Entinostat is a synthetic benzamide derivative that functions as a histone deacetylase (HDAC) inhibitor. This investigational drug is being studied for its potential in cancer treatment, as it influences gene expression and modifies cellular processes involved in cancer growth and survival.
How Entinostat Works
Entinostat works by selectively inhibiting Class I HDAC enzymes, specifically HDAC1 and HDAC3. Histone deacetylases (HDACs) are proteins that control the acetylation of histones, around which DNA is wrapped. When histones are acetylated, DNA is more open, allowing genes to be actively transcribed. Deacetylation by HDACs compacts DNA, which can silence gene transcription.
By inhibiting HDACs, entinostat increases histone acetylation, leading to a more relaxed chromatin structure. This can reactivate tumor suppressor genes silenced in cancer cells, hindering their growth. Entinostat also influences the acetylation of non-histone proteins, impacting cellular processes like cell cycle regulation, programmed cell death (apoptosis), and cell differentiation. This multifaceted mechanism can enhance the effectiveness of other anti-cancer treatments.
Medical Conditions Under Investigation
Entinostat is currently under investigation for various cancers, often combined with other therapies. It has shown preclinical activity in models of lung, prostate, breast, pancreas, and renal cell carcinoma. For example, in breast cancer, entinostat has been explored with hormone therapies like exemestane, particularly in postmenopausal women with estrogen receptor (ER)-positive metastatic breast cancer that progressed after prior hormonal treatment. This combination aims to reverse resistance to existing hormonal therapies.
Studies have also evaluated entinostat with chemotherapy and immunotherapy regimens. In extensive-stage small-cell lung cancer, entinostat has been tested alongside atezolizumab, carboplatin, and etoposide to improve standard treatment efficacy. Additionally, entinostat has been investigated with nivolumab and ipilimumab for renal cell carcinoma in patients who previously received immunotherapy. It is also being explored with capecitabine for metastatic breast cancer and high-risk breast cancer after neoadjuvant therapy.
Potential Side Effects and Safety
As an investigational drug, entinostat’s full safety profile is still being characterized through clinical trials. It has generally been well tolerated, both alone and in combination regimens. However, patients may experience various side effects, some being more common or significant.
Frequently observed side effects include hematologic toxicities, such as a decrease in white blood cells (neutropenia) and platelets (thrombocytopenia). Fatigue, hypophosphatemia, and gastrointestinal issues have also been reported. While some patients in trials have discontinued treatment due to severe side effects, many adverse events are manageable with dose modifications and supportive care.
Clinical Development and Approval Status
Entinostat has progressed through various stages of clinical development, including Phase I and Phase II trials in patients with advanced malignancies. Based on promising results from the Phase II ENCORE 301 study in advanced breast cancer, entinostat received a “Breakthrough Therapy” designation from the U.S. Food and Drug Administration (FDA) in 2013 for its use with exemestane in ER-positive metastatic breast cancer. This designation expedites drug development and review for serious conditions.
Despite this designation, entinostat does not currently have full regulatory approval for clinical use by any agency. A Phase III multicenter international registration trial, E2112, is ongoing to confirm the overall survival benefit observed in earlier studies for advanced breast cancer. While some study results have been conflicting, research and development of entinostat are continuing, especially outside the United States.