Scientists uncover a new approach for treating aggressive cancer

Researchers at the University of North Carolina at Chapel Hill and the UNC Lineberger Comprehensive Cancer Center have uncovered a new role of a chromatin-modulatory enzyme, termed EZH2, during cancer development. They then developed a new therapeutic approach with a potent small-molecule inhibitor of this enzyme.

Certain subtypes of blood cancers such as acute leukemias rely on multiple mechanisms for sustaining growth of aggressive cancer cells. Notably, these mechanisms include those driven by EZH2, a chromatin-modulatory enzyme, and cMyc, a prominent cancer-causing factor. UNC researchers now show that these two factors can directly associate with one another, modulating cancer-cell-specific programs of gene expression.

To develop pharmacological means of targeting both EZH2 and cMyc, they teamed with the chemical biologists at Icahn School of Medicine at Mount Sinai and designed a new small-molecule, MS177, based on the proteolysis-targeting chimera (PROTAC) technology. MS177 targets both EZH2 and cMyc and thus inhibit cancer growth.

Their findings are published online in Nature Cell Biology.

"EZH2 plays a very important role during cancer progression and is a known target suitable for drug development," said UNC Lineberger’s Greg Wang, PhD, associate professor of Biochemistry and Biophysics and Pharmacology at the UNC School of Medicine and co-lead author of this research article. "We are amazed by the efficiency of small-molecule PROTAC in simultaneously targeting EZH2 and cMyc in cancer cells."

They found that EZH2 possesses two different binding patterns on chromatin in acute leukemia cells, eliciting two distinct gene-regulatory programs (Figure 1). On the one hand, EZH2 forms a canonical protein complex termed PRC2, leading to gene repression at a set of genomic regions; on the other hand, EZH2 interacts with cMyc to activate gene expression at genomic sites distinctive from the above ones. "This explains why the current small-molecule inhibitors of EZH2 cannot block EZH2 completely. PROTAC addresses this gap," said Jun Wang, PhD, postdoctoral researcher at UNC Lineberger and co-first author of the work.

MS177 achieves on-target effect in cancer cells and exhibits profound tumor killing effects, the researchers report. "Compared to the existing enzymatic inhibitors, MS177 is more likely to behave much better for the treatment of patients with acute leukemias. To our knowledge, an agent for dual targeting of EZH2 and cMyc has not been developed before. cMyc is hard to 'drug,'" Greg Wang said. "MS177 thus represents a promising candidate for treating other cancers depending on the above tumorigenic pathways."

Wang J, Yu X, Gong W et al.
EZH2 noncanonically binds cMyc and p300 through a cryptic transactivation domain to mediate gene activation and promote oncogenesis.
Nat Cell Biol, 2022. doi: 10.1038/s41556-022-00850-x

Most Popular Now

Pfizer's elranatamab granted FDA Breakthrough Ther…

Pfizer Inc. (NYSE:PFE) announced its investigational cancer immunotherapy, elranatamab, received Breakthrough Therapy Designation from the U.S. Food and Drug Administrati...

Salvat Laboratories announces submission of New Dr…

Salvat Laboratories announced that it has submitted a New Drug Application (NDA) to the FDA for the approval of the first ocular corticosteroid formulated in a nanoemulsi...

Bayer with continued strong performance

The Bayer Group maintained its strong business performance across all three divisions in the third quarter. "Despite rising inflation and global supply chain problems, we...

Vividion Therapeutics names Jenna Goldberg as Chie…

Vividion Therapeutics, Inc., a biopharmaceutical company utilizing novel discovery technologies to unlock high value, traditionally undruggable targets with precision the...

New insights on antibody responses to Omicron vari…

Knowing how well vaccination against one SARS-CoV-2 strain (with or without previous infection) counteracts infection with a different strain is a critical research quest...

Pfizer and BioNTech receive positive CHMP opinion …

Pfizer Inc. (NYSE: PFE) and BioNTech SE (Nasdaq: BNTX) announced a booster dose of their Omicron BA.4/BA.5-adapted bivalent COVID-19 vaccine (COMIRNATY® Original/Omicron ...

Sugar molecules as a target in cancer therapy

Cancer cells use sugar molecules on their surface to disable attacks by the body's immune system. Researchers at the University of Basel now report on how this mechanism ...

COVID vaccination improves effectiveness of cancer…

Patients with nasopharyngeal cancer are often treated with drugs that activate their immune system against the tumor. Until now, it was feared that vaccination against Co...

Making melanoma immortal: Pitt scientists discover…

Scientists at the University of Pittsburgh School of Medicine have discovered the missing puzzle piece in the mystery of how melanoma tumors control their mortality. I...

New drug shows promise for fighting both COVID-19 …

While vaccination can provide life-saving protection against COVID-19, scientists are still searching for ways to treat severe infections, including in people who cannot ...

Study reveals vaccine confidence declined consider…

A new study suggests that, despite the success of the COVID-19 vaccination campaigns, vaccine confidence has declined significantly since the start of the pandemic. Re...

Sanofi and GSK's next-generation COVID-19 booster …

After the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for VidPrevtyn® Beta, the vaccine was approved by t...