University of Rochester Medical Center orthopaedic researchers have identified a new strategy to make a rare soft tissue tumor more sensitive to chemotherapy, and during the investigation they learned more about this malignancy’s stubborn resistance to systemic treatment.
“The problem with soft tissue sarcoma is that during the past 20 or 30 years the long-term survival rates have not budged beyond 50 percent, despite improvements in surgery that allow us to achieve local control of the cancer most of the time,” said Randy N. Rosier, M.D., Ph.D., professor of Orthopaedics who established the department’s Center for Musculoskelatal Research.
“Even if you successfully remove this cancer, unless you can kill any stray cells with chemotherapy the malignancy is likely to turn up somewhere else,” Rosier said.
Soft tissue sarcoma (STS) originates in the nerves, tendons, muscle fibers, blood vessels, and linings of the joints that connect and support other body structures. About 10,000 people a year are diagnosed with STS, and 60 percent arise in the arms, legs, hands and feet. The disease afflicts people of all ages, including children.
Dozens of subtypes of STS exist, and many diverse, inconsistent genetic changes fuel their growth. Thus, it has been difficult to find new, targeted therapies or combinations of therapies that might overcome the resistance to standard treatment and destroy the cancer.
In a study led by Rosier and corresponding author Erik R. Sampson, Ph.D., published recently in the Journal of Orthopaedic Research, they suggest that a known drug, vorinostat, could be used as a sensitizing agent in combination with doxorubicin, a chemotherapy, as a novel option for the treatment of one type of STS, fibrosarcoma.
The research is in early stages and still needs to be tested in clinical trials in humans. But scientists are optimistic because vorinostat is already known to have an impact on osteosarcoma and other cancers, Rosier said.
URMC researchers began looking at vorinostat after hypothesizing that STS might rely on a family of enzymes known as histone deacetylases (HDAC) to silence genes involved in cell death regulation, thereby allowing the tumor’s notorious resistance to chemotherapy. Vorinostat, an HDAC inhibitor, targets all four classes of HDACs. The drug’s ability to reverse the HDAC-specific changes to cancer cells is evidence of a selective toxicity toward a variety of cancer cells and not normal cells. Hence, researchers speculated that vorinostat might boost the sensitivity of cancer to chemotherapy, while sparing normal cells any harm.
Manufactured by Merck & Co., Inc., vorinostat was approved by the Food and Drug Administration in 2006 for the treatment of cutaneous T-cell lymphoma. It is now being investigated in nearly 100 clinical trials to treat a variety of other cancers. of the trials, however, are evaluating its effectiveness in overcoming chemo resistance in soft tissue sarcomas.
With funding from Merck, Sampson, Rosier and colleagues began preclinical tests of vorinostat in three diverse STS subtypes: fibrosarcoma, leiomyosarcoma, and liposarcoma, as well as in normal cell cultures. They found that vorinostat alone induced cell death in both normal and STS cells, though only modestly at doses that could be appropriately used in patients.
Next, they tested whether pre-treating STS cells with vorinostat prior to administering doxorubicin, the DNA-damaging chemotherapy drug routinely used to treat STS, would yield better results. According to the study, the combination had a “striking, synergistic effect” on cell death in fibrosarcoma cells. However, the two drugs did not have the same effect on leiomyosarcoma or liposarcoma.
The disparate results provide further evidence that no common gene patterns cross all of the STS subtypes. It is likely that leiomyosarcoma and liposarcoma may not co-opt HDACs during their malignant transformation, said Sampson, a research assistant professor in Orthopaedics at URMC.
The next step, Sampson said, is to identify the cell-death regulatory genes that are selectively lost in fibrosarcoma cells and then re-activated by vorinostat. That would provide scientists with biomarkers that could further aid physicians and patients in treatment decisions.
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