Aggressive PCa - Genetic Risk Factors
Cetuximab May Have Value to Target High Risk Prostate Cancer Gene SPINK1
Thursday, March 03 2011 00:00
Researchers at the University of Michigan Comprehensive Cancer Center have identified a potential target to treat an aggressive type of prostate cancer. The target, a gene called SPINK1, they say "could be to prostate cancer what HER2 has become for breast cancer."
Like HER2, they say in a press release, SPINK1 occurs in only a small subset of prostate cancers – about 10 percent. "But the gene is an ideal target for a monoclonal antibody, the same type of drug as Herceptin, which is aimed at HER2 and has dramatically improved treatment for this aggressive type of breast cancer."
"Since SPINK1 can be made on the surface of cells, it attracted our attention as a therapeutic target. Here we show that a 'blocking' antibody to SPINK1 could slow the growth of prostate tumors in mice that were positive for the SPINK protein," says study author Arul Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology and a Howard Hughes Medical Institute Investigator. The study appears in the March 2 issue of Science Translational Medicine.
The researchers found that SPINK1 can bind to a receptor called EGFR (epidermal growth factor receptor). So they tested effects on SPINK1 positive tumors of a drug that blocks EGFR, cetuximab. This drug, trade name Erbitux, is a chimeric (mouse/human) monoclonal antibody, an epidermal growth factor receptor (EGFR) inhibitor, given by intravenous infusion. Erbitux is already approved by the U.S. Food and Drug Administration and in use in treatment of metastatic colorectal cancer and head and neck cancer.
The first clinical trials for Erbitux took place in the 1990s. Then known as IMC-C225, it was tested in a trial at MSKCC for men with advanced prostate cancer.
In mice, the targeted therapy shrank tumors positive for SPINK1 up to 74 percent
The University of Michigan researchers have found that cetuximab (Erbitux) reduces the cancerous effects of SPINK1. Using mice, they first tested a monoclonal antibody specifically designed to target SPINK1. They then tested cetuximab. Tumors treated with the SPINK1 antibody shrank 60 percent, while tumors treated with cetuximab shrank 40 percent. By combining the two drugs, tumors were 74 percent smaller.
The effect was seen only in tumors that expressed SPINK1 and was not seen in tumors that did not express SPINK1.
Previous clinical studies that looked at cetuximab for men with metastatic prostate cancer, including the first round mentioned above, have been disappointing, with only 8 percent of patients showing some benefit. The researchers suggest that the poor results may be because the treatment is appropriate only for patients with SPINK1-positive tumors.
"About 10 percent of prostate cancer patients are SPINK1-positive and strategies to block SPINK1 signaling may have utility in this subset of patients. These studies should stimulate the development of antibody-based therapies against SPINK1 or targeting of EGFR in SPINK1-positive cancer patients," says study author Bushra Ateeq, a research fellow at the U-M Medical School.
SPINK1 is associated with a more aggressive form of prostate cancer. It can be detected in the urine of prostate cancer patients, making it an easy test for urologists to perform routinely.
"This non-invasive form of screening could be helpful in the molecular categorization of prostate cancer patients and administering therapies in a molecularly guided fashion," says Chinnaiyan, S.P. Hicks Endowed Professor of Pathology at the U-M Medical School and an American Cancer Society Research Professor.
The study suggests that side effects were limited in mice. Future studies will need to determine whether targeting SPINK1 in humans would affect normal tissue. The researchers will also look to further understand why SPINK1 is elevated in a subset of prostate cancers. Clinical trials testing SPINK1 therapies are not available at this time.
News and links edited by J. Strax at psa-rising.com.
Last updated Thur March 3, 1109 pm EST
References: Therapeutic Targeting of SPINK1-Positive Prostate Cancer Science Translational Medicine, Vol. 3, No. 72, March 2, 2011
Additional authors on this study: Scott A. Tomlins, Bharathi Laxman, Irfan A. Asangani, Qi Cao, Xuhong Cao, Yong Li, Felix Y. Feng, Kenneth J. Pienta and Sooryanarayana Varambally
Funding: U.S. Department of Defense, Early Detection Research Network, Prostate SPORE, National Institutes of Health, Prostate Cancer Foundation
Disclosure: The University of Michigan has filed for patents on SPINK1, on which Chinnaiyan and Tomlins are named as inventors. The diagnostic field of use has been licensed to Gen-Probe Inc., who was not involved in the design or funding of these studies.
The study is published as: A Two-Step Toward Personalized Therapies for Prostate Cancer Sci Transl Med 2 March 2011
Related publication: A First-Generation Multiplex Biomarker Analysis of Urine for the Early Detection of Prostate Cancer (2008)
Resources:
U-M Cancer AnswerLine, 800-865-1125
U-M Comprehensive Cancer Center, www.mcancer.org
Clinical trials at U-M, www.UMClinicalStudies.org
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