New Drug Targets Epigenetic Mark, May Help Treat Rare Cancer

In 2020, the FDA approved Epizyme’s drug tazemetostat (Brand name: Tazverik) to treat a rare type of solid tumor called epithelioid sarcoma. Tazemetostat targets the epigenetic enzyme EZH2, which is strongly linked to several cancer types. Now, Epizyme is seeking accelerated approval for tazemetostat to treat a common form of blood cancer called follicular lymphoma, and has clinical trials running for several additional cancer types.

Cancer is a genetic disease that causes unrestrained cell proliferation. Typically, chemotherapies treat cancer by attacking rapidly dividing cells, but this blunt approach can have the undesirable consequence of drowning healthily dividing cells in a flood of cytotoxic poison. With modern technologies, medical researchers can interrogate cancer genomes to uncover hidden genetic weaknesses and develop drugs that precisely exploit those vulnerabilities.

Epigenetics has emerged as a critical target in cancers, capable of triggering tumor initiation and growth. Now, epigenetic drugs are being developed to block the expression of genes that drive rapid cell division in cancer.

On January 23, 2020, America’s Food and Drug Administration (FDA) approved tazemetostat for the treatment of metastatic or locally advanced epithelioid sarcoma in patients who are not eligible for curative surgery. The accelerated approval of tazemetostat was granted to Epizyme Inc. based on the results of their phase 2, multi-national clinical trial, which involved a cohort of 62 subjects with metastatic or locally advanced epithelioid sarcoma1.

Complete or significant tumor shrinkage was observed in 9/62 of participants, with 6 participants presenting no tumor regrowth for six months or longer. Adverse reactions such as pain, fatigue, nausea, decreased appetite, vomiting, and constipation were detected in a third of participants requiring dosage interruptions during the study.

Epithelioid sarcomas are incredibly rare; accounting for approximately 1% of all soft tissue sarcomas, which itself is a rare form of cancer2. When caught early, epithelioid sarcomas can be removed surgically with a high likelihood of survival, but outcomes are often bleaker when patients present with metastatic or locally advanced tumors. With just a 14% overall response rate, the FDA’s approval of tazemetostat reflects the limited treatment options currently available.

As Robert Bazemore, president and CEO of Epizyme points out, tazemetostat is “the first and only FDA-approved treatment specifically indicated for ES patients.” Now tazemetostat provides patients suffering from epithelioid sarcoma with a vital treatment opportunity and a chance to improve an otherwise poor prognosis.

News of tazemetostat’s approval marks an important milestone for epigenetics in drug discovery. It is the first epigenetic drug approved for a solid tumor (other epigenetic drugs have already been approved for blood cancers), as well as the first approved drug that targets a histone methyltransferase.

Tazemetostat works by blocking the activity of a single epigenetic enzyme, called EZH2 (Enhancer of Zeste homolog 2). EZH2 enables cell division by epigenetically silencing genes that stop cells from dividing. EZH2 is a type of epigenetic enzyme, known as a histone methyltransferase, which chemically modifies the histone proteins that package genomic DNA. This silences gene expression by inducing the formation of a tightly packed and inaccessible structure called heterochromatin.

Normally, healthy embryos express EZH2 during development to allow for growth, while adults inactivate EZH2 expression. But some cancers have developed a nasty trick to drive aggressive tumor growth – hijack EZH2 to enable cell proliferation 3.

Drs. Stuart Orkin and George Roberts from the Dana-Farber Cancer Institute in Boston were studying the genetics of sarcomas when they discovered that SMARCB1, a type of tumor suppressor gene, was frequently lost while EZH2 was reactivated4. Further analysis showed that EZH2 was blocking the expression of second tumor suppressor called p16INK4a. They hypothesized that EZH2 may be essential for the survival of the cancer cells that already lack SMARCB1.

In collaboration with Epizyme, Orkin and Dr. George Demetri (also of Dana-Farber) developed tazemetostat to chemically inhibit EZH2. They found that tazemetostat could rescue the expression of the p16INK4a tumor suppressor and only kill cells lacking SMARCB1 while leaving SMARCB1-expressing cells unharmed5.

Looking forward, Epizyme sees tazemetostat helping more cancer patients. The FDA has granted priority review status to Epizyme’s newest application for tazemetostat to treat patients with relapsed or refractory follicular lymphoma.  Unlike epithelioid sarcoma, follicular lymphoma is a common type of cancer, accounting for a fifth of all non-Hodgkin lymphomas. And more clinical trials are underway to assess tazemetostat in a variety of different cancer types distinguished by EZH2 expression. Results eagerly awaited by many!


1. A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma. identifier: NCT02601950

2. Needs T and Fillman E (2019) Cancer, Epithelioid Sarcoma. StatPearls [Internet].

3. Kim KH and Roberts CWM (2016) Targeting EZH2 in cancer. Nat Med.

4. Wilson BG et al. (2010) Epigenetic Antagonism Between Polycomb and SWI/SNF Complexes During Oncogenic Transformation. Cancer Cell.

5. Knutson SK et al. (2013) Durable Tumor Regression in Genetically Altered Malignant Rhabdoid Tumors by Inhibition of Methyltransferase EZH2. PNAS.

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