The Search for Cancer Diagnostic Markers: A Race Against Time

The knowledge that early detection and treatment offers the best outcome for the patient has long driven the search for effective diagnostics.
Sep 01, 2005
Volume 18, Issue 9

At this time there are no effective diagnostic tests for cancer that are rapid, economical, highly specific, and highly sensitive. This deficiency means that many cases of malignancy go undetected until long past the time of effective treatment. Much cancer research, including investigations carried out by both the academic and private sector, is focused on combining therapy and diagnostics as "theragnostics."

Three approaches to diagnostics development include (1) a search for individual markers of specific malignancies; (2) a screening of a number of markers simultaneously in malignancies, to establish a diagnostic profile; (3) exploiting the antisera of patients in order to identify new antigens on cancer cells.

Classical markers of malignancy include prostate-specific antigen (PSA), carcinoembryonic antigen (CEA), and alpha fetoprotein, (AFP). Although widely utilized as diagnostic indicators, all have significant shortcomings.

Because of the complexity of the malignant phenotype and the fact that oncogenes are derived from normal cellular functions, designing a valid cancer test based upon a single marker may be extremely challenging, or even impossible. For this reason an evaluation of malignant cells based upon simultaneous profiling of a number of functions may be the most fruitful approach.

In the last decade the search for better identification of states of cancer has focused on new immunodiagnostic recognition systems for malignant disorders. This is one facet of the field of pharmacodiagnostics — the joining of cancer therapy to the outcome of a test measurement from a patient biopsy. Whereas the realization of effective cancer treatment requires successful cancer therapeutics, these markers may be exploited in the short run as cancer detection systems.

Detection of states of malignancy using antibodies has an extended history. The knowledge that the best outcome of the patient depends on the earliest possible detection and surgical removal of a tumor has long driven the search for effective diagnostics. It has been recognized since the origins of modern cancer treatment in the early 20th century that by the time a cancer produces clinical symptoms, the window of curative possibility has already passed.

Until recently, cancer screening was based on the use of low-tech approaches, such as the digital rectal examination for prostate cancer or X-rays for detecting breast cancer. This situation began to change in the 1970s with the development of tests based on the use of cancer-associated antigens using histochemical, immunofluorescent, and radioisotopic markers. These antigens have been localized using radiological, microscopic, and serum-based assay procedures. However, despite decades of use and exhaustive clinical evaluation, in most cases the results are highly controverted, and few tests are recognized as universally beneficial.

Table 1. Diagnostic Approaches Currently in Use
To be truly effective on a wide basis, a diagnostic test for cancer must be relatively non-invasive and economical. Thus biopsy of tissues (liver, kidneys, testicles) and the use of expensive medical equipment (MRI and CAT scans) do not lend themselves to population screening, or screening of the same individual on multiple occasions. For this reason, research has focused on markers present in the circulatory system because they can be detected in blood and/or urine. Table 1 outlines some of the most important diagnostic approaches currently in use.


Bogen and Sompuram1 propose three major approaches to the exploitation of cancer markers. The first is the traditional approach of characterization of a single cancer-related marker and its validation as an immunodiagnostic test. This strategy, which was advanced in the early days of hybridoma work, involved screening antibodies produced from mice immunized with mixtures of cancer cells. Labor intensive, thousands and thousands of hybridoma clones had to be screened, tested, and retested to generate a single candidate marker. With the technical improvement of recombinant DNA technology, routine manipulation of gene sequences allowed the cloning of recombinant antibodies and obviated the need for laborious hybridoma screening.

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