Phenotype-guided therapy may kill treatment-resistant cancer cells

By Robyn Boyle, RPh, for MDLinx
Published December 7, 2017

Key Takeaways

According to a study published in Nature Communications, cancer cells in treatment-resistant metastatic breast cancer tumors share common functional characteristics that could respond to targeted treatment strategies. This is similar to the approach used in lung cancer.

Researchers with the Cancer Systems Biology Consortium, an interdisciplinary group of scientists and oncologists, analyzed cancer cells from women with metastatic breast cancer at several points during the course of their disease to evaluate differences in individual cancer cells and to identify cells that became resistant to treatment.

Their analyses showed that treatment-resistant cells shared important functional characteristics, or phenotypes. The investigators were able to kill treatment-resistant cells with targeted therapy, guided by the phenotype.

“Patient-specific tumor information could help the oncologist select therapy to better control the disease for longer periods of time and spare patients the toxicities from drugs that are unlikely to control disease due to emerging drug resistance,” wrote the authors, led by Samuel W. Brady, Department of Pharmacology and Toxicology, College of Pharmacy, at the University of Utah in Salt Lake City.

Genetic and phenotypic evolution of metastatic breast cancer was evaluated in four patients to better understand how breast cancers become resistant to therapy. To accomplish this, samples were collected before treatment and over the course of their disease. Disease courses varied from several years to almost 15 years in one patient. Samples were typically taken from metastatic pleural or ascites fluids; patients were selected based on the availability of serial samples.

First, they performed genomic DNA sequencing to identify genetic events in cancer cells as they change during various treatments. Then, single-cell RNA sequencing was used to provide information on important pathways that represent specific phenotypes, such as cell growth and death. The investigators focused on linking tumor subclone evolution to emerging oncogenic phenotypes associated with resistance.

The evolution of the cancer cells followed a similar pattern in all patients. As cells sensitive to a given treatment died off, the surviving treatment-resistant subclones became predominant. When a new treatment was attempted, it worked for a while until new populations of resistant subclones formed.

The researchers noticed that at some point a single resistant population of cells survived and created a “bottleneck event.” This often occurred near the end of life.

“Together, these data indicate that using transcriptional profiling to measure the broad phenotypic changes in patients can permit individualized therapeutic approaches to more effectively combat the dynamic and heterogeneous nature of cancer,” the team noted.

Shannon Hughes, PhD, of NCI’s Division of Cancer Biology explains that findings from the study are preliminary.

“[However,] they are important because they demonstrate that the broader approach used in the study, which analyzes tumors as a biological system-rather than as a homogenous mass of cells-can provide new insights into the biology of disease and potentially new treatment options,” she said.

To read more about this study, click here

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