Biomarkers—the essential fuel for personalized medicine—play an ever-growing role in drug discovery, clinical development, and, at least for cancer, in the clinic where genomic profiling of individual tumors often informs therapy selection.
Advancing assay technology, improving techniques for working with FFPE tissue samples, and multistakeholder collaborations are all driving factors.
“This is a pivotal time in cancer research,” said Brian Leyland-Jones, Ph.D., institute director at the Edith Sanford Breast Cancer Institute, and a speaker at GTC’s recent “Oncology Biomarkers” conference. “We’re going to see this emergence of targeted therapies against individual genomic drivers, whatever their disease is, and breast cancer will be one of the first areas.”
The Sanford institute uses systems biology approaches to identify biomarkers. “Looking at one level isn’t enough,” says Dr. Leyland-Jones. “We are applying several complementary molecular profiling methods to tumor bank specimens from several international clinical trials that include all of the major breast cancer subtypes.”
These biomarker sets are being used to predict short-term (such as pathologic complete response) and long-term (such as distant disease free survival and overall survival) outcomes, as well as guide treatment strategies, and identify potential therapeutic targets.
Among several key technologies being used are:
- The whole-genome cDNA-mediated annealing, selection, extension, and ligation (WG-DASL) assay, which will enable the expression profiling of >24,000 protein-coding genes, is now available for use with FFPE specimens.
- Genomic instability, a hallmark of tumor progression and poor prognosis, can be assessed by array CGH with ultra–high-density arrays containing 2 million features providing unprecedented genomic resolution. Also, SNP analysis can now be performed on arrays that assay 1 million SNP loci.
- Genome-wide methylation arrays have become available to interrogate 27,578 CpG loci, covering more than 14,000 genes at single-nucleotide resolution.
Sanford also plans an initial study of 25 patients, “We will use several platforms (exome sequencing, RNAseq, various detailed protein arrays (e.g., phosphorylation arrays) to try to work out in 25 sequential patients in metastatic breast cancer what the individual drivers are,” explains Dr. Leland-Jones.
“Use of mouse models, including mouse avatars, will also be important. Past studies have suggested 10–13 pathway drivers including, for example, DNA repair, metabolism, and angiogenesis.
“I think it is going to be more complicated. It’s still anybody’s guess. Mine is that it’s going to be on the order of 30 to 40 pathways. No matter what it end ups being, I think treatment will require combinations of two or three agents for each of these subsets.”