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Old 11-26-2011, 08:16 AM   #1
'lizbeth
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Her 2/Her 3 article - I just found this, repost?

Breast Cancer Lab Discoveries Quickly Lead to New Clinical Trial

Mark Moasser

A new strategy for treating a common form of breast cancer has emerged from lab studies by UCSF oncologist Mark Moasser, MD. Clinical trials to evaluate the treatment approach already are underway at the UCSF Helen Diller Family Comprehensive Cancer Center.
The protocol being evaluated calls for giving women intermittent, higher-than-standard dosages of a newer biological agent used to fight breast cancer.
The strategy derives from new discoveries by Moasser’s lab team related to a major target in breast cancer that drives tumor growth in about one-in-four women with the disease.
Moasser’s enthusiasm for new treatment ideas that are emerging from scientists’ success in probing cancer cells was on display recently when he presented new research results to scientists and breast cancer advocates at an annual symposium organized by the Cancer Center’s Breast Oncology Program.
The approach of using larger drug dosages with breaks in between is based on what Moasser has learned about a protein called HER2 and its associates. HER2 and its protein partner HER3 make up a biochemical team that functions to regulate growth signals.
Due to genetic mutations, the cells of “HER2-positive” breast tumors make abnormally high amounts of HER2. This abnormality helps stimulate the growth of these breast cancers.
The first drug developed to target HER2 was Herceptin, which was approved by the US Food and Drug Administration in 1998. It has become a standard treatment for HER2-positive breast cancer. Herceptin was the first approved biological treatment developed to target a specific abnormality in breast cancer. By attaching to HER2, Herceptin inhibits HER2’s effectiveness in relaying growth signals.
Research advances in the decade since FDA approval of Herceptin have provided much greater insight into how HER2 functions. These insights have paved the way for the development of drugs that are much more effective than Herceptin, Moasser says. In particular, Moasser and his team have discovered that HER2 is protected by its partner HER3. The key to treatment of this disease is the inactivation of the HER2-HER3 team, according to Moasser.
In a study published in the January 27 issue of Science Translational Medicine, Moasser and colleagues found that the HER2-HER3 complex can be effectively inactivated, but to do so requires high doses of drugs which may produce toxicities. But they also found that toxicity from high doses can be avoided if there are breaks in drug therapy. This novel treatment design proved to be highly effective in mouse models of HER2-positive breast cancer.
A drug that targets HER2, called Tykerb, now is being used to test this new dosing strategy. In the clinical trial, women with advanced breast cancer are being treated with large, intermittent dosages of the drug instead of with daily, lower-dosage treatment. The larger dosage should more effectively kill tumor cells, Moasser, says. Breaks in treatment are intended to limit side effects.
UCSF oncologist Mark Moasser, MD, works with Natalia Sergina, PhD, now a former postdoctoral fellow in his lab, where research has led to a new strategy for treating a common form of breast cancer.

The Phase 1 clinical trial is open to women with HER2-positive breast cancers that continue to grow after prior treatment with standard therapies.
Sorting out the HER2 signaling pathway

The idea for using higher dosages emerged from lab findings. A compensatory biochemical response permits HER2-driven tumor cells to survive all but complete inhibition of HER2, a team led by Moasser and UCSF colleague Kevan Shokat, PhD, reported in a 2007 study.
HER2 signals must be relayed through other proteins downstream along the biochemical signaling pathway. The downstream signaling network creates a buffer, so that signaling can withstand drug treatment, Moasser says. If the dosage is increased, signaling revs up to compensate -- up to a point.
Dosages that are higher still can stop signaling, but are toxic when given continually. A minimum of three days without HER2 signaling is needed to kill HER2-positive breast cancer cells, Moasser says.
HER2 is able to transmit signals despite treatment thanks to its partner HER3. This is because HER3 is connected to a complex network that functions like an amplifier volume knob. If signaling decreases due to drug therapy, the network can increase signaling volume to compensate.
Understanding the network is a principle challenge for Moasser. “There’s a complex network in which HER2 and HER3 operate,” Moasser says. “We want to reduce its complexity. We want to know how big it is. We want to know where it is susceptible to attack.” Some of the most important proteins in HER2’s signaling pathway are downstream from HER3, Moasser says.
He says resistance to current treatments for HER2-driven breast cancer might one day be overcome by combining current HER2 inhibitors with other targeted drugs that separately attack either HER3 or proteins downstream in the signaling pathway.
In collaboration with Joe Gray, PhD, head of UCSF’s Breast Oncology Program and director of the Life Sciences Division at Lawrence Berkeley National Laboratory, Moasser is taking a systems biology approach. The researchers are trying to unravel the complexities of the network and to model it with mathematical formulas. These models would then allow computational methods to predict how cells will respond to specific drug treatments.
Moasser also continues to work with Shokat, a chemist who is innovative at making inhibitors that specifically target individual proteins. “Step by step we march down the pathway and interrogate the signaling circuitry with these inhibitors,” Moasser says. “At every step we measure how the cell responds.”
Although complexities of HER2-driven breast cancers have not yet been completely elucidated, these tumors may be less complex and resilient than many other cancers, Moasser says.
“In most solid tumors there are many signaling pathways that go wrong, and many genes that are mutated,” he says. “I think that this cancer is more simplistic, and that HER2 is the critical driver. I think we should be able to cure this cancer if we can shut down HER2, even in advanced cases.”
There is a precedent for using targeted drugs to vanquish cancers driven primarily by a single signaling pathway in the treatment of non-Hodgkin’s lymphoma and chronic myelogenous leukemia.

Resiliency and Vulnerability in the HER2-HER3 Tumorigenic Driver

Dhara N. Amin, Natalia Sergina, Deepika Ahuja, Martin McMahon, Jimmy A. Blair, Donghui Wang, Byron Hann, Kevin M. Koch, Kevan M. Shokat and Mark M. Moasser
Science Translational Medicine (January 27, 2010)
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Diagnosed 2007
Stage IIb Invasive Ductal Carcinoma, Pagets, 3 of 15 positive nodes

Traditional Treatment: Mastectomy and Axillary Node Dissection followed by Taxotere, 6 treatments and 1 year of Herceptin, no radiation
Former Chemo Ninja "Takizi Zukuchiri"

Additional treatments:
GP2 vaccine, San Antonio Med Ctr
Prescriptive Exercise for Cancer Patients
ENERGY Study, UCSD La Jolla

Reconstruction: TRAM flap, partial loss, Revision

The content of my posts are meant for informational purposes only. The medical information is intended for general information only and should not be used in any way to diagnose, treat, cure, or prevent disease
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Old 12-14-2011, 02:15 PM   #2
DeenaH
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Re: Her 2/Her 3 article - I just found this, repost?

I met Dr. Moasser while at my last UCSF appt. He is their HER3 guy.
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March 2010: Diagnosed with Stage IIIC IDC with axillary, mammary and suplaclavicular node involvement. ER/PR -, HER2+++. 7cm tumor in right breast.
April 2010: Started neoadjuvent chemo. 4 DD A/C every 2 weeks, 4 DD Taxotere every 3 weeks with Herceptin weekly.
August 2010: Finished chemo!
August 20, 2010: PET/CT showed no cancer in any nodes, and only a little uptake to the breast.
September 9, 2010: Bilateral mastectomy with immediate reconstruction with implants and Alloderm.
September 16, 2010: Pathology report showed 18/51 positive axillary nodes, 3.2cm tumor. Granual sized cancer found in the fatty tissue between levels 1 and 2.
October 19, 2010: CT showed several spots on lungs and 1 spot on liver. Liver spot is 2mm, lung spots range from 2mm to 4mm. We don't know if they are cancer or not.
12/15/10: Brain MRI clear
1/7/11: PET/CT
1/13/11: Recurrence in lungs. Start Tykerb
5/13/11: Progression in lungs
6/3/11: Lung surgery to get tumors for chemosensitivity testing.
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Old 12-31-2011, 07:32 PM   #3
Rohm
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Re: Her 2/Her 3 article - I just found this, repost?

I'm not a patient of Dr. Moasser, but I am participating in this trial. The trial isn't easy, but it has worked wonders for me!

I have read that article before and when I need a pick-me-up, I reread that last part... “I think that this cancer is more simplistic, and that HER2 is the critical driver. I think we should be able to cure this cancer if we can shut down HER2, even in advanced cases.”
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Old 01-02-2012, 10:56 PM   #4
Rich66
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Re: Her 2/Her 3 article - I just found this, repost?

Rohm,
Can you elaborate on your expreince with this?
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Old 01-03-2012, 08:06 AM   #5
Ellie F
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Re: Her 2/Her 3 article - I just found this, repost?

I would also be really interested to know if you get hercetin as well as tykerb?
Thanks
Ellie
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Old 01-03-2012, 11:38 AM   #6
Rohm
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Re: Her 2/Her 3 article - I just found this, repost?

My regime has me taking tykerb (2x a day with a low fat snack) with ketoconazole for 5 days, then I get 9 days off. There are a several anti-nausea drugs and antidiarrheals that I take too.

I am not on Herceptin while on this trial. I actually needed a 3 week washout before I could get started.

I was on this trial from May - September of 2011 and it worked beautifully until my brain met was found. I had that removed and radiated and now I'm back on the trial. Hoping it will get these skin mets under control and keep any new brain mets from cropping up! My team is hopeful that the radiation disrupted the BBB enough for tykerb to get through a bit more than usual.
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Old 01-10-2012, 11:28 AM   #7
Nancy L
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Re: Her 2/Her 3 article - I just found this, repost?

Thanks for posting this news article. I started my BC journey at UCSF and have great respect for their oncologists and research staff.

Dr. Slamon has told me that he now believes both Her2 and Her3 have to be blocked for advanced Her2 BC. I am Stage 4 and have been on Herceptin/Tykerb for 3 years and currently NED. I progressed after 4 years on Herceptin only. I suspect if I have a recurrence he will add another drug rather than take one away but I don't know that for sure. I am hoping to be one of the lucky ones to stay NED on my current therapy.
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