By Dr. Anirban Maitra
In conjunction with our outstanding gastroenterology team (Drs. Canto and Dunbar) and expert pathologist (Dr. Montgomery), my laboratory has been investigating molecular events that drive the progression of Barrett’s esophagus to esophageal cancer.
There are two very important issues that need to be addressed by the Barrett esophagus/ esophageal cancer research community:
a. First, we need better molecularly targeted treatment options for patients who already have established esophageal cancer. As we know, the vast majority of presents with advanced malignancy that is often amenable to surgery. For these patients, we need all the resources (“all hands on deck”) approach for cure.
b. Second, we need better molecular predictors for identifying those individuals with Barrett esophagus who will progress to cancer. Fortunately, the vast majority of patients with Barrett esophagus will never develop cancer in their lifetime – but a small minority will do so. If we can identify this subset right at the outset using genetic tools, we can focus most of our resources on this subset of patients.
In the past year, funded almost entirely by philanthropic monies received through this website and the D’Amato Foundation, we have achieved considerable progress in identifying new targets in Barrett esophagus using cutting edge gene chip and other molecular profiling technologies. One technique, that we call Serial Analysis of Gene Expression or SAGE, was first discovered right here at Hopkins in the laboratory of Dr. Bert Vogelstein, the most cited scientist in all of medicine. SAGE allows us to identify all of the abnormally expressed genes in a particular tumor type compared to normal tissues from that same organ. We have performed SAGE on endoscopic biopsies of Barrett esophagus and esophageal cancer, and have identified several new predictive and therapeutic targets (Figure 1).
Figure 1: A new molecular marker for Barrett progression identified by SAGE. Expression of this marker is progressively increased during the transformation of Barrett esophagus to high grade dysplasia and cancer. Moreover, cancers that express this molecule in the malignant cells have a worse prognosis than those that do not, suggesting it could have identify those patients who would need most aggressive therapy.
We have also developed a new technique of data integration in the laboratory called “Integrative Epigenomics” that uses a powerful computer algorithm to identify molecular abnormalities during Barrett progression (Figure 2). This program was built by a very talented scientist, Dr. Hector Alvarez, who has been funded by philanthropic resources to perform esophageal cancer research. Using this algorithm, we have also identified several promising new biomarkers for Barrett progression, including a particularly promising “blood test” for esophageal cancer.
Figure 2: Integrative epigenomics of Barrett esophagus progression. An algorithm to integrate gene chip data that looks at DNA and RNA abnormalities in Barrett esophagus and adenocarcinoma, and helps “zoom in” on those most likely to be a major player in cancer formation. This method can also help identify new biomarkers (for example, a new “blood test” that we are evaluating)