A new strategy for boosting PD-1 blockers in melanoma

Inhibiting the Siah2 protein in mouse models of melanoma sensitized the cancer to PD-1 blockade by limiting the activity of T regulatory cells, according to research from a team led by Sanford Burnham Prebys Medical Discovery Institute. (National Cancer Institute)

Immuno-oncology drugs like Bristol-Myers Squibb’s Opdivo and Merck’s Keytruda free up the immune system to attack cancer by blocking the checkpoint PD-1. But in melanoma, at least half of patients don’t respond to PD-1 blockers, and those who do often develop resistance to the drug.

Oncology researchers point to one likely culprit for PD-1 resistance: T regulatory cells (Tregs), which are immune cells that limit the ability of so-called killer T cells to destroy cancer. Now, a team led by Sanford Burnham Prebys Medical Discovery Institute is proposing a new way to control Tregs in a way that could boost PD-1 blockers in the treatment of melanoma.

The researchers showed in mouse models that inhibiting a protein called Siah2 can limit the activity of Tregs, making melanoma tumors sensitive to PD-1 blockade. They published the study in the journal Nature Communications.

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The Sanford Burnham Prebys team started with mice that were genetically engineered to lack the Siah2 gene and then introduced melanoma tumors with a BRAF mutation that’s found in about half of patients with the disease. In mice without Siah2, the tumors shrunk, but in animals with the gene, they grew. Administering PD-1 blockers to the mice eliminated melanoma in animals lacking the Siah2 gene.

The researchers went on to study tumors from the Siah2 mutant mice and discovered that they were filled with killer T cells. But there were few Tregs in sight.

Sanford Burnham Prebys has been studying the role of Siah2 in cancer for many years. In 2013, a team there discovered the protein plays an important role in making prostate tumors resistant to hormone therapy, for example.

RELATED: Using Bristol-Myers’ popular leukemia drug to improve anti-PD-1 cancer immunotherapy

Several other research teams are trying different strategies for inhibiting Tregs to improve immuno-oncology treatments. Scientists from Johns Hopkins Kimmel Cancer Center discovered that mice lacking the Yes-associated protein mounted an improved response to PD-1 inhibition in the treatment of aggressive melanoma.

Scientists at Columbia University have been examining the potential of improving anti-PD-1 responses with pentoxifylline, a drug that’s on the market to treat poor circulation. The drug alters the activity of Tregs, and, in mouse models of melanoma, combining it with checkpoint inhibition lowered the tumor burden.

A team at Sanford Burnham Prebys led by professor Ze'ev Ronai, Ph.D., has been studying Siah2 for the past several years because it is known to drive responses inside cells that are related to low oxygen and the unfolding of proteins—processes tumors use to maintain growth.

Ronai’s team is now searching for a small molecule that can be made into an Siah2-inhibiting medicine. "Our discovery only fuels our sense of urgency to find a drug that inhibits Siah2," Ronai said in a statement.

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