The findings, to be published in the January issue of the journal Nature Biotechnology, and available online December 23 (www.nature.com/naturebiotechnology), also may offer a new insight into the biology of the disease.
"The information based on this retrospective preliminary analysis may, in the future, be useful for physicians to decide among the many therapeutic options available for prostate cancer patients. As of today, these options are largely dependent on the stage of the disease," says Wadih Arap, M.D., Ph.D., the lead author of the study from the Department of Genitourinary Medical Oncology at M. D. Anderson.
By looking at the patterns of antibodies from cancer patients, the researchers found that reactivity against a protein that is present at high levels in prostate tumors correlated with poor prognosis and advanced disease. "Future studies based on these findings are likely to help us understand the mechanisms of disease progression," says co-author Renata Pasqualini, Ph.D.
In this report, the group led by Arap searched for small protein fragments (peptides) that can be recognized by antibodies found in the serum of prostate cancer patients. These small protein fragments turned out to be part of a tumor antigen called GRP78.
The protein fragments were isolated from a large collection of peptides displayed on the surface of small, virus-like particles (phage). These phage collections were incubated with the antibodies purified from the serum of prostate cancer patients, and then individual particles that bind to disease-associated antibodies were recovered.
The team then used the protein fragments and the corresponding native tumor antigen to screen the blood of 108 prostate cancer patients and 71 healthy, matched volunteers. Reactivity against the protein correlated with advanced disease.
GRP78 is a heat shock or "stress" protein that becomes expressed at high levels when cells are exposed to low concentrations of glucose or oxygen. Emerging research shows that heat shock proteins seem to play a role in signaling the immune system into action. What the researchers do not yet know and are currently investigating is whether or not GRP78 contributes directly to progression of prostate cancer, says Pasqualini.
"This study validates the hypothesis that humoral response can serve as a 'labeling system' of human cancer. The observations may be clinically meaningful because the presence of antibodies against this particular antigen correlated with disease progression and patient survival. The findings will stimulate investigation as to how the humoral immune response to cancer can be used as a method to monitor and understand cancer progression clinically," says co-author Christopher Logothetis, M.D., chairman of the Department of Genitourinary Medical Oncology.
According to Logothetis, if the disease is detected at early stages, prostate cancer can be managed by local treatments such as surgery or radiation. At later stages of progression, prostate cancer commonly spreads into specific sites such as the skeleton. When this happens, treatment options are more limited. Novel tools for biochemically staging disease would help physicians and patients evaluate and select the most appropriate therapeutic approach, says Logothetis.
According to researchers, the long-term purpose of this project is to identify circulating antibodies that can serve as an early warning system based on individual patients' immune response against tumors. These antibodies can be used to discover what protein fragments they are recognizing, and correlate their presence with patterns and speed of disease progression. The researchers at M. D. Anderson have demonstrated that phage display technology is effective in identifying such antibodies.
Before this novel blood test can be used clinically, it needs extensive validation, cautions Arap. Pasqualini adds that this particular "biological read-out" of prostate cancer progression based on the pattern of circulating antibodies in the serum of patients is just one in a series that the investigators are working to develop. "This may be one preliminary step towards the development of better tools to evaluate cancer progression."
Co-authors of the study include Drs. Paul J. Mintz, Jeri Kim, Kim-Anh Do, Xuemei Wang, Ralph G. Zinner, Massimo Cristofanilli, Marco A. Arap, Waun Ki Hong, Patricia Troncoso, Christopher J. Logothetis, Renata Pasqualini and Wadih Arap.
The research was funded by grants from the National Institutes of Health, the Gilson-Longenbaugh Foundation and CaP CURE.