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FDA, NCI Memorandum Indicates Growing Interest in Proteogenomics as Clinical Approach

NEW YORK (GenomeWeb) – Proteogenomics remains an emerging science, but a memorandum of understanding announced this week by the National Cancer Institute and the US Food and Drug Administration indicates growing interest in the approach as a tool for research and precision medicine.

The MOU calls for the two agencies "to share information that will accelerate the development of proteogenomic technologies and biomarkers, as it relates to precision medicine in cancer," and reflects FDA's view of proteogenomics as a likely significant clinical technology in coming years.

"Looking ahead and kind of skating to where the puck will be, we think that more and more sponsors will be embedding proteogenomics [in their submissions]," said Gideon Blumenthal, deputy director, Office of Hematology and Oncology Products, Center for Drug Evaluation and Research at FDA. "It's more exploratory now, but probably in the next five to 10 years it will be potentially used for more clinical decision making. So we feel we need to get ahead of the science and learn about the state of the science with experts and other sister agencies like NCI."

Driven by technologies like next-generation sequencing and improvements in the breadth and quality of proteomic data, proteogenomics has seen increasing adoption in recent years. The approach aims to integrate both protein and nucleic acid data in the hope that combining  multiple levels of molecular information will enable better understanding of biological and disease processes and improve biomarker discovery and development.

For instance, while genomic studies have discovered a large number of genomic changes in cancer tissue, it is difficult to assess which are meaningful and which have little or no biological relevance. Proteogenomics can potentially aid such efforts by adding proteomic data to the mix. The hope is that by looking at proteomic data, researchers can identify which genomic aberrations are ultimately translated into changes at the protein level, with the assumption being that such changes are more likely to be of significance than those that do not lead to protein alterations.

While individual labs and researchers have begun to adopt proteogenomic methods, one of the most notable drivers of the technologies has been the NCI's Clinical Proteomic Tumor Analysis Consortium (CPTAC), which focused on development and application of proteogenomic workflows in its recently completely second phase and will feature the technology prominently in its just-launched third phase.

In a recent interview discussing proteogenomics and the CPTAC initiative, Henry Rodriguez, director of the Office of Cancer Clinical Proteomics Research, Center for Strategic Initiatives at NCI, which is representing the proteogenomics MOU from NCI's side, noted that, "genetic information about a person’s cancer has provided a wealth of knowledge and significant progress in stratifying patients over the last decade, especially in the discovery and development of treatments that target specific genetic abnormalities."

"However," he added, "prediction of drug response and toxicity and the relatively rapid acquisition of resistance to such treatments significantly limit their utility and remains a challenge. Complementing genomic analysis with proteomic analysis would systematically capture the interrelationship and provide new insights to predicting clinical response to therapeutic agents."

Blumenthal said that he saw cancer immunotherapies as an area where proteogenomics has potential to improve treatment.

"We know that particularly with immunotherapy and some of the existing biomarkers looking at proteins like PDL1 using immunohistochemistry, there are some limitations with those technologies," he said. "Perhaps down the road proteogenomic technologies will be able to better characterize the tumor and surrounding microenvironment and better predict which patients will or will not respond to immunotherapy, or which patients may need combinatorial approaches."

To an extent, the field is already seeing what might be thought of as early proteogenomic approaches to immunotherapy, Blumenthal said, citing assays that look at, for instance, PDL1 protein expression along with tumor mutational burden and RNA-based measures of inflammation.

"We are starting to see more of these composite scores looking at DNA, RNA, and protein, that are perhaps better refining patient populations," he said.

The approach has potential outside immunoncology, as well, noted Blumenthal's FDA colleague Reena Philip, director, Division of Molecular Genetics and Pathology, Office of In Vitro Diagnostic Devices and Radiological Health, Center for Devices and Radiological Health. She cited the Applied Proteogenomics Organizational Learning and Outcomes (APOLLO) Network, part of the Cancer Moonshot initiative.

A collaboration between CPTAC, the US Department of Defense, and the Veteran Affairs Veterans Health System, the APOLLO effort aims to build a system in which VA and DoD cancer patients routinely undergo proteogenomic profiling with the goal of matching their tumor types to targeted therapies.

Announced last year, the project is initially focused on analyzing a cohort of 8,000 lung cancer patients drawn from the VA and DoD systems, but plans to expand into a broad range of cancers, Philip said. She noted that FDA is also participating in the project, "contributing whatever we can in terms of how to do the analytical validation."

Philip said that given the relative newness of proteogenomics technologies, FDA was still developing its understanding of the approach and what challenges it might present from a regulatory perspective.

"This is really very new for us, so as we are learning the challenges, being involved in [the MOU and other proteogenomics efforts] will help us," she said. "We are trying to understand from the experts, but then we can contribute in terms of sometimes they don't quite understand how the regulatory process works. So, that is [how we can help] in terms of some of the validation aspects."

Philip also suggested that FDA and its collaborators might undertake as part of the project a mock 510(k) submission for a proteogenomic assay.

She noted that in addition to collaborations with outside entities like NCI, FDA has established a technical working group focused on proteogenomics that brings together people from the different centers within the agency to explore the technology.