Epigenetic Combo Therapy Shows Promise Against Rare Sarcomas

Epithelioid sarcoma, a rare aggressive cancer that usually strikes young adults, and rhabdoid tumors, which affect children, have long been difficult to treat. However, the outlook for people with these subtypes of soft tissue sarcoma brightened in 2020 when the U.S. FDA approved a targeted therapy called tazemetostat (Tazverik™) for certain patients.

Memorial Sloan Kettering Cancer Center (MSK) sarcoma expert Mrinal Gounder, MD, led the research study that resulted in tazemetostat’s approval for people whose tumors contained a mutation in a gene called SMARCB1. Unfortunately, tazemetostat has not worked in most people with the mutation, and some patients who initially respond develop resistance to the drug.

Now an MSK research team led by physician-scientist Alex Kentsis, MD, PhD, together with Gounder and colleagues, has identified mechanisms that activate resistance to tazemetostat in epithelioid sarcoma and rhabdoid tumors. Based on this discovery, the researchers designed a combination therapy that overcomes the resistance in a lab setting. The researchers report their findings in Cancer Discovery.

The combination therapy uses an epigenetic treatment strategy, aiming to alter gene expression. Epigenetic therapies are a new class of drugs that focus on modifying the activity of genes without changing the underlying DNA sequence. In some cases, these therapies can reprogram cancer cells to turn them into normal cells. 

Mutation in SMARCB1 leads to overactive EZH2 protein

Epithelioid and rhabdoid sarcomas develop when SMARCB1, a tumor suppressor gene, gets mutated. Loss of SMARCB1 function causes the EZH2 protein to become overactive, driving the cell to grow uncontrollably and become cancerous.

In people whose tumors respond to tazemetostat, the drug blocks EZH2 and restores the normal expression of genes, including those that regulate cell growth. This reprograms the cancer cells so they behave like normal cells. But in most patients, blocking EZH2 alone is not enough. Either the drug has no effect, or it works for a short time and then the cancer begins to grow again.

To understand how resistance to tazemetostat develops, Kentsis and colleagues studied samples from patients with epithelioid sarcomas or rhabdoid tumors. They analyzed tumors from 33 patients using MSK-IMPACT^®, a tumor-sequencing test that looks for mutations in more than 500 genes.

“It can be difficult to study rare cancers due to the challenge of getting enough tumors to generate answers,” Kentsis says. “But we were able to take advantage of being at a research institution like MSK, where our patients generously donate their samples and participate in clinical trials.”

Adding immunotherapy to the combination

Kentsis’ lab will also explore the possibility of combining tazemetostat with immune checkpoint inhibitors, which release a natural brake on the immune system so T cells recognize and attack tumors. 

Immunotherapy has been effective against some sarcomas, but the researchers need to understand how it would work with epigenetic therapy. A successful combination with immunotherapy might provide a more lasting therapeutic response. “Our long-term objective is to cure these patients definitively,” Kentsis says.

- This press release was originally published on the Memorial Sloan Kettering Cancer Center website