Analysis of rogue proteins could direct future breast cancer treatments

Genomic testing is an important method of identifying DNA errors that can become a target of therapies in patients with difficult-to-treat cancers. This method is valuable, but it may overlook rogue proteins—another potential marker that may drive cancer cells and direct treatment.

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Advances in cancer proteomics increase the speed of measurement and move medicine toward including genomic and proteomic analyses of tumors.

Advances in cancer proteomics increase the speed of measurement and move medicine toward including genomic and proteomic analyses of tumors.

The systematic study of proteins in tumors—cancer proteomics—is of particular interest since the majority of cancer therapies developed using genetic studies actually target proteins.

In an article published in Nature Communications, researchers studied mice with breast tumors transplanted from human patients, then analyzed the tumor proteins. They demonstrated that some protein alterations could be used to identify potential cancer treatments.

The work is part of the National Cancer Institute’s (NCI) Clinical Proteomic Tumor Analysis Consortium efforts, and involved researchers from Washington University School of Medicine in Saint Louis, The Broad Institute of MIT and Harvard, and Baylor College of Medicine.

“Proteins carry out most of the biological functions in the cell,” said senior author Li Ding, PhD, Associate Professor of Medicine at Washington University. “Knowing the DNA sequence does not automatically tell us everything about the proteins doing work in the cells. This is another layer of tumor complexity that we need to explore to identify new therapies.”

Recent advances in mass spectrometry and in the techniques used to analyze massive quantities of data have allowed researchers to perform complex studies of the proteins in tumor cells. R. Reid Townsend, MD, PhD, Professor of Medicine and Director of the Proteomics Shared Resource at Washington University, stated that identifying the rogue proteins is an important pathway toward developing new drugs.

“In addition,” Ding said, “[Proteomics] is another tool to uncover additional events that drive cancer and are specific to individual patient tumors, including the amount of the ‘rogue’ protein, its specific form, or the type and extent of chemical modifications of the proteins that we know are treatable with approved or investigational drugs. We also can test these therapies in the mice before we evaluate them in patients.”

 Steven A. Carr, PhD, of the Broad Institute, said the team analyzed a chemical modification called phosphorylation. This plays a central role in how healthy and diseased cells communicate.

“Disruption or enhancement in such signaling is often directly related to disease mechanism and can be targeted for therapy,” Carr explained.

The team studied 24 tumor samples from breast cancer patients after the samples were transplanted into mice. Twenty-two of the transplanted samples retained their genetic and proteomic identities as specific types of breast cancer. A proteomic analysis of the tumors also identified multiple protein targets with the potential to respond to drugs.

For example, the researchers showed dialed-up activity of multiple protein pathways that could be targeted with investigational PI3K inhibitors and mTOR inhibitors—both separately and in combination—depending on the tumor.

They also showed that drugs for HER2-positive breast cancer (eg, lapatinib) have the potential to benefit more patients when tumor proteins are taken into consideration.

Most of these tumor models recapitulated specific types of breast cancer, but Ding said the team was surprised that 2 of the 24 tumors evolved into a different type of cancer after transplantation into the mice. Instead of breast cancer, the tumors resembled lymphoma, and were driven by the Epstein-Barr virus. The lymphoma may have arisen from lymphatic tissue present in the breast tumors transplanted into the mice.

The unintentional analysis of the lymphoma-like cancers was the first proteomic study of this type of tumor. Ding said the analysis provides an explanation for why investigational drugs that inhibit BTK have been effective as a treatment for lymphoma.

“Since it is the proteins that interact directly with drugs, the strength of studying proteomics in patient-derived tumor models is the ability to test drug treatment in the mice,” he explained. “With advances in cancer proteomics that increase the speed of measurement, we are moving toward a future that includes genomic and proteomic analyses of patient tumors.”

Co-author Matthew J. Ellis, MD, PhD, of Baylor, agreed. “The mouse work is promising enough to adapt these technologies for real time analysis of patient materials so that clinical trials can be designed to test this new diagnostic and drug selection approach,” he said.

Kuan-lin Huang, a PhD student in genomics and bioinformatics at Washington University, Shunqiang Li, PhD, an Assistant Professor of Medicine at Washington University, Philipp Mertins, PhD, of The Broad Institute, and Sherri Davies, a senior scientist at Washington University were also key contributors to the research.