Stanford study probes how MYC oncogenes cause cancer, and how to stop them

A superfamily of genes involved in the most common human cancers not only fosters tumor growth but also helps shut down immune system defenses against the cancer, according to a recent study.

The MYC oncogene is considered to be a "master regulator" of many of the cellular processes involved in human cancers. Although many studies have documented MYC's role in cancers, there are as yet no clinical treatments that aim to inactivate it.

An extensive review of the research on how the MYC oncogene works, and the promising methods for targeting it, appears in Nature Reviews: Clinical Oncology, Sept. 10. The authors, led by Dean Felsher, are from Stanford University School of Medicine.

How it works

Oncogenes are mutated genes that have the potential to cause cancer. Normal cells control MYC genes. But genetic alterations can increase MYC expression, setting it on a course of rewiring the complex metabolic pathways that make tumors grow and replicate. 

"MYC drives cancer by both enforcing immortal cell growth through increasing replication, rewiring metabolism, blocking mortality and by enabling cancer cells to force the host to provide them with both nutrients and to block the ability of the host immune system to attack the tumor," says senior author Felsher, a professor of medicine-oncology and pathology.

MYC oncogenes are doubly dangerous as they not only spur tumor growth, but also disarm the body's immune system, preventing immune cells from finding cancer cells. 

As Felsher characterizes it, "MYC hijacks the immune system by causing tumor cells to put on their surface, `do not attack me' signals and by secreting factors into the blood that suppress immune cell maturation and activation."

Developing therapies

Cancer is a complex process, and despite evidence from mouse cancer studies showing that targeting MYC can shrink tumors, many difficulties have prevented translating this into clinical therapies for humans. 

The researchers review work on several promising strategies for creating drug therapies to deactivate MYC. These include inhibiting MYC signaling, decreasing its stability, reducing its mRNA stability, targeting upstream regulators to stop its transcription, and other approaches.

Asked which of these potential therapeutic strategies had the best chance for success, Felsher said. "Best would-be drugs that directly block specific MYC functions. But, so far what has been most promising has been drugs that particularly kill cancers that are high in MYC. We highlighted one way to do this last year, where we showed that blocking fat production kills MYC cancer cells."

Felsher's laboratory at Stanford has developed a nano-immunoassay method to analyze tiny amounts of blood or tumor tissue, which has promise as a diagnostic tool for cancer.

Felsher highlighted the inspiration for the laboratory's work.

"All of this work started out with my work as a fellow with J. Michael Bishop, whose Nobel Prize-winning research with Harold Varmus, really provided the entire paradigm that this work started," he said. "Their suggestions really inspired me in all my work for the last more than 20 years."

--------------

R. Dhanasekaran et al. The MYC oncogene — The grand orchestrator of cancer growth and immune evasion. Nat Rev Clin Oncol (Sept. 10, 2021). https://doi.org/10.1038/s41571-021-00549-2