HER2/Neu Gene Associated With Breast Cancer May Play Major Role In Prostate Cancer Recurrence

Herceptin may not be the key therapy

April 20; updated Oct 24, 2005-- The HER2/neu gene, associated with breast cancer, may also play a major role in the recurrence of prostate cancer, according to research from the University of North Carolina at Chapel Hill School of Medicine and UNC Lineberger Comprehensive Cancer Center.

Herceptin, a drug which targets HER2/neu and has "stunning" effects for some women with breast cancer. Another drug called lapatinib (GlaxoSmithKline) is now in clinical trial to see if it blocks HER2/neu's effects in men with recurrent or metastatic prostate cancer. This trial is running at several Canadian centers and at Fox Chase Cancer Center, Philadelphia,  Pennsylvania (see link below).

The most common cancer in men, prostate cancer can be effectively treated with surgery or radiation when detected early. But advanced prostate cancer is usually treated by drugs or surgery aimed at reducing the level of testosterone and other male hormones, or androgens, that stimulate cancer cell growth. While the disease usually regresses after such treatment, prostate cancer invariably comes back, although it's not clear why it recurs and progresses.

The UNC study, published last April 15 in the journal Cancer Research, indicates that the gene HER-2 is a key culprit in prostate cancer recurrence. The findings also suggest a new treatment strategy for targeting HER-2 in patients with advanced prostate cancer.

HER-2 refers to human epidermal growth factor receptor 2. The gene helps control how cells grow, divide and repair themselves, and directs the production of a special protein called HER-2 tyrosine kinase. This protein acts as receptors on the cell membrane, and when activated by external hormones, it promotes cell growth and division.

In about one in four breast cancers, a genetic mutation creates too many HER-2 receptors. This helps spur rapid cancer cell growth. While treatment with the antibody drug Herceptin can be effective in slowing breast cancer growth, this is not the case in prostate cancer, researchers said.

"The treatment with the antibody has been a uniform failure in prostate cancer because the gene is not over-expressed in this disease. We need a different approach to attack HER-2 in prostate cancer," said the study's senior author, Dr. Young Whang. He is an assistant professor of medicine and medical oncologist at UNC and a member of UNC Lineberger.

"We believe that the driving force for recurrence of prostate cancer is the reactivation of the androgen receptor, which normally requires the presence of androgen, and this reactivation of the androgen receptor underlies tumor progression of prostate cancer despite hormonal therapy. Exactly how this occurs, we're not sure, but our hypothesis is that activation of HER-2 tyrosine kinase leads to activation of the androgen receptor."

In testing their hypothesis, Whang and his co-authors inhibited HER-2 activity in two laboratory experiments involving human cancer cells. In the first, they used an artificial antibody to HER-2 delivered directly into the cells via a modified virus. In the second, they used an experimental drug that specifically inhibits HER-2 tyrosine kinase activity. In both experiments, tyrosine kinase activity and androgen receptor function were largely derailed.

"We discovered that inhibition of HER-2 strongly inhibits proliferation of prostate cancer cells and the function of androgen receptor," Whang said.

To properly carry out its function, the androgen receptor protein binds specifically to the regulatory DNA sequence of the genes regulated by androgens such as testosterone, he said. "And we have shown that inhibition of HER-2 impairs the androgen receptor function at this step of binding to the DNA sequence of critical genes such as prostate specific antigen."

The implication of this work, he added, is that HER-2 is important and necessary for prostate cancer viability and progression.

"This provides the rationale for initiating a clinical trial of this novel drug inhibiting HER-2, which is being planned for patients within several months," Whang said. "I envision this drug becoming one of several that could be used in combination with other specifically targeted drugs to prolong the lives of prostate cancer patients."

UNC co-authors with Whang include postdoctoral researchers Drs. Yuanbo Liu and Samarpan Majumder; Wesley McCall, research technician; Dr. Carolyn Sartor, assistant professor of radiation oncology; Dr. James Mohler, professor of surgery; and Dr. Shelton Earp, director, UNC Lineberger. Dr. Christopher Gregory, former UNC assistant professor of pathology and another co-author, is now with Voyager Pharmaceutical Corp. in Raleigh.

The research was supported by grants from the U.S. Army Medical Research and Materiel Command and the National Cancer Institute, a component of the National Institutes of Health.

Original news release by LESLIE H. LANG, UNC School of Medicine. Updated by J. Strax, psa-rising.com, Oct 24 2005.

UPDATED TRIAL RESULTS 2011:

A phase II study of lapatinib, a dual EGFR and HER-2 tyrosine kinase inhibitor, in patients with castration-resistant prostate cancer, March 2011

Phase II Trial of lapatinib in men with biochemically relapsed, androgen dependent prostate cancer, July 2011.

Research followup 2011

Sarcosine induces increase in HER2/neu expression in androgen-dependent prostate cancer cells....

Archival Links and Sources

Cancer Res. 2005 Apr 15;65(8):3404-9.
Inhibition of HER-2/neu kinase impairs androgen receptor recruitment to the androgen responsive enhancer. Liu Ym Majumder S, Sartor CI, Mohler JL, Whang YE et al. Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.

Lapatinib in Treating Patients With Recurrent or Metastatic Prostate Cancer This study is completed.

Clinical Cancer Research Vol. 11, 1704-1712, March 2005 Heregulin-Induced Activation of HER2 and HER3 Increases Androgen Receptor Transactivation and CWR-R1 Human Recurrent Prostate Cancer Cell Growth Christopher W. Gregory , Young E. Whang , et al. University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC.

PNAS Vol. 96, Issue 10, 5458-5463, May 11, 1999
FREE Full text article From HER2/Neu signal cascade to androgen receptor and its coactivators: A novel pathway by induction of androgen target genes through MAP kinase in prostate cancer cells

Shuyuan Yeh, et al.
George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Cancer Center, University of Rochester, Rochester, NY

Molecular Cancer Research 1:385-392 (2003)
FREE Full text article Androgen Receptor Activity at the Prostate Specific Antigen Locus: Steroidal and Non-Steroidal Mechanisms Jia L, Kim, Coetzee GA, et al. Department of Urology, Norris Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA

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LAPATINIB - DUAL TYROSINE KINASE INHIBITOR FOR THE TREATMENT OF SOLID TUMOURS

http://www.drugdevelopment-technology.com/projects/lapatinib/

ERB receptors consist of three components: the extracellular domain to which ligands bind; a transmembrane domain; and an intracellular domain that includes tyrosine kinase. (expand image)

Lapatinib ditosylate (GSK572016) is an epidermal growth factor receptor (EGFR) and ErbB-2 (Her2/neu) dual tyrosine kinase inhibitor under development by GlaxoSmithKline as a treatment for solid tumours such as breast and lung cancer. This novel investigational agent has attracted considerable interest, as it appears to arrest the development of breast cancer in some patients with metastatic, treatment-refractory disease. If preliminary findings are supported by data from larger phase III trials then lapatinib could become an important new treatment option for breast cancer patients and potentially those with other difficult-to-treat solid tumours.

This page reported by J. Strax, updated October 24, 2005 and July 2011.

Information on this web site is not intended as medical advice nor to be taken as such. Consult qualified physicians specializing in the treatment of prostate cancer. Neither the editors nor the publisher accepts any responsibility for the accuracy of the information or consequences from the use or misuse of the information contained on this website.