Cancer-cell biology is dictated by alterations in epigenetic regulation of gene expression. Mechanisms underlying these regulators are increasingly being elucidated, and agents that alter their function are being developed as treatments.

The HDAC inhibitors are a new family of antineoplastic agents. Since the entry of these agents into our therapeutic armamentarium, there has been increasing interest in their use. Although this family comprises chemical compounds from unrelated chemical classes that have different HDAC isoform specificities, they surprisingly have very similar toxicity profiles. In contrast, the observed toxicity profile is somewhat different from that of traditional cytotoxic chemotherapeutic agents and from other epigenetic agents. While some of the side effects may be familiar to the oncologist, others are less commonly seen. As some patients remain on therapy for a prolonged period of time, the long-term sequelae need to be characterized. In addition, since preclinical models suggest promising activity when used in combination with other antineoplastic agents, combination trials are being pursued. It will thus be important to distinguish the relative toxicity attributed to these agents and be alert to the exacerbation of toxicities observed in single agent studies. Notably, few of the agents in this class have completed phase 2 testing. Consequently, more clinical experience is needed to determine the relative frequency of the observed side effects, and to identify and develop approaches to mitigate potential clinical sequelae.

Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease to treat. Despite advances in surgical techniques, radiation, and medical therapies, the 5-year survival rate remains below 9%. Over the past decade, the genomic landscape of PDAC has been well studied and BRCA mutations have emerged as a target for the development of more effective therapies. Alterations in germline BRCA and PALB2 are detected in approximately 5– 9% of patients with PDAC and can lead to homologous repair deficiency (HRD). PDAC with HRD is more susceptible to cytotoxic agents, such as platinum salts and topoisomerase inhibitors, that cause DNA damage. Furthermore, PARP inhibitors have emerged as an effective non-cytotoxic approach to treating HRD-PDAC. In addition to BRCA and PALB2, germline mutations in other genes involved in the homologous DNA repair pathway – such as ATM and RAD51 – are potential targets, as are patients with the “BRCAness” phenotype and somatic mutations in the DNA repair pathway. Given the clinical implications of germline mutation related HRD in PDAC, universal germline testing is now recommended. In this review, we will discuss current and emerging biomarkers for HRD in PDAC, treatments, and the challenges associated with them.

Epigenetic aberrations offer dynamic and reversible targets for cancer therapy; increasingly, alteration via overexpression, mutation, or rearrangement is found in genes that control the epigenome. Such alterations suggest a fundamental role in carcinogenesis. Here, we consider three epigenetic mechanisms: DNA methylation, histone tail modification and noncoding, microRNA regulation. Evidence for each of these in lung cancer origin or progression has been gathered, along with evidence that epigenetic alterations might be useful in early detection. DNA hypermethylation of tumor suppressor promoters has been observed, along with global hypomethylation and hypoacetylation, suggesting an important role for tumor suppressor gene silencing. These features have been linked as prognostic markers with poor outcome in lung cancer. Several lines of evidence have also suggested a role for miRNA in carcinogenesis and in outcome. Cigarette smoke downregulates miR-487b, which targets both RAS and MYC; RAS is also a target of miR-let-7, again downregulated in lung cancer. Together the evidence implicates epigenetic aberration in lung cancer and suggests that targeting these aberrations should be carefully explored. To date, DNA methyltransferase and histone deacetylase inhibitors have had minimal clinical activity. Explanations include the possibility that the agents are not sufficiently potent to invoke epigenetic reversion to a more normal state; that insufficient time elapses in most clinical trials to observe true epigenetic reversion; and that doses often used may provoke off-target effects such as DNA damage that prevent epigenetic reversion. Combinations of epigenetic therapies may address those problems. When epigenetic agents are used in combination with chemotherapy or targeted therapy it is hoped that downstream biological effects will provoke synergistic cytotoxicity. This review evaluates the challenges of exploiting the epigenome in the treatment of lung cancer.

Summary: Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T‐cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long‐term disease control and the ability to retreat patients relapsing off‐therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third‐line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3·5 months to 10 years; in four of six patients, re‐initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics‐mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T‐cell lymphoma, but suggests a complex mechanism of action.

Purpose: Romidepsin is a potent histone deacetylase inhibitor (HDI) with activity in T-cell lymphoma. Given preclinical data showing greater induction of gene expression with longer exposures to HDIs, a phase I study of a day 1, 3, and 5 romidepsin schedule was evaluated. A secondary objective was to assess the effect of romidepsin on radioactive iodine (RAI) uptake in thyroid cancers. Experimental Design: Open-label, single-arm, phase I, 3 + 3 dose escalation study. Romidepsin was administered as a 4-hour infusion on days 1, 3, and 5 of a 21-day cycle. Pharmacokinetics (PK) and pharmacodynamics (PD) were assessed, including histone acetylation in peripheral blood mononuclear cells (PBMC), RAI uptake in refractory thyroid cancer, and HDI-related ECG changes. Results: Twenty-eight patients with solid tumors, including 11 patients with thyroid cancer were enrolled. Six dose levels were explored, and 7 mg/m² on days 1, 3, and 5 was identified as tolerable. No Response Evaluation Criteria In Solid Tumors–defined objective responses were recorded although 9 patients had stable disease a median 30 weeks (range, 21–112) including 6 with thyroid cancer a median of 33 weeks. PD studies detected acetylated histones in PBMCs and ECG changes beginning at low dose levels. Follow-up RAI scans in patients with RAI refractory thyroid cancer did not detect meaningful increases. Conclusions: A romidepsin dose of 7 mg/m² administered on days 1, 3, and 5 was found tolerable and resulted in histone acetylation in PBMCs. Although there were no objective responses with romidepsin alone, this schedule may be useful for developing combination studies in solid tumors. Clin Cancer Res; 19(16); 4499–507. ©2013 AACR.