This story originally ran on March 25.
By Tony Fong
A proteomic technology will be used to help discover and identify new biomarkers to evaluate five new investigational breast cancer drugs as part of one of the biggest screening trials for the disease.
Last week, the Biomarkers Consortium announced the launch of I-SPY2 for the screening and development of new drugs to treat high-risk, fast growing breast cancers.
The trial, anticipated to last five years and to cost $26 million, will emphasize a microarray-based gene expression test from Agendia and MRI imaging technology from Sentinelle Medical. However, reverse-phase protein microarray technology developed by Lance Liotta and Emanuel Petricoin, co-directors of the Center for Applied Proteomics and Molecular Medicine at George Mason University, will also be used.
The protein arrays — the only proteomic technology that will be used in I-SPY2 — will be used to profile a "few hundred signaling protein activations in the laser-capture microdissected tumors." The activations will include the targets for the different target inhibitors included in the trial, Petricoin told ProteoMonitor last week.
Five investigational agents have been selected for the first phase of I-SPY2: Abbot Laboratories' ABT-888, or veliparib, a PARP inhibitor; Amgen's AMG 655, or conatumumab, an APO/TRAIL inhibitor, and AMG 386, an angiogenesis inhibitor; and Pfizer's CP-751,871, or figitumumab, an IGFR inhibitor, and HKI-272, or neratinib.
The drugs are molecularly targeted inhibitors, not broad-scale chemotherapeutics, and the role of the reverse-phase protein microarray technology is to measure how tumors respond to them.
Donald Berry, the co-PI on I-SPY2, told ProteoMonitor that proteomic biomarkers "are not fundamental to the design of the trial" but would rather be "correlative."
Berry is professor and chair of the department of biostatistics and division head for quantitative sciences at the University of Texas MD Anderson Cancer Center.
"We'll take the information [generated by Petricoin and his team], look back at the data on particular drugs, and see if there's any information that particular drugs are doing better," he said.
I-SPY2 stands for Investigation of Serial Studies to Predict Your Therapeutics Response with Imaging and Molecular Analysis 2. To date, more than 20 cancer centers, including many of the National Cancer Institute’s Comprehensive Cancer Centers, are participating in the trial, including the Mayo Clinic in Rochester, Minn., and Scottsdale, Ariz.; the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center; and Inova Health Systems in Virginia.
The participating centers will recruit and treat patients.
In a statement announcing I-SPY2, the Biomarker Consortium said that the trial "will focus on treatment in the neoadjuvant therapy setting, in which chemotherapy is given to patients to reduce tumor size before surgery."
All patients in the trial will receive the standard of care and "most" participants will receive one investigational drug. Up to 12 different cancer drugs will be tested during the course of the trial.
The Foundation of the National Institutes of Health, one of the members of the Biomarker Consortium, received a master Investigational New Drug approval from the US Food and Drug Administration. This will allow the I-SPY2 organizers and administrators to "graduate, drop, and add drugs seamlessly throughout the course of the trial without having to stop the trial to write a whole new protocol," reducing the amount of time required to move from one drug to another in the trial, the consortium said.
The Biomarkers Consortium is a public-private partnership comprised of the FDA, the NIH, the Pharmaceutical Research and Manufacturers of America, major drug manufacturers, and the Biotechnology Industry Organization.
Because the focus of the I-SPY2 trial is on discovery, Petricoin emphasized that the work being carried out by his center will be done for research purposes only, and that no patients will be stratified initially based on their findings.
"It will all be basically for biomarker discovery and correlative analysis, meaning initially what we'll be doing is seeing response rates," he said. Because it is a neoadjuvant trial, "we'll be able to see response very quickly and be able to match that against the signaling signatures that we're getting from the tumors."
But the discovery work, he added, could lead to stratification-based research down the line.
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"The hope is that if we see pathway activation that correlates with response to the different targeted therapies, then we can graduate those [discovery] markers into stratification markers," Petricoin said.
The reverse-phase protein microarray technology allows researchers to look at the activity level of proteins in tissue specimens, which in turn allows them to measure how the protein drug targets respond to the drugs in vitro [See PM 03/29/07].
The trial is the follow-up to I-SPY1, a trial conducted between 2003 and 2009 that sought to identify the best MRI and molecular markers of early response to systemic treatment of breast cancer. CAPMM also participated in I-SPY1.
According to Petricoin, the center's involvement in the trials results from collaborations between himself, Liotta, and I-SPY2 co-PI Laura Esserman that looked at signaling signatures of breast cancer. That work dated back to the days when Liotta and Petricoin were at the NIH. Esserman is a professor and director of the Carol Franc Buck Breast Cancer Center at the UCSF.
"As we graduated the reverse-phase array technology, we started working with [Esserman] on I-SPY1 material because she saw the value of the kind of network analysis that we could do," Petricoin said.
In the first I-SPY trial, the Liotta-Petricoin team measured "broad-scale signaling networks to see if we could identify biomarkers that correlated with response to taxane and [Adriamycin] therapy," the standards of care.
Unlike I-SPY2, no new investigational drugs were tested in I-SPY1.
While there was no formal vetting process for the reverse-phase protein microarray technology, in effect I-SPY1 was a dry run for the technology, Petricoin said. Immunohistochemistry and fluorescence in situ hybridization are the FDA-approved methods for measuring HER2 proteins, and during I-SPY1, he and his colleagues were able to show 97-percent concordance with those two methods in HER2 protein measurements, he noted.
"And so that gave all of us further confidence that when there's a marker where we already know what the expression levels are … we found that we are very concordant," he said.
Aside from I-SPY2, the CAPMM team is using the reverse-phase protein technology in other projects to bring proteomics into the realm of personalized medicine. One is investigating Gleevec as a potential treatment for colorectal cancer. The drug, manufactured by Novartis, was approved by the FDA in 2001 for treating chronic myelogenous leukemia. It also is used for treating gastrointestinal stromal tumors [See PM 01/22/10].
Another study, funded by the Side-Out Foundation, is testing each of the 13 FDA-approved targeted cancer therapies as a treatment for breast cancer [See PM 03/12/10].
None of the work from these two projects will be incorporated into the I-SPY2 trial.
According to the Biomarker Consortium, the trial has the potential to significantly reduce the cost of drug development and hasten the drug-screening process "with the goal of bringing safe and effective new drugs to market more efficiently." Currently it takes between 12 and 15 years and more than $1 billion to bring a drug to market.
"The I-SPY2 trial explores a whole new way to rapidly screen new cancer treatments and match the therapy to specific markers," Janet Woodcock, director of the Center for Drug Evaluation and Research at the FDA, said in a statement. "Developing individualized medicines needs a solution bigger than any one group can generate," and the I-SPY2 project represents a new model for such efforts, she added.