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Old 04-28-2015, 10:35 AM   #1
Lani
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Join Date: Mar 2006
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Thumbs up a cure for her2+ BCs--by making sure the puppy never gets born!

perhaps I should call it a cure/prevention.... if you prevent the causative switch from causing her2+ bd (birth of puppy) there is no puppy to escape to try to chase the squirrels!



works better than combo of herceptin, pertuzumab & cetuximab as the puppy never gets born in the first place rather than has to be contained sucessfully by being locked in the house by closing the front door, the back door and the window so it can't get out to chase the squirrels.



This is HUGE!(not just blocking the receptors so ligands cannot bind but preventing dimerization (the "holding of hands" of different her2s,her2s with her3s,her4s and egfrs) so the pathway never gets activated
ie those with the hands cannot join together create something greater than themselves & be able to to wreak havoc...

(((my "puppy" analogy posted previously:
Cancer is like a puppy dog that wants to get out of the house to chase the squirrels. Herceptin is like locking the front door. They puppy may learn it is possible to get out to play with the squirrels by going out the backdoor instead (eg, using her3, EGFR, IGFR, ER, etc paths to escape the blockade of the her2 pathway). Giving chemo is often like accelerating the aging of the puppy. It gets taller and able to jump on the dresser and jump out the window!!

For Stage IVs, it is usually just a question of what they will add next to herceptin if monotherapy is inssufficient to keep it from progressing(like which window/door to close in addition in the case of the puppy) )))




PUBLIC RELEASE: 27-APR-2015
Mayo Clinic-led research team identifies master switch for cancer-causing HER2 protein
MAYO CLINIC

SHARE PRINT E-MAIL
ROCHESTER, Minn. -- Herceptin has been touted as a wonder drug for women with HER2-positive breast cancer, an aggressive form of the disease that is fueled by excess production of the HER2 protein. However, not all of these patients respond to the drug, and many who do respond eventually acquire resistance.

A team of researchers led by Mayo Clinic has found a promising way to circumvent this obstacle. They identified a small site in the HER2 protein that enables it to form a molecular switch that sets off a cascade of events that turn normal cells cancerous. The researchers showed that disrupting this site can stem the growth of breast cancer cells, even more effectively than drugs currently used in the clinic. Their study is published in the Journal of the National Cancer Institute.

"This study is the first to look at the specific sequences for dimerization of HER2 as a possible anti-cancer target," says the study's senior author Ruth Lupu, Ph.D., a professor of experimental pathology and laboratory medicine and biochemistry and molecular biology at Mayo Clinic. "This finding could be beneficial not only for breast cancer, but also for other cancers with abnormal HER2 levels, such as ovarian, stomach and prostate cancer."

MULTIMEDIA ALERT: Video and audio are available for download on the Mayo Clinic News Network.

One in every five breast cancers is HER2-positive, meaning that they have too many copies of the HER2 gene and/or produce too much of its product, the human epidermal growth factor receptor 2 (HER2) protein. A receptor like HER2 sits idle on the surface of the cell, becoming active only after pairing up with itself or other members of the protein family. These pairings create a kind of molecular key that opens up communication channels into the cell for stimulating proliferation and growth. When there is too much HER2 around, the protein pairs up even when it should not and that sends in a constant stream of signals telling the cell to grow out of control.

The discovery of HER2 and its role in breast cancer has led to the development of several therapies that specifically target its ability to transform cells. Trastuzumab (known commercially as Herceptin), pertuzumab and cetuximab have together significantly extended the lives of women with HER2-positive breast cancer. But none of the treatments has specifically targeted the ability of HER2 cells to join together or with other proteins, an essential first step in tumor growth.

Dr. Lupu hypothesized that HER2 activation occurs through a "functional site," a section of protein that is ultimately responsible for forming pairs with itself or other proteins of the same receptor family. If such a site exists, then blocking it would deactivate HER2, stopping tumor growth and metastasis. Dr. Lupu and her colleagues studied the protein sequence of HER2 and found a region that appeared to be involved in its dimerization.

They introduced a series of deletions into this region and eventually zeroed in on a section that contained just a short stretch of 16 amino acids, the building blocks of proteins. The researchers showed that unlike the wild-type HER2, a mutant protein that was missing this short sequence could not transform normal cells into cancer. Most importantly, when they added this mutant protein to HER2-positive breast cancer cells they showed that it halted the growth of these cells, overcoming the molecular makeup that made them aggressive. At the same time, they treated HER2-positive cells with the drugs trastuzumab, pertuzumab and cetuximab and found that the HER2-mutant outperformed all three HER2-targeted therapies.

"Our study demonstrates that this protein sequence is a druggable target," says Dr. Lupu. "Targeting this sequence could have a much broader impact than other drugs that are currently available because it does not just disrupt HER2, but it actually gets in the way of HER2's dimerization to itself and other family members. As a result, this approach could block many of the different pathways by which cancer-causing signals get sent into the cell."

Dr. Lupu and her colleagues are now confirming the anti-tumor activity of the HER2 mutant in relevant animal models, a necessary step before studies can move on to clinical testing. They are also investigating drugs -- such as mimetic agents, targeted antibodies and small molecules -- that could specifically block this site responsible for HER2's oncogenic potential.

###

Co-authors of the paper include Barbara Schroeder, Ph.D. of Mayo Clinic, Javier Menendez, Catalan, Institute of Oncology, Susan Peirce, Ph.D., Emory University Medical School, Luciano Vellon, Ph.D., University of Buenos Aires School of Medicine, Adriana Papadimitropoulou, Laboratory of Molecular Biology & Immunobiotechnology, Hellenic Pasteur Institute and Ingrid Espinoza Ph.D., University of Mississippi Medical Center.

The work was supported by the U.S. Army Medical Research and Materiel Command (W81XWH-06-1-0686).

About Mayo Clinic Cancer Center

As a leading institution funded by the National Cancer Institute, Mayo Clinic Cancer Center conducts basic, clinical and population science research, translating discoveries into improved methods for prevention, diagnosis, prognosis and therapy. For information on cancer clinical trials, call 1-855-776-0015 (toll-free).

About Mayo Clinic

Mayo Clinic is a nonprofit organization committed to medical research and education, and providing expert, whole-person care to everyone who needs healing. For more information, visit http://mayocl.in/1ohJTMS, or http://newsnetwork.mayoclinic.org/.
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Old 04-28-2015, 12:44 PM   #2
Mtngrl
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Re: a cure for her2+ BCs--by making sure the puppy never gets born!

Wow! This is exciting.
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Amy
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4/19/11 Diagnosed invasive ductal carcinoma in left breast; 2.3 cm tumor, 1 axillary lymph node, weakly ER+, HER2+++
4/29/11 CT scan shows suspicious lesions on liver and lungs
5/17/11 liver biopsy
5/24/11 liver met confirmed--Stage IV at diagnosis
5/27/11 Begin weekly Taxol & Herceptin for 3 months (standard of care at the time of my DX)
7/18/11 Switch to weekly Abraxane & Herceptin due to Taxol allergy
8/29/11 CT scan shows no new lesions & old lesions shrinking
9/27/11 Finish Abraxane. Start Herceptin every 3 weeks. Begin taking Arimidex
10/17/11--Brain MRI--No Brain mets
12/5/11 PET scan--Almost NED
5/15/12 PET scan shows progression-breast/chest/spine (one vertebra)
5/22/12 Stop taking Arimidex; stay on Herceptin
6/11/12 Started Tykerb and Herceptin on clinical trial (w/no chemo)
9/24/12 CT scan--No new mets. Everything stable.
3/11/13 CT Scan--two small new possible mets and odd looking area in left lung getting larger.
4/2/13--Biopsy of suspicious area in lower left lung. Mets to lung confirmed.
4/30/13 Begin Kadcyla/TDM-1
8/16/13 PET scan "mixed," with some areas of increased uptake, but also some definite improvement, so I'll stay on TDM-1/Kadcyla.
11/11/13 Finally get hormone receptor results from lung biopsy of 4/2/13. My cancer is no longer ER positive.
11/13/13 PET scan mixed results again. We're calling it "stable." Problems breathing on exertion.
2/18/14 PET scan shows a new lesion and newly active lymph node in chest, other progression. Bye bye TDM-1.
2/28/14 Begin Herceptin/Perjeta every 3 weeks.
6/8/14 PET "mixed," with no new lesions, and everything but lower lungs improving. My breathing is better.
8/18/14 PET "mixed" again. Upper lungs & one spine met stable, lower lungs less FDG avid, original tumor more avid, one lymph node in mediastinum more avid.
9/1/14 Begin taking Xeloda one week on, one week off. Will also stay on Herceptin and Perjeta every three weeks.
12/11/14 PET Scan--no new lesions, and everything looks better than it did.
3/20/15 PET Scan--no new lesions, but lower lung lesions larger and a bit more avid.
4/13/15 Increasing Xeloda dose to 10 days on, one week off.
7/1/15 Scan "mixed" again, but suggests continuing progression. Stop Xeloda. Substitute Abraxane every 3 weeks starting 7/13.
10/28/15 PET scan shows dramatic improvement everywhere. All lesions except lower lungs have resolved; lower lungs noticeably improved.
12/18/15 Last Abraxane. Continue on Herceptin and Perjeta alone beginning 1/8/16.
1/27/16 PET scan shows cancer is stable.
5/11/16 PET scan shows uptake in some areas that were resolved on the last two scans.
6/3/16 Begin Kadcyla and Tykerb combination
6/5 - 6/23 Horrible diarrhea from K&T together. Got pneumonia.
7/15/16 Begin Kadcyla only every 3 weeks.
9/6/16 Begin radiation therapy on right lung lesion that caused the pneumonia.
10/3/16 Last of 12 radiation treatments to right lung.
11/4/16 Huffing and puffing, low O2, high heart rate, on tiniest bit of exertion. Diagnosed as radiation pneumonitis. Treated with Prednisone.
11/11/16 PET scan shows significant improvement to radiated part of right lung BUT a bunch of new lung lesions, and the bone met is getting worse.
11/22/16 Begin Eribulin and Herceptin. H every 3 weeks. E two weeks on, one week off.
3/6/17 Scan shows progression in lungs. Bone met a little better.
3/23/17 Lung biopsy. Tumor sampled is ER-, PR+ (5%), HER2+++. Getting Herceptin and Perjeta as a maintenance treatment.
5/31/17 Port placement
6/1/17 Start Navelbine & Tykerb
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Old 04-28-2015, 08:22 PM   #3
annettchen
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Re: a cure for her2+ BCs--by making sure the puppy never gets born!

Intriguing! Thanks for Posting this, Lani!
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03/2014: Diagnosed with ER/PR-, HER2+++ MBC (bone mets, oligometastatic)
04/2014: Started 6 cycles of "PHD" (Perjeta, Herceptin, Docetaxol)
07/2014: Finished 6 cycles of PHD; restaging; 2 bone mets are sclerotic - looks like Herceptin and Perjeta is working
10/2014: STABLE!
01/2015: STABLE!
04/2015: STABLE!
08/2015: STABLE!
12/2015: BRAIN METS. BODY STABLE.
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Old 04-30-2015, 05:21 PM   #4
Lani
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Re: a cure for her2+ BCs--by making sure the puppy never gets born!

more...



ABSTRACT: Blockade of a Key Region in the Extracellular Domain Inhibits HER2 Dimerization and Signaling
[Journal of the National Cancer Institute]

Background: Several treatment strategies target the human epidermal growth factor receptor 2 (HER2) in breast carcinomas, including monoclonal antibodies directed against HER2’s extracellular domain (ECD) and small molecule inhibitors of its tyrosine kinase activity. Yet, novel therapies are needed that prevent HER2 dimerization with other HER family members, because current treatments are only partially effective.

Methods: To test the hypothesis that HER2 activation requires a protein sequence in the HER2-ECD that mediates HER2 homo- and heterodimerization, we introduced a series of deletion mutations in the third subdomain of HER2-ECD. These deletion mutants were retrovirally expressed in breast cancer (BC) cells that naturally overexpress HER2 and in noncancerous, HER2-negative breast epithelial cells. One-factor analysis of variance or Student’s t test were used to analyze differences. All statistical tests were two-sided.

Results: The smallest deletion in the ECD domain of HER2, which removed only 16 amino acids (HER2-ECDΔ451–466), completely disrupted the oncogenic potential of HER2. In contrast to wild-type HER2, the mutant-inhibited anchorage-independent growth (mean number of colonies: mutant, 70, 95% confidence interval [CI] = 55 to 85; wild-type, 400, 95% CI = 320 to 480, P < .001) increased sensitivity to paclitaxel treatment in both transformed and nontransformed cells. Overexpression of HER2Δ451–466 efficiently inhibited activation of HER1, HER2, and HER3 in all cell lines tested.

Conclusions: These findings reveal that an essential “activating” sequence exists in the extracellular domain of HER2. Disruption of this sequence disables the HER2 dimerization loop, blocks subsequent activation of HER2-driven oncogenic signaling, and generates a dominant-negative form of HER2. Reagents specifically against this molecular activation switch may represent a novel targeted approach for the management of HER2-overexpressing carcinomas.
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Old 05-04-2015, 05:21 PM   #5
Teal55
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Re: a cure for her2+ BCs--by making sure the puppy never gets born!

Hi Lani,

Where can I read about this finding? Is it currently available or still in research. Was it FDA approved? I will be starting TCHP on Thursday. I will have my port put in on Wed.
I'm in a clinical trial but was randomized for the TCHP. I have Her2 positive, 75% Estrogen +, 2.6 cm. tumor, Invastive ductal carcinoma.

I really don't know what to expect. I'm concerned about all the side effects and returning.

I'm always looking for better treatments out there. So much really depends also on your insurance.

How are you doing?

Thanks for sharing,
Teal
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Old 05-05-2015, 09:00 AM   #6
Lani
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Re: a cure for her2+ BCs--by making sure the puppy never gets born!

there is not yet a trial yet an FDA approved drug or gene therapy based on this new knowledge-- your decision has to be based on the here and now

REST assured treatments for her2+ breast cancer before it metastasizes have transformed it from one of the worst types to have to one of the best and the more specific the therapy the less the needless side effects

GOOD LUCK
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Old 05-05-2015, 09:43 AM   #7
thinkpositive
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Re: a cure for her2+ BCs--by making sure the puppy never gets born!

Lani,

Thanks for all of your informative posts! All of us here on this site appreciate having folks like you who continually post about new developments in HER2. It gives us hope.

Thanks again,

Brenda
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8/2013 Diagnosed IDC Left Breast ER-/PR-/HER2+ Stage 3C, DCIS ER+/PR+/HER2- Right Breast (54 yr)
8/2013 PET/CT scan shows mass in uterues and suprclavicular nodes
8/20/13 Begin 6 rounds TCH chemo, Perjeta added for rounds 4-6
9/2013 After 1st round of chemo, mass in neck and breast no longer able to feel
11/2013 Hysterectomy, mass from PET/CT scan not cancer (adenomylosis)
12/2013 Finished chemo
1/2014 Double mastectomy with chest expanders
1/2014 Pathology report from surgery and SNB show complete pathological response!
3/2014 Finish IMRT radiation
8/2014 Fat transfer to radiated breast
8/2014 Completed 1 yr of Herceptin
10/2014 exchange surgery expanders removed implants placed
6/2015 3D nipple and areola tattoos
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