Matching the right patient to the right precision drug is one of the most critical challenges in cancer research today.
For more than 16 years, Fred Hutchinson Cancer Research Center oncologist Dr. Amanda Paulovich has been refining a technology to match proteins on the surfaces of tumors with drugs that can precisely target cells carrying those telltale signatures.
“We tune our instruments to look for proteins because we think they’re important biomarkers,” said Paulovich, who holds the Aven Foundation Endowed Chair at Fred Hutch. “Understanding proteins, which are in fact the targets of the vast majority of modern cancer therapies, is an important component in trying to match patients and treatments.”
That research, which could lead to new cancer drugs and diagnostics, has largely been confined to the laboratory, but it is now about to begin a new phase, translating discoveries into clinical benefit.
With a green light from regulators, Paulovich’s lab is poised to participate in human clinical trials using the technology to measure the amount of a protein called HER2 in breast tumor tissue. Since 1998, breast cancer patients whose tumors are laden with this protein are treated with a laboratory-made antibody, trastuzumab — or Herceptin — that interferes with the dangerous growth of these cells or marks them for destruction by the body’s immune system.
Tumors expressing high levels of HER2 are identified for Herceptin therapy using long-established laboratory methods. However, a new generation of HER2-targeting drugs show benefit even in patients whose breast cancers make low levels of HER2 protein — levels too low to reliably measure with existing tests. Paulovich’s system, called multiple reaction monitoring mass spectrometry or MRM-MS provides reliable and precise measurements of HER2 protein in these low-expressing tumors.
The new generation of drugs, called antibody drug conjugates, use antibodies to ferry attached drug molecules to the tumor site, where they can deliver micro-doses that kill the tumor while sparing healthy cells. They work more like a chemical scalpel than a hammer.
The promise of MRM-MS protein analysis extends well beyond HER2’s role in breast tumors. The Paulovich lab is developing the same technology for other cancers and other proteins targeted by cancer therapies, in hopes of matching patients to the growing array of precise, antibody-based cancer therapies that have been developed since Herceptin. That will likely include tests for tumors bearing PD-L1 and other proteins that are targeted by immunotherapy with a class of drugs called immune checkpoint inhibitors, which work spectacularly well in some patients, and not at all in others. Indeed, the laboratory is currently developing MRM-MS methods to quantify hundreds of proteins that affect our immune system’s responses to cancers.
— Dr. Amanda Paulovich
Paulovich has been driven in her research by the observation that nearly all modern cancer drugs act on cellular proteins. The science of genome sequencing has helped identify the broken or amplified genes that are implicated in many cancers, but the drugs that are meant to treat tumors target proteins, not genes. To understand those relationships, Paulovich steered her research toward identification of biological proteins, their forms and functions — a field called proteomics.
Mass spectrometry was invented by physicists to identify and analyze molecules of all shapes and sizes. Using a zap of electricity, their machines basically blow proteins apart, identifying them by the pattern of debris left behind — a molecular signature as distinct as a fingerprint. It is an exquisite way to identify the cast of characters involved and measure the amounts of these molecules in a sample. In other words: a more accurate way to diagnose and treat disease.
“The gold standard today for measuring proteins in tissues is based on 50-year-old technologies,” said Paulovich. Breast cancer is a case in point.
For decades, biopsy samples have been analyzed with immunohistochemistry, or IHC, which requires highly skilled pathologists to scan microscopic images of stained tumor slices for signs of too much HER2. As a back-up, potential positive samples are re-examined in a test called fluorescence in situ hybridization, or FISH, which can tell if the tumor has an excess amount of HER2-making genes.
Yet these methods of grading and evaluating tumors fall far short of what is needed in the coming era of personalized medicine, where therapies are custom-tailored to fit the unique genetic and molecular profiles of a given patient.
The approval of the HER2 MRM-MS proteomic test by the Clinical Laboratory Improvement Amendments program, or CLIA, is the first for what is anticipated to be hundreds of similar clearances for matching patients to a specific drugs based on proteins found on their tumors.
Little known outside the world of medical testing, CLIA is a regulatory mechanism run by the Centers for Medicare and Medicaid Services to assure that standardized medical tests involving humans are carried out with accuracy and reliability. Nationwide, more than 260,000 laboratories fall under CLIA’s jurisdiction. Strict rules require that laboratory equipment is properly calibrated, that technicians are properly trained and that the step-by-step procedures to carry out a test are understood and could be followed by similarly trained and equipped labs elsewhere.
“With CLIA certification of the HER2 assay, it establishes that our lab has become a ‘CLIA environment,’” said Dr. Jeffrey Whiteaker, the staff scientist in charge of the mass spectrometry at the Paulovich lab.
“This takes us from the research space into the clinical space. It basically provides the rigor and assurance to patients and physicians that the testing is being done in a reproducible and robust manner.”
Establishing the lab as a CLIA environment sets the stage for those hundreds of other assays developed in the Paulovich lab to gain speedier certification for human trials. The full potential of this technology will be realized when a single sample can be tested at once for dozens of cancer-related proteins. Because each biopsy specimen is precious, this “sample-sparing” ability is a critical advantage for the development of mass spectrometry as a tool in cancer care.
For Fred Hutch itself, the CLIA certification of the HER2 assay is a milestone in a strategy to bring advanced research technology to the bedside of cancer patients. Under the direction of CLIA Medical Director Dr. Cecilia Yeung, the cancer center is working to coordinate the development of “homegrown” tests as they move from a Hutch research idea to clinical trials to a new standard of patient care.
For more than 20 years, the Hutch has carried out CLIA-approved testing involving DNA and RNA probes in the Molecular Oncology laboratory headed by Dr. Jerry Radich. The CLIA certification ensures that gene sequencing and PCR probes — like those used to identify viruses by telltale snippets of genetic material — are accurate and meet federal guidelines.
A third lab in the Hutch trio of clinical testing laboratories that perform CLIA-certified tests carries out tissue dissections and a variety of advanced diagnostic and pathology tests, including immunohistochemistry assays like those regularly used in HER2 studies.
Yeung said that with the growth of personalized medicine, the need for reliable, accurate diagnostic tests of new biomarkers is expanding and becoming ever more important.
“Increasingly, pathologists are helping out in clinical trials. We’re moving to the forefront here, in how we help patients that are in these trials,” said Yeung. “Our goal is to make sure we produce the best data for clinical trials, and that we are absolutely spot-on accurate with our measurements.”
Sabin Russell is a former staff writer at Fred Hutchinson Cancer Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and he wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT and a freelance writer for the New York Times and Health Affairs.
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