September 1, 2009 (Vol. 29, No. 15)
Tumor-Specific Antigens Could Positively Impact Diagnosis, Imaging, and Therapy
The medical literature abounds with examples of the benefits of early cancer detection. Cure rates are always dramatically higher before the tumor has spread and while surgery is still an option. For example in cervical cancer, detection at the earliest stages of the disease is associated with a 99% five-year survival rate. Similarly encouraging statistics may be found for cancers of the breast, ovaries, colon, skin, and other sites.
Cancer detected through physical examination or medical imaging is usually too advanced for hope of a cure, which has led to an explosion of research into molecular diagnostics. Immunoassays, the leading category of such tests, are exquisitely sensitive and have the potential to diagnose cancer at the stage of just a few cells. Unfortunately commercial molecular diagnostics for cancer suffer from a lack of specificity, sensitivity, and overall robustness.
An Ounce of Prevention
Cancer biomarker discovery has been hampered by the heterogeneity of the diseases known as cancer. Even within one cancer type, for example breast, several distinct clinical types exist; moreover, within these researchers have found dozens of genotypic differences. Despite these challenges, the search goes on for these important diagnostic tools.
Once cancer biomarkers are discovered and approved, their dissemination among medical specialists is relatively uncontrolled. Three cancer markers that immediately come to mind are prostate-specific antigen (PSA) for prostate cancer, CA-125 for ovarian malignancies, and HER2-neu in breast cancer.
PSA is found in normal prostate tissue and at elevated levels when the gland is inflamed. Since PSA is not specific to prostate malignancy, diagnosis of prostate cancer based on rising PSA serum levels results in a high rate of false positives—up to 75% according to some studies. False positives are highly undesirable because they trigger costly, invasive medical interventions that divert healthcare resources that could be better spent.
Biopsies of 100 suspected prostate cancer patients with PSA readings of 3 ng/mL or higher will return only 25 confirmed cases. In addition, 40% of PSA-negative readings are false. PSA was approved by the FDA at a time when prostate cancer diagnostics were essentially nonexistent. Were the PSA test to come up for regulatory review today, it is unlikely it would be approved for prostate cancer screening.
Diagnostic tests that are approved for one purpose are often applied to situations for which the test was not designed. PSA is a prime example. PSA was originally approved in 1985 as a test for the recurrence of prostate cancer in men who had been treated with radiation or surgery. Today the test is routinely prescribed as a screening tool despite the fact that evidence linking PSA testing to improved outcomes is lacking.
The U.S. Preventive Services Task Force concluded after reviewing the literature that it would take 1,000 PSA screenings to prevent one death from prostate cancer. At the same time the numerous false positives and inconclusive results would subject hundreds of these men to unnecessary interventions that include biopsies, surgery, and medical treatment, not to mention the anxiety of uncertainty regarding their health status.
Clearly a useful cancer test will possess high diagnostic specificity and sensitivity, be expressed exclusively by tumors of one type, and detect cancer early to provide a reasonable hope of cure. The ability to predict both outcomes and response to therapy could be considered added benefits.
One example of a true antigenic surface marker specific to cancer cells is EGFRvIII, a mutation in the epidermal growth factor receptor (EGFR) found in a variety of different cancers but not in normal cells. This true cancer marker is different from the native EGFR that has served as a target for nonspecific cancer therapy (e.g., Genentech/Roche’s monoclonal antibody Avastin) in those cancers in which EGFR is overexpressed. Discovered about ten years ago, EGFRvIII was originally dismissed by scientists but has shown usefulness as a possible therapeutic target. However, while this receptor is cancer specific, it is not organ specific since it appears in several cancer types.
Another potentially useful cancer-specific marker is TMPRSS2:ERG, the fusion product of the prostate-specific marker TMPRSS2 and the transcription factor ERG. TMPRSS2:ERG levels accurately predict the likelihood that prostate cancer patients will relapse after surgery. However, just half of prostate cancer patients express TMPRSS2:ERG, which does not bode well for using this marker as a screening test or general diagnostic.
So despite increasing knowledge in molecular biology in recent years, discovery of cancer-specific, cell-surface antigens remains a challenge. We know genes mutate inside cancer cells, but the molecular manifestation of these events as surface antigens has largely eluded detection and characterization.
This is not surprising, as cancer cells have evolved numerous escape mechanisms for overcoming not just pharmacologic intervention, but the body’s own defense mechanisms. Masking of tumor-specific antigens (TSAs) by a cell’s native surface antigens, which prevents direct interaction with TSAs, is just one such mechanism. Another is the relatively poor immunogenicity of TSAs compared with neighboring antigens.
The standard approach to discovering new proteins involves explicit knowledge of their existence and the ability to isolate them. Barring a first-in-kind discovery, it is quite unlikely that TSAs will be characterized sufficiently given the current state of technology.
MabCure scientists have developed a technique for generating antibodies against TSAs without a priori knowledge of their location or structures. The key is the classic hybridoma technology that was re-engineered and optimized. The technique, which is still in the early validation stage, has produced specific antibodies against melanoma and ovarian cancers.
While TSAs will require development work before approval and commercialization, they provide the scientific basis for designing numerous products for cancer diagnosis, imaging, and therapy.
Cancer-specific antibodies may help change the molecular diagnosis and treatment of cancer. If produced at reasonable cost, such antibodies may be able to improve sensitivity and specificity for cancer screening and diagnosis as well as monitoring of therapy. Similarly tumor-specific mAbs, when coupled with the appropriate radionuclide, might one day pinpoint micrometastases for diagnostic purposes and/or direct radiotherapy. Finally, studies involving the mAbs and their cancer-cell targets may lead to the discovery and characterization of TSAs, which themselves might be the targets of pharmacologic intervention.
Amnon Gonenne, Ph.D. (firstname.lastname@example.org), is president and CEO of MabCure. Web: www.mabcure.com.