Research Update Corner: Fall 2010
Signs of the Times: Biomarkers Offer Clinical Promise in Pancreatic Cancer
Historically, cancers have been understood and treated based on their physical attributes: what we can “see” about them, including where they started, and what they look like under a microscope and through imaging (CT, MRI, etc.). The TNM (tumor/node/metastasis) staging system, introduced more than fifty years ago, remains the gold standard for classifying tumors based on their primary size and location (T), and whether they have metastasized (spread) to lymph nodes (N) and distant parts of the body (M). Today, individuals diagnosed with cancer are evaluated for TNM, and these descriptions are combined to determine a disease stage. Additionally, a pathologist examines the microscopic structure of the tumor’s cells to determine its histological classification. Together, this information helps guide oncologists in determining an optimal treatment course.
Although TNM staging and histology remain important to determining therapeutic intervention, new factors, such as biomarkers, are playing an increasing role in cancer care. Biomarkers are molecules (proteins, DNA or RNA) that can be used to indicate the presence of cancer. They are found in blood or other body fluids (such as urine and saliva), or in tumor tissue. Biomarkers are exciting to cancer researchers and clinicians because they help divide tumor classifications into smaller groupings, called ‘molecular subtypes,’ that behave in distinctly different ways. These cancer ‘signatures’ can be used to aid in treatment decisions, as well as for early detection and monitoring of response to treatment.
Biomarkers can be used to detect the presence of cancer before it is visible. Think of biomarkers as cancer’s “pool water test strips.” Pool owners understand the benefits of using test strips to monitor pH balance and chlorine level. Each week, we faithfully dip our test strip into the water and wait for a chemical reaction to take place, the different colors of the strip assuring us to varying degrees whether the water is safe to swim or if an adjustment is required. Suppose we forego the test strip for several weeks, relying solely on our eyes as evidence that clear-looking water indicates balanced levels? We may be surprised one day to return to our pools goggles in hand, only to find our beloved oasis has an eerie green tint.
How did the water turn green, seemingly “out of nowhere?”
Actually, for days and possibly weeks, the pool water was undergoing chemical changes that led to the growth of algae and eventually turned the water green – only these changes were not visible to the eye. Using test strips allows us to detect subtle chemical reactions in the pool water before they become visible (and the water turns green). Also, we can use information gained from pool test strips to make necessary pH and chlorine adjustments that will clear the water. Perhaps our tests strips can even zero-in on the exact type of algae that has run amok, allowing us to add a single chemical to eliminate the specific culprit (rather than blast our pool full of a chemical cocktail so potent that it burns our guest’s eyes). This is similar to how cancer biomarkers can work: Although they cannot be observed through traditional medical tests, they can be quite effective in alerting oncologists that something is amiss, and often, in guiding them on how best to proceed. Biomarkers help clinicians to look beyond the tangible signs of cancers, allowing their individual chemical compositions (‘signatures’) to speak for themselves.
Biomarkers for Early Detection
With a disease like pancreatic cancer where early detection can influence prognosis, we want to find cancerous cells long before we can “see” them. One such effort to identify various pancreatic cancer signatures is the Foundation’s Biomarker Development Initiative. The Initiative aims to identify protein signatures for pancreatic cancer. Ultimately, the goal is to use these signatures as a basis for developing early detection and screening methods. Earlier this year it was announced that the team successfully developed antibodies for candidate biomarkers. Identifying the correct biomarkers and producing antibodies against them is the first step toward developing an early detection test for pancreatic cancer. The Foundation recently launched Phase II of the Initiative, which seeks to validate the newly developed antibodies. Once validated, the antibodies will be tested in the serum of pancreatic cancer patients to determine whether they show promise for clinical use.
In addition to protein-based biomarkers, major technological advances, such as the high-throughout technology used for DNA sequencing in the pancreatic cancer genome project, supported in part by The Lustgarten Foundation, are enabling scientists to catalog DNA signatures for various cancer cells. The hope is that one day, DNA signatures can be compared against normal cells to check for variations that would indicate the presence of early stage pancreatic cancer. The Lustgarten Foundation supports this kind of leading-edge research.
Biomarkers for Therapeutics
As we grow our understanding of cancer signatures, we can determine which signatures respond to which therapies, widening cancer’s playing field of ‘personalized medicine.’ Breast cancer’s HER2 biomarker (human epidermal growth factor receptor 2) is an example of how enhanced understanding of cancer biology has led to improved, targeted therapies: As with pancreatic cancer, treatment for breast cancer has been selected based on TNM stage and tumor histology. But thanks in part to the identification of certain biomarkers, breast cancer is now also classified based on ‘molecular subtype.’ Today, HER2-positive breast cancer patients have improved prognoses regardless of the stage of their disease, largely because HER2-positivity makes them candidates for targeted therapies. Ideally, we would like to apply this concept of cancer signatures to pancreatic cancer and in fact, much emphasis in the research community today is being placed on identifying pancreatic cancer biomarkers. The pancreatic cancer genome project set the stage for the identification of new DNA signatures by identifying a “treasure trove” of genes involved in the disease.
In addition to uncovering new biomarker signatures for pancreatic cancer, we can apply our existing understanding of biomarkers across cancers that bear similar signatures. For example, abnormal BRCA1 and BRCA2 genes are associated with inherited pancreatic cancer. A recent study in non-small call lung cancer⊃; found that an investigational therapy (olaparib) showed significant antitumor activity in patients with BRCA1 and BRCA2 gene mutations. Olaparib is a poly ADP-ribose polymerase (PARP) enzyme inhibitor. BRCA1 and BRCA2 mutations are also involved in hereditary breast cancer, and PARP is also being evaluated as a potential target for treatment of this disease. Increasingly, the scientific and clinical communities are calling for the development of therapies based on these kinds of ‘crossover’ cancer signatures that show similar molecular defects, but originate in different locations.⊃; The Lustgarten Foundation is exploring opportunities to support these kinds of promising studies in pancreatic cancer.
Individuals with pancreatic cancer have had limited treatment options. The development of targeted therapies has expanded the pool of potential treatments for the disease, but clinicians still lack a reliable way to determine which therapies would prove most effective for individual patients. Biomarkers offer promise in the fight against pancreatic cancer at every level – from early detection, to selection of therapy, to monitoring of treatment response.
⊃; Kin, ES et. al. The BATTLE trial: Personalizing therapy for lung cancer. AACR 2010; Abstract LB-1.
⊃; Ludwig, J. et. Weinstein, J. (2005) Biomarkers in cancer staging, prognosis and treatment selection. Nature Reviews(5), pp. 845-856.