Caitlin Smith has a B.A. in biology from Reed College, a Ph.D. in neuroscience from Yale University, and completed postdoctoral work at the Vollum Institute.
When cell signaling pathways go awry, uncontrolled growth of cancer cells may result. But there are so many types of cancer, in all kinds of cells, that there isn’t a one-size-fits-all diagnostic or treatment approach. As cancer drugs and other therapeutics become more targeted, which makes them more effective and helps minimize side-effects, it becomes even more crucial to use the right one. This calls for smarter and more effective diagnostic tools than ever before. For example, diagnostics that involve cancer biomarkers – molecular indicators used to assess the disease’s progression or the therapy’s effectiveness – are increasingly important in targeting the right systems for cancer treatment.
Biomarkers in the body
Biomarkers can be attached to magnetic beads, which can then be manipulated – and separated from other reagents – using magnetic force. Bio-Rad’s new Bio-Plex Pro™ Human Cancer Biomarker Panel 1 is a mixture of magnetic bead-based assays based on Luminex’s xMAP® technology; these assays allow you to multiplex assays for 16 biomarker proteins known to play roles in key processes such as angiogenesis, metastasis, cell proliferation, cell adhesion/migration, apoptosis, and inflammation. The panel includes eight new targets, such as sEGFR, sVEGFR-1, and osteopontin, which are associated with cancer progression.
Luminex’s xMAP Technology detects and measures biomarkers that are attached to tiny microspheres, which can then be highly multiplexed in a “liquid ELISA” type of analysis. According to Luminex, it is possible to analyze up to 500 analytes per well – a powerful approach when combined with biomarkers for cancer. Though they don’t manufacture their own, diagnostic kits for cancer using their xMAP system are available from Luminex’s partners, Novagen (part of EMD Merck) and Tellgen Life Science. Novagen offers WideScreen™ Biomarker Assay Kits using xMAP® Technology, and Tellgen Life Science Co. offers the Tellgenplex™ Multiple Tumor marker assay kit that also runs on Luminex’s platform.
Proteome Sciences uses proteomic analysis to identify cancer autoantibodies. They make a range of patented biomarkers from blood which detect several types of cancers, including lung, breast, esophageal and colorectal cancers, as well as neuroblastoma. “One of the unique aspects in our portfolio is the range of autoantibodies markers,” says Ian Pike, chief operating officer at Proteome Sciences. “These are produced early in disease in response to proteins expressed by the tumor that are not normally seen in a healthy person. In many patients, these trigger an immune response and antibodies are formed. The antibodies are present in blood at much higher levels than the tumor protein, and so are easier to detect in a small blood sample.” Developing tests that can detect tumors earlier, he says, can help guide the selection of drug treatment.
Profiling the cell signaling pathways active in cancer can help to find cancer-related biomarkers, which can be used to diagnose tissue biopsies. Proteome Sciences’ SysQuant™ is a profiling tool designed to accomplish this. “More importantly, we can also show which of the pathways would be the best to target with the new selective drugs being developed, and also which other pathways may lead to resistance,” says Pike. “This will allow better selection of drug combinations to ensure prolonged treatment benefit.” Their ultimate goal is to use the biomarkers from profiling tools like SysQuant to examine sampled blood, and possibly tumor imaging using biomarker-specific labels to guide treatment and improve outcomes.
Mass spectrometry to test large panels of biomarkers
Proteome Sciences is developing a new diagnostic testing platform based on mass spectrometry called TMTcalibrator™ that can measure hundreds of proteins in one clinical sample, and then quantify them against standard curves produced within the test itself. “This can dramatically improve the number of markers we can analyze in a patient,” says Pike. “[This helps us to] learn far more about the underlying basis of their tumor and so what treatment regime will be most successful.” In collaboration with research groups at the Buck Institute and the Moffitt Cancer Center, they hope to have this tool available before the end of the year. “We hope to have mass spectrometry methods for monitoring drug responsiveness of breast cancer available for research use later this year, and will look to develop these for clinical use thereafter,” says Pike.
Pike believes that a need exists for biomarkers to serve as more useful predictors of disease outcomes. For example, recently, biomarkers such as PSA and homovanillic acid have led to the over treatment of prostate cancer and neuroblastoma, respectively. “Whilst the overall benefit of these markers justifies their use, we hope that more prognostic markers will be added to the portfolio of tests available to reduce this burden,” says Pike.
Companion diagnostics and diagnostic imaging
Getting the best medicine to a cancer patient, and at the best time, is key to successful treatment. Wilex has developed a line of diagnosis and treatment called Companion Diagnostics for Personalized Medicine. This means that they can use diagnostic tests in conjunction with specific pharmaceutical drugs for treatment – at the right time.
An example of Wilex’s method is their FDA-approved blood test for the circulating form of the HER-2 protein that is found in patients with and without HER-2 positive breast cancer. “Once a HER-2 positive tumor is removed, it is likely that HER-2 positive tumor cells have already spread in the body,” says Walt Carney, chief scientific officer at Wilex. “As these grow and women develop metastatic breast cancer, the blood level of the HER-2 protein will increase – which is an early sign of cancer progression.” Research has shown that women who had originally been classified as HER-2 negative, can nevertheless have pockets of HER-2 positive cells that lead to these women developing a HER-2 positive breast cancer tumor later in life. “The serum HER-2 blood test can help find these women who would not normally get access to HER-2 positive therapies such as [the drug] Perception,” says Carney. All women with breast cancer can benefit from Wilex’s specific HER-2+ biomarker blood test, because it helps to monitor breast cancer patients and help doctors make therapy decisions. “If serum HER-2 increases it is a sign of cancer progression, which is an actionable event for an oncologist,” says Carney. “We also know serum HER-2 increases months before clinical signs of a tumor recurrence, so it is an early warning system that HER-2 tumor cell growth is on the increase.”
Carney believes that cancer diagnostics can be improved by relying more on biomarker blood tests, rather than tissue or genetic testing. “Gene tests give us probabilities of what will happen, [while] blood tests are a real time snap shot of what is happening with the body of a cancer patient at that time in the life of the patient,” he says. “Primary tumor data is old news in someone who has a new metastasis and therefore the most practical way to get the new news is with a blood test. We need biomarkers like HER-2, uPA, TIMP-1 that are found expressed in the primary tumor tissue, and once the tumor is removed, can be followed with a blood test. Most likely these biomarkers are found in very small quantities in early cancer but increase in the blood with the growth of metastatic tumors.”
For cancer inside the body in less accessible areas, diagnostic imaging tests may be invaluable. The key is making them specific enough to give a clear diagnostic result. Last week the U.S. FDA’s Oncologic Drugs Advisory Committee (ODAC) gave unanimous support to the clinical utility of imaging an indeterminant renal mass, if the imaging test shows labeled clear cell renal cell carcinoma (ccRCC) within the kidneys. According to Paul Bevan, director of R&D at Wilex, this is particularly important because kidney cancer is rarely found as a result of symptoms of illness. “Discovering kidney cancer often happens as an incidental result of screening for something else, and while they are looking in there, they find a lump on a kidney.” Determining whether the tumor is malignant before surgery is crucial. “Because you remove the kidney for biopsy, and then it turns out to be benign, you can’t put it back in again!” says Bevan. “We have biomarkers for malignant tumors that can clearly label malignant kidney cells by their expression of carbolic anhydrous (CA-9), which is labeled with iodine-124 and imaged in PET/CT scanners.” If the diagnostic imaging test shows no CA-9 labeling, then the kidney tumor is benign, and there is no need for surgery. Periodic imaging checks for changes in the tumor are all that is needed.
Removing future limitations
A major limitation in cancer diagnostics, according to Pike, is improving our still vastly incomplete understanding of cancer biology, and how the tumor and host interact over time. “The recent improvements in quantitative proteomics developed by Proteome Sciences and others in the field means we are able to delve deeper into these issues to provide new diagnostic markers,” says Pike. “We still need to improve the integration of proteomic data with genomics and other clinical and biological measures and perhaps finally debunk the myth that the genome can predict everything.” Indeed, as Bevan says, we are now moving from an anatomic to a biological description of a tumor, which will be more effective at diagnosing cancer for the next generation.
The image at the top of the page is from Bio-Rad's Bioradiations article on their Bio-Plex® Human Cancer Assays.