new approach to her2+ breast cancer--higher drug doses given intermittently vs her2&3

[Lani]

Breast Cancer Lab Discoveries Quickly Lead to New Clinical Trial
March 3, 2010

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.

[Lani]

Sci Transl Med 27 January 2010:
Vol. 2, Issue 16, p. 16ra7
DOI: 10.1126/scitranslmed.3000389
RESEARCH ARTICLE
Resiliency and Vulnerability in the HER2-HER3 Tumorigenic Driver
Dhara N. Amin1,2, Natalia Sergina1,2, Deepika Ahuja1,2, Martin McMahon3,4, Jimmy A. Blair4,*, Donghui Wang2, Byron Hann2, Kevin M. Koch5, Kevan M. Shokat6 and Mark M. Moasser1,2,â€*
+ Author Affiliations

1Department of Medicine, University of California, San Francisco, CA 94143, USA.
2Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.
3Cancer Research Institute, University of California, San Francisco, CA 94143, USA.
4Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143, USA.
5Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
6Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA.
â€*To whom correspondence should be addressed. E-mail: mark.moasser@ucsf.edu
ABSTRACT

About 25% of breast cancers harbor the amplified oncogene human epidermal growth factor receptor 2 (HER2) and are dependent on HER2 kinase function, identifying HER2 as a vulnerable target for therapy. However, HER2-HER3 signaling is buffered so that it is protected against a nearly two-log inhibition of HER2 catalytic activity; this buffering is driven by the negative regulation of HER3 by Akt. We have now further characterized HER2-HER3 signaling activity and have shown that the compensatory buffering prevents apoptotic tumor cell death from occurring as a result of the combined loss of mitogen-activated protein kinase (MAPK) and Akt signaling. To overcome the cancer cells’ compensatory mechanisms, we coadministered a phosphoinositide 3-kinase–mammalian target of rapamycin inhibitor and a HER2 tyrosine kinase inhibitor (TKI). This treatment strategy proved equivocal because it induced both TKI-sensitizing and TKI-desensitizing effects and robust cross-compensation of MAPK and Akt signaling pathways. Noting that HER2-HER3 activity was completely inhibited by higher, fully inactivating doses of TKI, we then attempted to overcome the cells’ compensatory buffering with this higher dose. This treatment crippled all downstream signaling and induced tumor apoptosis. Although such high doses of TKI are toxic in vivo when given continuously, we found that intermittent doses of TKI administered to mice produced sequential cycles of tumor apoptosis and ultimately complete tumor regression in mouse models, with little toxicity. This strategy for inactivation of HER2-HER3 tumorigenic activity is proposed for clinical testing.

↵* Present address: Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
Citation: D. N. Amin, N. Sergina, D. Ahuja, M. McMahon, A. Blair, D. Wang, B. Hann, K. M. Koch, K. M. Shokat, M. M. Moasser, Resiliency and Vulnerability in the HER2-HER3 Tumorigenic Driver. Sci. Transl. Med. 2, 16ra7 (2010).
Received September 15, 2009. Accepted January 8, 2010.

[Joe]

I believe that this is the clinical trial that Lani referred to:

Clinical Trial UCSF

I cannot overemphasize the importance of participating in Clinical Trials. For those who saw the movie "Living Proof", the story of Barbara Bradfield is true.

Barbara is currently in complete remission after being treated in the Phase I trial of Herceptin (1995 ?) and has had no chemotherapy since !!!

Regards
Joe

[CourtneyL]

Thanks for posting this, Lani. Dr. Moasser is doing some great work at UCSF. If you are interested in learning more about his work, there is a great article on UCSF's website about Moasser's work with HER2/HER3. This sounds so promising!

http://bms.ucsf.edu/faculty/moasser.html

[Ellie F]

Thanks Lani for posting and also Joe and Courtney for the additional info.
Each day we move on a little further. Lets hope that very soon her 2 breast cancer,as predicted, will be able to be effectively managed for a long time.
Ellie