“A single marker or molecule does not control what the cell does—you need to look at the pathway. That’s why a systems approach is necessary—you have to understand the functional aspects so you can find biomarkers and look at them in a coordinated manner, rather than one at a time,” states Gordon Mills, M.D., Ph.D., chair of the department of systems biology, and codirector of the Kleberg Center for Molecular Markers at M.D. Anderson Cancer Center.
Dr. Mills says there are currently several companies that won’t build a drug without a proposed biomarker. “That’s as big a paradigm shift as you can imagine from when companies were worried about segmentation of the market to currently where they are worried about finding a drug that works.”
Dr. Mills’ research group is performing mutational detection across large numbers of individuals to identify genetic aberrations to match patients to particular therapies. A new pilot project, called the “Kleberg Program in Personalized Medicine” will involve 10,000 patients. “We will perform mutation detection in patients for whom there is no standard therapy, and who are likely to be entered into clinical trials. The idea will be to use that data to choose the best clinical trial for them independent of their disease of origin.”
The mutation detection assay will be done on the patient’s original diagnostic paraffin block, which has been designed to be CLIA-compatible and has been validated. Dr. Mills says the idea is to target the patient for treatment with an appropriate drug and determine in the trial whether targeting, meaning the drug fits the mutation versus standard of care, will improve outcome. “This pilot project is really to determine if mutational detection for a specific type of biomarker can be used.”
Oncology Biomarker Development
Eli Lilly’s corporate strategy of tailored therapeutics is focused not only on improving outcomes for patients, but to “assure the right drug for the right patient at the right time and dose,” says John Bloom, DVM, Ph.D., executive director, diagnostic and experimental medicine. “Our strategy is to leverage biomarkers to achieve two high-level things: defining probability of technical success so that we’re able to apply quick wins and quick fails, and differentiating our products in the market.”
Dr. Bloom adds that developing oncology therapeutics has its own requirements. These include evidence of target engagement, defined entities the drug is directed toward and the dose-response relationship, and determination of the biologically effective dose and markers to illustrate MOA. There is also the challenge of the normal biology of the host versus the biology of the tumor.
Currently, there are well-characterized pathways of metastases, apoptosis, and DNA repair. “Using molecular profiling, we can better anticipate markers for pathway modulation. Platforms and tools such as mutation analysis or translocations are providing opportunities to advance science at a pace that’s faster than drug development, which is a problem.”
The challenges of applying these tools to oncology include having the right surrogate to validate targets in early discovery. “Cell lines and xenografts are remote with limited relevance to cancer in the human body. Access to tumor and relevant tissue is a major problem—we have to rely on solid tissue markers and use immunohistochemistry, which is arduous and expensive.” He says that the company is building a capability to integrate the steps of translational biomarker research. “This remains a major unmet need in the area of cancer biomarker development in an R&D setting.”
In addition, Dr. Bloom says that the tumor’s phenotype and genotype often change over treatment, so establishing markers to track these changes can be difficult. Cell-free DNA and circulating tumor cells may provide a noninvasive way to monitor tumor cell biology.
“Blockbuster drugs don’t work in every patient. There are ways to stratify patients,” summarizes Dr. Bloom. “It’s not only going to be good business, but we’re going to be compelled to do it.”