Ovarian cancer is the deadliest gynecologic malignancy, with a 5-year survival rate of approximately 47%, a number that has remained constant over the past two decades. Early diagnosis improves survival, but unfortunately only 15% of ovarian cancers are diagnosed at an early or localized stage. Most ovarian cancers are epithelial in origin and treatment prioritizes surgery and cytoreduction followed by cytotoxic platinum and taxane chemotherapy. While most tumors will initially respond to this treatment, recurrence is likely to occur within a median of 16 months for patients who present with advanced stage disease. New treatment options separate from traditional chemotherapy that take advantage of advances in understanding of the pathophysiology of ovarian cancer are needed to improve outcomes. Recent work has shown that mutations in genes encoding epigenetic regulators are mutated in ovarian cancer, driving tumorigenesis and resistance to treatment. Several of these epigenetic modifiers have emerged as promising drug targets for ovarian cancer therapy. In this article, we delineate epigenetic abnormalities in ovarian cancer, discuss key scientific advances using epigenetic therapies in preclinical ovarian cancer models, and review ongoing clinical trials utilizing epigenetic therapies in ovarian cancer.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0602-0) contains supplementary material, which is available to authorized users.

Long-standing efforts to identify the multifaceted roles of histone deacetylase inhibitors (HDACis) have positioned these agents as promising drug candidates in combatting cancer, autoimmune, neurodegenerative, and infectious diseases. The same has also encouraged the evaluation of multiple HDACi candidates in preclinical studies in cancer and other diseases as well as the FDA-approval towards clinical use for specific agents. In this review, we have discussed how the efficacy of immunotherapy can be leveraged by combining it with HDACis. We have also included a brief overview of the classification of HDACis as well as their various roles in physiological and pathophysiological scenarios to target key cellular processes promoting the initiation, establishment, and progression of cancer. Given the critical role of the tumor microenvironment (TME) towards the outcome of anticancer therapies, we have also discussed the effect of HDACis on different components of the TME. We then have gradually progressed into examples of specific pan-HDACis, class I HDACi, and selective HDACis that either have been incorporated into clinical trials or show promising preclinical effects for future consideration. Finally, we have included examples of ongoing trials for each of the above categories of HDACis as standalone agents or in combination with immunotherapeutic approaches.

Novel therapies are urgently needed for ovarian cancer, the deadliest gynecologic malignancy. Ovarian cancer has thus far been refractory to immunotherapies that stimulate the host immune system to recognize and kill cancer cells. This may be because of a suppressive tumor immune microenvironment and lack of recruitment and activation of immune cells that kill cancer cells. Our previous work showed that epigenetic drugs including DNA methyltransferase inhibitors and histone deacetylase 6 inhibitors (DNMTis and HDAC6is) individually increase immune signaling in cancer cells. We find that combining DNMTi and HDAC6i results in an amplified type I interferon response, leading to increased cytokine and chemokine expression and higher expression of the MHC I antigen presentation complex in human and mouse ovarian cancer cell lines. Treating mice bearing ID8 Trp53−/− ovarian cancer with HDAC6i/ DnMti led to an increase in tumor-killing cells such as ifng+ CD8, NK, and NKT cells and a reversal of the immunosuppressive tumor microenvironment with a decrease in MDSCs and PD-1 hi CD4 T cells, corresponding with an increase in survival. Thus combining the epigenetic modulators DNMTi and HDAC6i increases anti-tumor immune signaling from cancer cells and has beneficial effects on the ovarian tumor immune microenvironment. The five-year survival for ovarian cancer has remained unchanged for decades, and novel therapies are urgently needed 1. Ovarian cancer has the deadliest outcome among gynecologic cancers due to its late (typically Stage III or IV) presentation and aggressive phenotype. High-grade serous ovarian cancer, the most common subtype, is characterized by genomic instability with >95% of cases exhibiting mutations in the tumor suppressor P53 2. Treatment involves surgical staging and optimal debulking to reduce tumor burden, followed by chemotherapy with a platinum-based agent and a taxane, or vice versa (chemotherapy before surgery). Unfortunately most cancers recur within two years of chemotherapy. Significant advances in the pathobiology of the disease, including the identification of a subset of tumors with defects in homologous recombination (HR), have led to the use of PARP inhibitors, which can cause synthetic lethality in HR-deficient tumors. However, less than half of ovarian cancers are HR-deficient and there is no curative therapy for the majority of ovarian cancer patients 1,3. Cancer cells may be recognized as foreign by host immune cells that kill the cancer cells, but as they progress cancers exhibit mechanisms of immune evasion or immunoediting 4. The tumor microenvironment (TME) is composed of both pro-and anti-cancer immune cells. These include CD8 effector T cells that recognize specific antigens on tumor cells to kill them, natural killer (NK) cells, part of the innate immune system that can kill tumor cells, and immuno-suppressive cell types including macrophages, regulatory T cells, and myeloid-derived suppressor cells. Novel drugs that activate CD8 effector T cells to fight cancer cells, includ...

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Objectives Viscosupplementation with new-generation, polyol-containing, cross-linked hyaluronic acid (HA) gels reduces joint inflammation in patients with knee osteoarthritis. Gait analysis is a complementary outcome measure to standard patient-reported scores and physical measures for testing the effect of HA injection. This three-arm, prospective, randomized, controlled, double-blind, feasibility pilot study investigated which gait parameters are more sensitive following a single bolus injection of polyol-containing HA for knee osteoarthritis. Methods Twenty-two patients with Ahlbäck grade II–III knee osteoarthritis were randomly allocated into three groups: (1) HA + mannitol ( n = 9), (2) HA + sorbitol ( n = 5), and (3) saline placebo ( n = 8). Patients were assessed by blinded observers prior to injection and at 4 weeks post-injection (4W). Outcome measures included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Society score (KSS), EuroQol in five-dimensions (EQ-5D), VAS pain, and VAS stiffness. Gait was assessed over 30 m using a portable inertial-based data logger (Physilog®). Results Differences between 4W and baseline were statistically significant for the mannitol-containing viscosupplement, with a median increase of 0.076 m/s on gait speed ( p = 0.039), 0.055 m on stride length ( p = 0.027), and 15 points on the KSS ( p = 0.047). In contrast, the HA + sorbitol and saline groups demonstrated no significant changes from baseline to 4W in any gait parameters or self-reported outcome measures (all p > 0.3). The observed increase in gait speed is approximately 13% greater than the mean difference between healthy subjects and those with knee osteoarthritis, is clinically important, and thus is a sensitive gait parameter. Conclusions This study demonstrated gait speed and stride length are the most relevant gait parameters to investigate when assessing the effect of polyol-containing HA viscosupplementation. This study supports the need for a larger, randomized, controlled, clinical trial to assess the effect of a single-bolus HA injection versus multiple injections in people with knee osteoarthritis using both gait performance and self-reported parameters of knee function. Trial registration This study was retrospectively registered at clinicaltrials.gov on August 20, 2018, and assigned # NCT03636971 . Level of evidence I