine sites against 93 human SH2 domains and 2 phosphotyrosine binding (PTB) domains. From 358,944 polarization measurements, the affinities for 1,405 unique biological interactions were determined, 83% of which are novel. In contrast to data from previous reports, our analyses suggested that ErbB2 was not more promiscuous than the other ErbB receptors. Our results showed that each receptor displays unique preferences in the affinity and location of recruited SH2 domains that may contribute to differences in downstream signaling potential. ErbB1 was enriched versus the other receptors for recruitment of domains from RAS GEFs whereas ErbB2 was enriched for recruitment of domains from tyrosine and phosphatidyl inositol phosphatases. ErbB3, the kinase inactive ErbB receptor family member, was predictably enriched for recruitment of domains from phosphatidyl inositol kinases and surprisingly, was enriched for recruitment of domains from tyrosine kinases, cytoskeletal regulatory proteins, and RHO GEFs but depleted for recruitment of domains from phosphatidyl inositol phosphatases. Many novel interactions were also observed with phosphopeptides corresponding to ErbB receptor tyrosines not previously reported to be phosphorylated by mass spectrometry, suggesting the existence of many biologically relevant RTK sites that may be phosphorylated but below the detection threshold of standard mass spectrometry procedures. This dataset represents a rich source of testable hypotheses regarding the biological mechanisms of ErbB receptors.
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Old 09-09-2012, 12:09 PM   #2
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Re: and what have your HERs been up to? Scientist ID many more interactions of her1-4

Ok, so how to target her3???
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9/2004 Diag: Stage IV extensive liver mets (!) ER/PR- Her2+++
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04/05 - 4/07 Herception every 3 wks, Continue NED
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02/10 Continue NED. 5/10 9/10 Scans NED 10/10 Scans NED
12/10 Scans not clear....4/11 Scans suggest progression 6/11 progression confirmed in liver
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11/12 Poops! progression in liver, Stop Perjeta/Taxo/Herc
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Old 09-09-2012, 12:29 PM   #3
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Re: and what have your HERs been up to? Scientist ID many more interactions of her1-4

Guess whatever that targets PI3K will have some effect on Her3... (?) [http://her2support.org/vbulletin/showthread.php?t=52707&highlight=PI3K]

Biochem J. 2012 Aug 2. [Epub ahead of print]
HER3 signaling is regulated through a multitude of redundant mechanisms in HER2-driven tumor cells.

Amin DN, Sergina N, Lim L, Goga A, Moasser MM.
Abstract

HER2-amplified tumors are characterized by constitutive signaling via the HER2-HER3 co-receptor complex. While phosphorylation activity is driven entirely by the HER2 kinase, signal volume generated by the complex is under control of HER3 and a large capacity to increase its signaling output accounts for the resiliency of the HER2-HER3 tumor driver and accounts for the limited efficacies of anti-cancer drugs designed to target it.

Here we describe deeper insights into the dynamic nature of HER3 signaling. Signaling output by HER3 is under several modes of regulation including transcriptional, post-transcriptional, translational, post-translational, and localizational control. These redundant mechanisms can each increase HER3 signaling output and are engaged in various degrees depending on how the HER3-PI3K-Akt-mTor signaling network is disturbed.

The highly dynamic nature of HER3 expression and signaling, and the plurality of downstream elements and redundant mechanisms that function to ensure HER3 signaling throughput identify HER3 as a major signaling hub in HER2-amplified cancers and a highly resourceful guardian of tumorigenic signaling in these tumors.
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Old 09-09-2012, 12:59 PM   #4
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Re: and what have your HERs been up to? Scientist ID many more interactions of her1-4

"Researchers from the University of Chicago identified more than 1,000 new interactions for the four members of the HER family of growth-factor receptors, with the largest number of new additions linked to HER3."

The above quote from the article contains staggering information.

With so many interactions, no wonder it has been so difficult to pinpoint some reasonabe explanation for development of drug resistance OR just plain "the drug does not work for some patients."

Lani - thank you for posting this breakthrough information.
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Old 09-10-2012, 03:06 AM   #5
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Re: and what have your HERs been up to? Scientist ID many more interactions of her1-4

Lani
As ever thanks for posting. As Steph says this is staggering. I don't know how to feel, whether happy with progress or anxious that the task seems HUGE!
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Old 09-10-2012, 05:53 AM   #6
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Re: and what have your HERs been up to? Scientist ID many more interactions of her1-4

Well let's hope they create a drug soon.
Dr Slamon is still my hero, he persevered when Genetech didn't want to pay anymore and raised the money to finish his study. Without him, there would be no Herceptin, he finished the job and thanks to Lilly Tartikoff. Genetech had given up on it. Genetech made a few bucks from Herceptin though. I don't begrudge Genetech the money they made and make but glad there was an outsider on the case or we still wouldn't have it. God bless those obsessive, selfless researchers, may they always find a guardian angel to finance them.
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Old 09-10-2012, 01:41 PM   #7
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Re: and what have your HERs been up to? Scientist ID many more interactions of her1-4

that is why I would probably call Dr Slamon the father of herceptin (responsible for its birth) rather than the inventor

Dr. Ullrich left Genentech many years ago. I do not know why, Maybe he too disagreed with their behavior

Unfortunate, Genentech is now part of an enormous multinational pharma so all the more difficult to influence.

As I said I do not want to detract from Dr Slamon in any way. Just pointing out whom the cancer researchers honor as the "inventor" and that they felt this was only one of many groundbreaking discoveries on his part. Should really try to look up what else he has done, because they felt this was just one of truly many discoveries that turned science on its head.
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Old 09-10-2012, 03:33 PM   #8
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Re: and what have your HERs been up to? Scientist ID many more interactions of her1-4

All the more reason why access to Pertuzumab (blocking HER2 pairing with other proteins in the HER family) needs to be widened beyond it's current frontline approval!
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Old 09-10-2012, 03:34 PM   #9
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Re: and what have your HERs been up to? Scientist ID many more interactions of her1-4

Dr. Osborne and his research team at Baylor in Houston have been trying to answer the Her 3 question for at least a few years... working hard on this. Steph's comments are clear and correct! "Staggering information".
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Old 09-10-2012, 04:15 PM   #10
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Re: and what have your HERs been up to? Scientist ID many more interactions of her1-4

I've met Dr. Jones! Our Y-Me of Chicago (no relation to the group that closed it's doors) has hosted a softball tournament for the past 18 years. The money raised has funded THREE bc research trials at the University of Chicago. During last years tournament, Dr. Jones came out and talked during the survivors game. He gave a great talk about how thankful they were for the funding and how there were new discoveries. He was thanked by many of us survivors and I think he was quite moved to put a face to his research.
Lani, is there a link to this article? I would like to post it on their facebook page.
Ok, why won't my bold turn off? haha! So sorry!
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Old 09-10-2012, 06:40 PM   #11
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Re: and what have your HERs been up to? Scientist ID many more interactions of her1-4

I remain terrible at linking

I googled PLOSone and checked off the oncology box and entered ERBB into the search box and came up with, among others:


Comprehensive Binary Interaction Mapping of SH2 Domains via Fluorescence Polarization Reveals Novel Functional Diversification of ErbB Receptors
Ronald J. Hause, Kin K. Leung, John L. Barkinge, Mark F. Ciaccio, Chih-pin Chuu, Richard B. Jones
Novel Functional Diversification of ErbB Receptors SH2 Domain Recruitment by ErbB Receptors Ronald ... Comprehensive Binary Interaction Mapping of SH2 Domains via Fluorescence Polarization Reveals Novel Functional Diversification of ErbB Receptors ... between SH2 domains and ErbB receptor phosphosites
PLoS ONE: Research Article, published 04 Sep 2012
10.1371/journal.pone.0044471
Views: 475Citations: NoneBookmarks: None


If you put Dr. Barkinge's name into the search box after googling Entrez pubmed this should come up and it is a free article.

Someone better than me at creating links--- please do so! It is not my forte (can't even find the right accent key!)
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Old 09-11-2012, 01:40 PM   #12
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Re: and what have your HERs been up to? Scientist ID many more interactions of her1-4

Thank you Lani!
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Old 08-23-2013, 11:37 AM   #13
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Re: and what have your HERs been up to? Scientist ID many more interactions of her1-4

Dr. Richaed Jones will once again be in attendance at this years Y-ME softball tournament. All funding from the event will be going to Dr. Jones and his research. It's not often one of us gets to meet one of the researchers, so if there is anything you would like me to ask, please let me know. Of course, the question of 'so, when will you find a cure?' will most likely be asked by many of the women there.

This women's softball tournament was started 19 years ago by a bc survivor who wanted to make a differnce. The first couple of years they didnt have enough 'survivors' to play in the 2 inning game and ceremony. Sadly, there are now more than enough to man two teams and all of these ladies are neighborhood gals. This little tournament has grown through the years, resulting in 3 completely funded trials at the University of Chicago. UofC was also a hospital where Dr. Slamon walked the halls!

So, when I shake Dr. Jones' hand and look him in the eye, I will tell him...Thank you from all of us HER2 gals.
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Old 08-23-2013, 03:00 PM   #14
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Re: and what have your HERs been up to? Scientist ID many more interactions of her1-4

This work is really interesting. Her3 testing is not done that frequently. It would be interesting to determine if this is why certain treatments worked with Nina and others did not.
By the way, there are as many details on the development of Herceptin as there are people telling them. Some of the work that I did in the 1980s helped make this drug available at clinical and commercial scale. People I know at Genentech at the bench scale did incredible things to get the drug available for the clinical trials. Growing the cells, producing the Monoclonal Antibodies so they were not rejected by patients (resulting in only three injections before the patient had shock symptoms), purifying them so they did not pick up endotoxin from processing, and freeze drying them so they could have a storage time of more than two weeks were all done by people who received no credit for their work. I know these people and they are proud of their work on this drug. I know women that were part of the testing through the military (including my mother) for this drug. I know the people doing these same tasks for the current drugs going into clinical trials and manufacturing. There is often the General McAurther's who are cited as the leaders, the thing is that the men and women who do the work to get the drug to market, who find out the reasons why the equipment needs to be changed, and who are working through the night to repair a critical piece of equipment so the patient can be treated are there as well. I tend to be one of those people and appreciate the masses rather than the figurehead.
I know more than I can write about concerning most drugs and many clinical trials. The pharma community of the US is second to none in terms of the development of drugs and the safe production of drugs. I am proud to be part of that community.
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Old 08-23-2013, 03:51 PM   #15
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Re: and what have your HERs been up to? Scientist ID many more interactions of her1-4

Glad you found this old post of mine.

The efficacy of pertuzumab speaks to the importance of her3 in her2+ breast cancer

There are so many to thank for developing, testing, manufacturing, even figuring out safe transporting and storing these drugs
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Old 08-23-2013, 04:00 PM   #16
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Re: and what have your HERs been up to? Scientist ID many more interactions of her1-4

The worker bees are most always out of the limelight/spotlight, but I have had the wonderful opportunity to meet many of them both at the AACR (American Academy of Cancer Researchers) conferences and the Breast Cancer symposiums in San Antonio. They come out to interact with each other and even take the time to visit the booths of the patient advocate groups.

These researchers never have the chance to meet the actual patients and show very keen interest in each of our individual stories.

Did I read the NICE in Great Britain is NOT approving Pertuzumab?
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"When I hear music, I fear no danger. I am invulnerable. I see no foe. I am related to the earliest times, and to the latest." H.D. Thoreau
Live in the moment.

MY STORY SO FAR ~~~~
Found suspicious lump 9/2000
Lumpectomy, then node dissection and port placement
Stage IIB, 8 pos nodes of 18, Grade 3, ER & PR -
Adriamycin 12 weekly, taxotere 4 rounds
36 rads - very little burning
3 mos after rads liver full of tumors, Stage IV Jan 2002, one spot on sternum
Weekly Taxol, Navelbine, Herceptin for 27 rounds to NED!
2003 & 2004 no active disease - 3 weekly Herceptin + Zometa
Jan 2005 two mets to brain - Gamma Knife on Jan 18
All clear until treated cerebellum spot showing activity on Jan 2006 brain MRI & brain PET
Brain surgery on Feb 9, 2006 - no cancer, 100% radiation necrosis - tumor was still dying
Continue as NED while on Herceptin & quarterly Zometa
Fall-2006 - off Zometa - watching one small brain spot (scar?)
2007 - spot/scar in brain stable - finished anticoagulation therapy for clot along my port-a-catheter - 3 angioplasties to unblock vena cava
2008 - Brain and body still NED! Port removed and scans in Dec.
Dec 2008 - stop Herceptin - Vaccine Trial at U of W begun in Oct. of 2011
STILL NED everywhere in Feb 2014 - on wing & prayer
7/14 - Started twice yearly Zometa for my bones
Jan. 2015 checkup still shows NED
2015 Neuropathy in feet - otherwise all OK - still NED.
Same news for 2016 and all of 2017.
Nov of 2017 - had small skin cancer removed from my face. Will have Zometa end of Jan. 2018.
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Old 08-23-2013, 05:01 PM   #17
Lani
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Join Date: Mar 2006
Posts: 4,778
Re: and what have your HERs been up to? Scientist ID many more interactions of her1-4

http://www.breakthrough.org.uk/news/...rough-responds
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