Another resource that gives Memorial Sloan-Kettering a distinct advantage in the field is its Genomics Core Laboratory and its DNA Sequencing Core Laboratory. The latter recently received a huge boost in sequencing capabilities through the purchase of an instrument called a 454 -- a "next generation" DNA sequencer. Both facilities are led by Agnès Viale. The genomics lab analyzes tumor cells using various microarrays (also called "chips"), which can monitor thousands of genes at the same time to look for changes in the number of copies of a gene or determine whether a gene is expressed, for example. Data from these microarrays might explain differences between tumor cells and normal cells or distinguish different subtypes of the same cancer.
Using next-generation sequencing, investigators are able to sequence each individual DNA molecule separately, rather than combining the sequences of all fragments, as older sequencing machines do. "What this means," explained Dr. Viale, "is that if only 1 percent of cells in a tumor have an additional mutation that confers resistance to a drug treatment, we can find it. That small number of cells is what likely would be responsible for disease recurrence, and up until now we had no way to detect that rare additional mutation. This technology is beautiful, absolutely cutting edge."
Recently the Center's tumor analysis capabilities were further enhanced by the creation of the Geoffrey Beene Translational Oncology Core Facility, under the leadership of Adriana Heguy. The facility, which is part of HOPP, extracts DNA from patient tumor samples, prepares the DNA for sequencing, and then outsources the material to high-volume sequencing facilities. It also performs mutation detection and data analysis using software designed by Memorial Sloan-Kettering's bioinformatics team and maintains a centralized database.
"The goal of our core is to identify novel mutations in different cancer types, as well as to characterize the samples for known mutations that can ultimately translate to new options for patient care," Dr. Heguy said. "Our laboratory has been in operation for less than six months, and we are already collaborating with a large number of researchers across Memorial Sloan-Kettering who are utilizing our technology in diverse tumor types."
The Center's research on genomic changes in lung adenocarcinoma is moving forward. A multidisciplinary team of clinicians and basic scientists, led by medical oncologist Mark G. Kris, has received a large grant from the National Institutes of Health to expand the work started by the LCOG. Members of the team are working on a variety of projects, including the development of newer targeted therapies; the search for additional genes that cause the formation of lung cancer, as well as genes that mediate the metastasis of lung cancer to the brain; and the study of genes related to disease persistence.
"Disease persistence means that even in patients for whom targeted therapies like gefitinib and erlotinib induce massive tumor shrinkage, you never get rid of all the cancer," explained Dr. Pao. "So we're trying to figure out why these cells persist."
Members of Memorial Sloan-Kettering's lung team also have participated in the Tumor Sequencing Project (TSP), a federally funded, multi-institutional collaboration that is seeking to map genomic changes in lung adenocarcinoma. In November 2007, the TSP team published a paper in Nature identifying more than 40 previously unknown genomic regions that are frequently altered in lung adenocarcinoma. The paper was based on a different approach than the one used by LCOG, a technique called single nucleotide polymorphism (SNP, pronounced "snip") profiling, which allows investigators to look for changes in the number of DNA copies that occur in tumors on a genome-wide level. [PubMed Abstract]
