Targeted therapies represent a significant advance in medical treatment, particularly in oncology. These approaches focus on specific molecular pathways or genetic alterations within diseased cells, aiming to disrupt their growth and survival more precisely than traditional treatments. EZH2 inhibitors are an important class of these targeted agents, offering a novel strategy for combating certain conditions. This approach seeks to minimize harm to healthy cells while effectively treating the underlying disease.
The Role of EZH2 in the Body
Enhancer of Zeste Homolog 2 (EZH2) is an enzyme crucial for epigenetics, the study of heritable changes in gene expression that occur without altering the underlying DNA sequence. EZH2 functions as the catalytic component of a protein complex called Polycomb Repressive Complex 2 (PRC2). This complex silences genes by adding methyl groups to a specific site on histone proteins, known as histone H3 lysine 27 (H3K27). This modification, called H3K27 trimethylation (H3K27me3), leads to a more compact chromatin structure, making genes less accessible for transcription.
Normally, EZH2’s gene-silencing activity is vital for normal biological processes, including embryonic development, cell differentiation, and maintaining stem cell identity. It helps ensure that genes are activated or silenced at appropriate times. However, dysregulation or overexpression of EZH2 can contribute to disease, particularly cancer.
When EZH2 activity becomes excessive or mutated, it can aberrantly silence genes that normally suppress tumor growth. This includes silencing tumor-suppressor genes that regulate cell cycle progression or promote programmed cell death. The uncontrolled silencing of these protective genes allows for unchecked cell proliferation, promoting cancer development, progression, and even metastasis.
How EZH2 Inhibitors Function
EZH2 inhibitors are a class of drugs designed to counteract the abnormal activity of the EZH2 enzyme. These inhibitors work by blocking or reducing EZH2’s ability to add methyl groups to histone H3 lysine 27. By preventing this methylation, EZH2 inhibitors disrupt the gene-silencing process.
This inhibition leads to the re-expression of genes that were previously silenced by overactive EZH2, including tumor suppressor genes. Once reactivated, these genes can resume their normal functions, such as halting uncontrolled cell proliferation, promoting cell differentiation, or inducing programmed cell death in cancerous cells.
By interfering with EZH2’s enzymatic activity, these drugs restore a more normal gene expression pattern within cancer cells. The goal is to revert the cancerous phenotype by allowing the body’s natural anti-cancer mechanisms to function effectively again.
Targeting Diseases with EZH2 Inhibitors
EZH2 inhibitors are primarily developed for treating various types of cancer where EZH2 plays a significant role in disease progression. These inhibitors target cancers characterized by either EZH2 overexpression or specific mutations that enhance its activity. Follicular lymphoma, a common type of non-Hodgkin lymphoma, is a key target, as activating mutations in EZH2 are found in a notable subset of patients. Even in cases without specific EZH2 mutations, the enzyme’s overactivity can contribute to the disease by silencing genes that would otherwise limit B-cell proliferation.
Diffuse large B-cell lymphoma (DLBCL) also shows promising responses to EZH2 inhibition. In certain subtypes of DLBCL, EZH2 gain-of-function mutations are identified as driver mutations. Inhibiting EZH2 in these lymphomas can help restore immune surveillance, making cancer cells more visible to the immune system.
Beyond lymphomas, EZH2 inhibitors are being investigated for solid tumors, notably epithelioid sarcoma. This aggressive soft-tissue sarcoma often exhibits a loss of INI1 protein, which leads to an oncogenic dependence on EZH2. Other solid tumors, including some prostate, breast, and lung cancers, have also shown EZH2 overexpression, indicating potential broader applications.
EZH2 Inhibitors in Clinical Use
Tazemetostat is a notable EZH2 inhibitor approved for clinical use. It was initially approved for adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma that cannot be completely removed by surgery. This approval was based on its effectiveness in patients whose tumors lacked INI1 expression, a characteristic feature of this sarcoma subtype.
Subsequently, tazemetostat also gained approval for specific indications in follicular lymphoma. It is approved for adult patients with relapsed or refractory follicular lymphoma whose tumors have an EZH2 mutation and who have received at least two prior systemic therapies. Additionally, it is approved for adult patients with relapsed or refractory follicular lymphoma who have no other satisfactory treatment options, regardless of EZH2 mutation status.
Ongoing clinical trials are exploring EZH2 inhibitors in other cancer types and in combination with other therapies. These trials aim to broaden the applicability of these drugs and enhance treatment outcomes. While generally considered to have a manageable safety profile, side effects can occur, including fatigue, nausea, and changes in blood counts. The administration typically involves oral tablets.