Beyond PSA: Prostate Cancer Biomarkers

Prostate cancer is the most common cancer among men worldwide and is the second leading cause of death in men after lung cancer in the U.S. The American Cancer Society estimates that in 2010 there will be about 217,730 new cases of prostate cancer diagnosed and about 32,050 deaths. The principal factor contributing to the high mortality in patients with prostate cancer is our inability to identify the presence of primary and metastatic occult prostate lesions in men prior to the manifestation of pathologic signs and symptoms—the earliest and most curable stage, says Amin I. Kassis, PhD, professor of radiology and director of radiobiology and experimental radionuclide therapy at Harvard Medical School, Boston.

Prostate-specific antigen (PSA) is the most commonly used screening test in men over 50 years of age as well as tool to monitor patients who have a history of prostate cancer. While the PSA assay continues to play a significant role in the diagnosis of prostate cancer and in the monitoring of treatment of this devastating disease, its specificity, sensitivity, and accuracy continues to be inadequate, says Kassis. He believes that this is a consequence of the dependence on average genomic/proteomic signature profiles that are obtained from the blood of “healthy” men, which are not specific to the genetic makeup of the individual being tested.  

At Harvard Medical School, Kassis has recently described proprietary methods that are suited to the facile identification and differentiation of “tumor-specific” and “normal-specific” signatures which do not depend on population-derived average signature profiles and/or biomarker values obtained from “healthy” controls. Early findings in tumor-bearing mice and in a small number of patients have shown so far that the approach is absolutely effective in the detection of various types of cancer, adds Kassis.

Enzyme-mediated cancer imaging

Kassis’s group is developing Enzyme-Mediated Cancer Imaging and Therapy (EMCIT). The idea is to develop water-soluble radioimaging and radiotherapeutic pharmaceuticals that are specifically hydrolyzed by enzymes to water insoluble molecules that precipitate within solid tumors and get permanently entrapped. When the trapped compound is radiolabeled with a gamma or positron emitting radionuclide, it will enable the selective imaging (SPECT/PET) of tumors. On the other hand, when the trapped molecule is radiolabeled with an energetic alpha- or beta-particle-emitting radionuclide, it will irradiate the tumor mass and eradicate the tumor.

A cell surface serine protease, hepsin, has consistently been identified as being over expressed in prostate cancer cells compared with nonmalignant prostatic epithelial cells. Kassis envisions that peptide-conjugated, water-soluble and radioactive prodrugs that are hepsin substrates could be developed for noninvasive diagnosis of prostate disease based on the EMCIT concept.

Many biomarkers, few clinical uses

With the arrival of the post-genomic era, there is increasing interest in the discovery of biomarkers for the accurate diagnosis, prognosis, and early detection of prostate cancer, but most promising biomarkers have not been validated for clinical use. In the last 25 years, we haven’t found a better molecule than PSA, says Eleftherios P. Diamandis, MD, PhD, division head of clinical biochemistry in the department of pathology and laboratory medicine at Mount Sinai Hospital in Toronto in Ontario, Canada, and division head of clinical biochemistry in the department of laboratory medicine and pathobiology at the University of Toronto.

Diamandis recently reviewed some biomarkers initially hailed as breakthroughs and their subsequent failings in an article published in the October 2010 issue of the Journal of the National Cancer Institute. Diamandis concludes that problems with study design and interpretation, as well as statistical deficiencies could lead to generation of data that could be highly mis-leading.

“There is not a single, common pathway that predicts for the development of a clinically relevant prostate cancer. That’s largely the basis behind why it has been so difficult to find the perfect biomarker for prostate cancer,” explains Timothy A. Masterson, MD, assistant professor, department of Urology, Indiana University Medical Center in Indianapolis.

The problem in commercializing any marker for prostate cancer, and for that matter any disease, Kassis says, is it relies on our ability to 1.) validate in a large number of patients the utility of the marker in addressing an important and useful clinical question (e.g, can it differentiate between indolent and aggressive disease?), and 2.) ascertain that the sensitivity, specificity, and accuracy of the test is higher than that of PSA. Carrying on a human trial can take several years, and is feasible as long as a putative marker has been identified and the financing is available. However, we need to remember that the probability of success is always going to be low and never to give up hope in our quest for a perfect biomarker.

Cholesterol Sulfate: Potential Lipid Biomarker

Negative ion mode tissue imaging showing cholesterol sulfate in the prostate tumor and not in the normal prostate tissue.Image source: Analytical Chemistry, American Chemical Society Scientists have recently used Desorption Electrospray Ionization Mass Spectrometry (DESI-MS) imaging to analyze the lipid profiles of thin tissue sections of human prostate cancer and normal tissue. DESI-MS imaging is a type of molecular-specific imaging done on tissue sections in its ambient environment using a stream of charged microdroplets as the imaging agent, explains R. Graham Cooks, PhD, Henry B. Hass distinguished professor of chemistry, Purdue University, West Lafayette, Indiana, who led the study. There is significantly increased intensity of cholesterol sulfate in prostate cancer tissue, which is undetectable in the normal prostate tissue, says Cooks. The study was published in the May 2010 issue of Analytical Chemistry. Both Cooks and Masterson, a co-investigator of the study, agree that cholesterol sulfate is a potential biomarker and confirmation through larger and more diverse cohorts and correlations with clinical outcome data is needed. Masterson and colleagues are currently doing serum and urine studies to see if higher detectable levels of cholesterol sulfate can be identified in prostate cancer patients compared to normal patients without prostate cancer. His team also is looking at the absolute amounts and intensity of cholesterol sulfate within prostate tissues and correlating with other clinical features like the stage of the prostate cancer and whether it is possible to predict metastasis. “Theoretically this would be useful in the screening of patients for prostate detection. But we don’t have all the answers yet,” concludes Masterson.