Genomic, Proteomic Tumor Analyses May Advance Breast Cancer Treatment

Employing proteogenomics helps identifies therapeutic targets in breast cancer.

Rogue proteins that drive cancer cells may be a potential therapeutic target for cancer, according to a study published in Nature Communications.

In mouse models of breast cancer, the investigators analyzed proteins present in the tumors. The results of the study showed that some protein alterations can be used to identify drugs that could work against some cancers.

“Proteins carry out most of the biological functions in the cell,” said senior author Li Ding, PhD. “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.”

According to Ding, an important reason to prioritize the systematic study of cancer proteomics is that most cancer therapies developed from genetic studies specifically target proteins.

“Identifying the rogue proteins of cancer is an important pathway toward developing new drugs,” said co-author Reid R. Townsend, MD, PhD.

Ding added that proteomics can also be used to validate and confirm their genomic findings.

“In addition, it’s another tool to uncover additional events that drive cancer and are specific to individual patient tumors, including the amount of ‘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,” Ding said. “We also can test these therapies in the mice before we evaluate them in patients.”

For the study, the investigators analyzed the chemical modification phosphorylation, which plays a 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,” said investigator Steven A. Carr, PhD.

The investigators examined 24 tumor samples obtained from patients with breast cancer that were transplanted into mice. They found that 22 of the transplanted samples retained their genetic and proteomic identities as specific types of breast cancer.

A proteomic analysis of the tumors was also conducted, and identified multiple protein targets that have the potential to respond to drugs.

The investigators showed dialed-up activity of multiple protein pathways that could be targeted using PI3K and mTOR inhibitors, both separately and in combination, depending on the tumor.

They also demonstrated that drugs against HER2 positive breast cancer, such as the dual ERBB2/EGFR inhibitor lapatinib, could potentially benefit more patients than are currently receiving treatment, when an analysis of the tumor proteins is considered.

Although a majority of the tumor models recapitulated specific types of breast cancer, surprisingly, 2 of 24 tumors evolved into a completely different type of cancer after transplantation into the mice. Instead of showing breast cancer, the tumors resembled lymphoma and were driven by Epstein-Barr, according to the authors.

The authors noted that the analysis of lymphoma-like cancers was the first proteomic study of this specific tumor type, and that it provides an explanation for why investigational drugs that inhibit BTK have been successful in treating 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 mice,” Ding said. “With advances in cancer proteomics that increase the speed of measurement, we are moving forward a future that included genomic and proteomic analyses of patient tumors.”

Co-author Matthew J. Ellis, MD, PhD, agreed, saying that the findings provide promise.

“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,” Ellis concluded.