Use Of Epigenetic Drugs Research Articles

Abstract P150: Epigenetic Mechanisms Linking Early-Life Stress to Hypertension Development: Implications for Prevention and Treatment

Purpose: Adverse childhood experiences (ACEs) and early-life stress (ELS) have been identified as significant risk factors for the development of hypertension later in life. This review synthesizes current evidence on how ELS induces epigenetic modifications, particularly DNA methylation and histone modifications, that predispose individuals to hypertension and discusses the implications for prevention and treatment strategies. Methods: A comprehensive literature review was conducted to identify studies examining the relationship between ELS, epigenetic modifications, and hypertension development. The search included studies investigating specific genes involved in stress response, inflammation, and cardiovascular regulation, such as NR3C1, SLC6A4, BDNF, OXTR, and FKBP5. Results: Studies have shown that ELS exposure can lead to persistent epigenetic alterations in genes involved in stress response, inflammation, and cardiovascular regulation. These modifications may contribute to impaired stress reactivity, heightened inflammation, and dysregulation of the renin-angiotensin system and endothelial function, potentially leading to the development of hypertension. The identification of ELS-induced epigenetic signatures opens up new avenues for early detection and intervention. DNA methylation biomarkers could be used to identify individuals at increased risk for hypertension due to ELS exposure, allowing for targeted prevention strategies. Moreover, the reversibility of epigenetic modifications presents an opportunity for novel treatment approaches, such as the use of epigenetic drugs and lifestyle interventions to mitigate the adverse cardiovascular effects of ELS. Conclusion: Understanding the epigenetic mechanisms linking ELS to hypertension development provides valuable insights for designing targeted prevention and treatment strategies. Future research should focus on translating these findings into clinical practice and developing personalized interventions based on an individual's ELS exposure and epigenetic profile. A multidisciplinary approach integrating epigenetics, stress neurobiology, and preventive medicine is required to address the long-term cardiovascular consequences of ELS effectively.

Epigenetic and gene therapy in human and veterinary medicine.

Gene therapy is a focus of interest in both human and veterinary medicine, especially in recent years due to the potential applications of CRISPR/Cas9 technology. Another relatively new approach is that of epigenetic therapy, which involves an intervention based on epigenetic marks, including DNA methylation, histone post-translational modifications, and post-transcription modifications of distinct RNAs. The epigenome results from enzymatic reactions, which regulate gene expression without altering DNA sequences. In contrast to conventional CRISP/Cas9 techniques, the recently established methodology of epigenetic editing mediated by the CRISPR/dCas9 system is designed to target specific genes without causing DNA breaks. Both natural epigenetic processes and epigenetic editing regulate gene expression and thereby contribute to maintaining the balance between physiological functions and pathophysiological states. From this perspective, knowledge of specific epigenetic marks has immense potential in both human and veterinary medicine. For instance, the use of epigenetic drugs (chemical compounds with therapeutic potential affecting the epigenome) seems to be promising for the treatment of cancer, metabolic, and infectious diseases. Also, there is evidence that an epigenetic diet (nutrition-like factors affecting epigenome) should be considered as part of a healthy lifestyle and could contribute to the prevention of pathophysiological processes. In summary, epigenetic-based approaches in human and veterinary medicine have increasing significance in targeting aberrant gene expression associated with various diseases. In this case, CRISPR/dCas9, epigenetic targeting, and some epigenetic nutrition factors could contribute to reversing an abnormal epigenetic landscape to a healthy physiological state.

Exploring epigenetic strategies for the treatment of osteoporosis.

The worldwide trend toward an aging population has resulted in a higher incidence of chronic conditions, such as osteoporosis. Osteoporosis, a prevalent skeletal disorder characterized by decreased bone mass and increased fracture risk, encompasses primary and secondary forms, each with distinct etiologies. Mechanistically, osteoporosis involves an imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Current pharmacological interventions for osteoporosis, such as bisphosphonates, denosumab, and teriparatide, aim to modulate bone turnover and preserve bone density. Hormone replacement therapy and lifestyle modifications are also recommended to manage the condition. While current medications offer therapeutic options, they are not devoid of limitations. Recent studies have highlighted the importance of epigenetic mechanisms, including DNA methylation and histone modifications, in regulating gene expression during bone remodeling. The use of epigenetic drugs, or epidrugs, to target these mechanisms offers a promising avenue for therapeutic intervention in osteoporosis. In this review, we comprehensively examine the recent advancements in the application of epidrugs for treating osteoporosis.

The role of epigenetics in anxiety disorders.

Anxiety disorders (ADs) are extremely common psychiatric conditions that frequently co-occur with other physical and mental disorders. The pathophysiology of ADs is multifaceted and involves intricate connections among biological elements, environmental stimuli, and psychological mechanisms. Recent discoveries have highlighted the significance of epigenetics in bridging the gap between multiple risk factors that contribute to ADs and expanding our understanding of the pathomechanisms underlying ADs. Epigenetics is the study of how changes in the environment and behavior can have an impact on gene function. Indeed, researchers have found that epigenetic mechanisms can affect how genes are activated or inactivated, as well as whether they are expressed. Such mechanisms may also affect how ADs form and are protected. That is, the bulk of pharmacological trials evaluating epigenetic treatments for the treatment of ADs have used histone deacetylase inhibitors (HDACi), yielding promising outcomes in both preclinical and clinical studies. This review will provide an outline of how epigenetic pathways can be used to treat ADs or lessen their risk. It will also present the findings from preclinical and clinical trials that are currently available on the use of epigenetic drugs to treat ADs.

Abstract 6001: Epigenetic regulation of BARD1 confers resistance to anti-VEGF therapy in ovarian cancer

Abstract Introduction: Vascular endothelial growth factor (VEGF) is a key promoter of angiogenesis and disease progression in epithelial ovarian cancer (OC). Bevacizumab, a humanized anti-VEGF monoclonal antibody, is approved for treatment of patients with ovarian and other cancers. Despite the wide use of anti-VEGF therapy for cancer treatment, most patients develop resistant disease. Therefore, new combinations/strategies are needed to reduce adaptive resistance to anti-VEGF antibody (AVA) therapy. Our aim is to determine the potential role of epigenetic changes in AVA-adaptive resistance. We identified and characterized epigenetic changes in BARD1, a tumor suppressor, at the emergence of AVA resistance. Methods: To define epigenetic changes during AVA therapy induced resistance, we performed series of in vitro (methylation array, RNA sequencing) and in vivo (orthotopic OC (PDX-MDA-OVCA1, immunocompetent-IG10, and immunocompromised-SKOV3) and fibrosarcoma-HT1080, an inherently VEGF resistant model) experiments. The biological effects of DNA methylation agent (5`-Azacytidine; 5`-Aza) with B20 (murine anti-VEGF antibody) treatment were subsequently tested using in vivo models. Results: To determine whether 5`-Aza can enhance the efficacy of AVA therapy and overcome resistance to AVA in OC, we established AVA-resistant SKOV3 model. In AVA-resistant mice treated with B20 + 5`-Aza, there was a statistically significant reduction in tumor weight (p=0.03). Next, we performed a Human 450k methylation and mRNA arrays from xenografts of SKOV3 tumors. Based on both analyses, we demonstrated that BARD1 was one of the top candidate which was highly expressed (p=0.02) and less methylated (p<0.05) in the combination of B20 and 5`-Aza group compared to B20 alone. Our data also showed that BARD1 expression was restored in the combination therapy. The sequential treatment with 5`-Aza reverted the resistance towards the AVA therapy in SKOV3 model. Furthermore, the combination of B20 and 5`-Aza significantly decreased tumor weight in SKOV3 (p=0.005), IG10 (p<0.05), MDA-OVCA1 (p=0.01), and HT1080 (p<0.05). BARD1 expression levels were substantially increased in combination therapy compared to the B20 alone group (>4-fold, p=0.006). Tumor weight and BARD1 expression were inversely correlated. To determine the biological significance of BARD1, we knockdown BARD1 using Tet-inducible shRNA system. Our data showed a significant reduction in tumor weight in the BARD1 knockdown group in SKOV3 model (p=0.021). RNA-sequencing of BARD1 knockdown showed an enrichment of the angiogenesis pathway. Moreover, BARD1 expression levels were decreased in hypoxic conditions both in vitro and in vivo. Conclusion: Our findings indicate a previously unrecognized role for BARD1 in mediating resistance to AVA therapy. Use of epigenetic drugs to control the expression of tumor suppressor genes may enhance the efficacy of AVA therapy in OC. Citation Format: Emine Bayraktar, Cristian Rodriguez-Aguayo, Sudhir Kumar, Elaine Stur, Lingegowda S. Mangala, Stephen Baylin, Gabriel Lopez-Berestein, Sunila Pradeep, Anil K. Sood. Epigenetic regulation of BARD1 confers resistance to anti-VEGF therapy in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6001.

Non-Coding RNAs in Cell-to-Cell Communication: Exploiting Physiological Mechanisms as Therapeutic Targets in Cardiovascular Pathologies.

Cardiovascular disease, the leading cause of death worldwide, has been characterized at the molecular level by alterations in gene expression that contribute to the etiology of the disease. Such alterations have been shown to play a critical role in the development of atherosclerosis, cardiac remodeling, and age-related heart failure. Although much is now known about the cellular and molecular mechanisms in this context, the role of epigenetics in the onset of cardiovascular disease remains unclear. Epigenetics, a complex network of mechanisms that regulate gene expression independently of changes to the DNA sequence, has been highly implicated in the loss of homeostasis and the aberrant activation of a myriad of cellular pathways. More specifically, non-coding RNAs have been gaining much attention as epigenetic regulators of various pathologies. In this review, we will provide an overview of the ncRNAs involved in cell-to-cell communication in cardiovascular disease, namely atherosclerosis, cardiac remodeling, and cardiac ageing, and the potential use of epigenetic drugs as novel therapeutic targets.

Effects of Structurally Different HDAC Inhibitors against Trypanosoma cruzi, Leishmania, and Schistosoma mansoni.

Neglected tropical diseases (NTDs), including trypanosomiasis, leishmaniasis, and schistosomiasis, result in a significant burden in terms of morbidity and mortality worldwide every year. Current antiparasitic drugs suffer from several limitations such as toxicity, no efficacy toward all of the forms of the parasites’ life cycle, and/or induction of resistance. Histone-modifying enzymes play a crucial role in parasite growth and survival; thus, the use of epigenetic drugs has been suggested as a strategy for the treatment of NTDs. We tested structurally different HDACi 1–9, chosen from our in-house library or newly synthesized, against Trypanosoma cruzi, Leishmania spp, and Schistosoma mansoni. Among them, 4 emerged as the most potent against all of the tested parasites, but it was too toxic against host cells, hampering further studies. The retinoic 2′-aminoanilide 8 was less potent than 4 in all parasitic assays, but as its toxicity is considerably lower, it could be the starting structure for further development. In T. cruzi, compound 3 exhibited a single-digit micromolar inhibition of parasite growth combined with moderate toxicity. In S. mansoni, 4’s close analogs 17–20 were tested in new transformed schistosomula (NTS) and adult worms displaying high death induction against both parasite forms. Among them, 17 and 19 exhibited very low toxicity in human retinal pigment epithelial (RPE) cells, thus being promising compounds for further optimization.

Epigenetic drugs induce the potency of classic chemotherapy, suppress post-treatment re-growth of breast cancer, but preserve the wound healing ability of stem cells

ABSTRACT Epigenetic therapy augments neoadjuvant chemotherapy (NACT) in breast cancer and may aid post-surgical wound healing affected by NACT. Our study investigates: (1) The cytotoxicity of classic paclitaxel chemotherapy on triple negative breast cancer (TNBC) independently and in combination with epigenetic drugs. (2) The sustainable inhibition of breast cancer regrowth following paclitaxel and epigenetic therapies. (3) The effects of paclitaxel with and without epigenetic therapy on the post-treatment viability and wound healing potential of adipose stem cells (ASCs). Cytotoxicity assays were performed on TNBC and ASCs. Cells were treated and recovered in drug-free medium. Cell viability was measured via cell counts and MTT assays. W -ound healing was tested with scratch assays. The combination of epigenetic drugs shows increased toxicity against TNBC cells compared to standard chemotherapy alone. Moreover, the combination of paclitaxel with epigenetic treatments causes cancer toxicity that is sustainable to TNBC cells after the drugs’ removal with minimal effect on ASCs wound healing ability. The use of epigenetic drugs in addition to standard chemotherapy is cytotoxic to TNBC cells and prevents post-treatment recovery of TNBC while maintaining ASC wound healing ability. This strategy may be useful in maximizing post-surgical wound healing following NACT in TNBC.

DNA methylation and breast cancer: A way forward (Review).

The current management of breast cancer(BC) lacks specific non‑invasive biomarkers able to provide an early diagnosis of the disease. Epigenetic‑sensitive signatures are influenced by environmental exposures and are mediated by direct molecular mechanisms, mainly guided by DNA methylation, which regulate the interplay between genetic and non‑genetic risk factors during cancerogenesis. The inactivation of tumor suppressor genes due to promoter hypermethylation is an early event in carcinogenesis. Of note, targeted tumor suppressor genes are frequently hypermethylated in patient‑derived BC tissues and peripheral blood biospecimens. In addition, epigenetic alterations in triple‑negative BC, as the most aggressive subtype, have been identified. Thus, detecting both targeted and genome‑wide DNA methylation changes through liquid‑based assays appears to be a useful clinical strategy for early detection, more accurate risk stratification and a personalized prediction of therapeutic response in patients with BC. Of note, the DNA methylation profile may be mapped by isolating the circulating tumor DNA from the plasma as a more accessible biospecimen. Furthermore, the sensitivity to treatment with chemotherapy, hormones and immunotherapy may be altered by gene‑specific DNA methylation, suggesting novel potential drug targets. Recently, the use of epigenetic drugs administered alone and/or with anticancer therapies has led to remarkable results, particularly in patients with BC resistant to anticancer treatment. The aim of the present review was to provide an update on DNA methylation changes that are potentially involved in BC development and their putative clinical utility in the fields of diagnosis, prognosis and therapy.

A Review on the Therapeutic Role of TKIs in Case of CML in Combination With Epigenetic Drugs.

Chronic myeloid leukemia is a malignancy of bone marrow that affects white blood cells. There is strong evidence that disease progression, treatment responses, and overall clinical outcomes of CML patients are influenced by the accumulation of other genetic and epigenetic abnormalities, rather than only the BCR/ABL1 oncoprotein. Both genetic and epigenetic factors influence the efficacy of CML treatment strategies. Targeted medicines known as tyrosine-kinase inhibitors have dramatically improved long-term survival rates in CML patients during the previous 2 decades. When compared to earlier chemotherapy treatments, these drugs have revolutionized CML treatment and allowed most people to live longer lives. Although epigenetic inhibitors’ activity is disrupted in many cancers, including CML, but when combined with TKI, they may offer potential therapeutic strategies for the treatment of CML cells. The epigenetics of tyrosine kinase inhibitors and resistance to them is being studied, with a particular focus on imatinib, which is used to treat CML. In addition, the use of epigenetic drugs in conjunction with TKIs has been discussed. Resistance to TKIs is still a problem in curing the disease, necessitating the development of new therapies. This study focused on epigenetic pathways involved in CML pathogenesis and tumor cell resistance to TKIs, both of which contribute to leukemic clone breakout and proliferation.

Nanoparticle-based Drug Delivery Systems for Targeted Epigenetics Cancer Therapy

This review summarizes the epigenetic mechanisms of deoxyribonucleic acid (DNA) methylation, histone modifications in cancer and the epigenetic modifications in cancer therapy. Due to their undesired side effects, the use of epigenetic drugs as chemo-drugs in cancer therapies is limited. The drug delivery system opens a door for minimizing these side effects and achieving greater therapeutic benefits. The limitations of current epigenetic therapies in clinical cancer treatment and the advantages of using drug delivery systems for epigenetic agents are also discussed. Combining drug delivery systems with epigenetic therapy is a promising approach to reaching a high therapeutic index and minimizing the side effects.

Methylation in HOX Clusters and Its Applications in Cancer Therapy.

HOX genes are commonly known for their role in embryonic development, defining the positional identity of most structures along the anterior–posterior axis. In postembryonic life, HOX gene aberrant expression can affect several processes involved in tumorigenesis such as proliferation, apoptosis, migration and invasion. Epigenetic modifications are implicated in gene expression deregulation, and it is accepted that methylation events affecting HOX gene expression play crucial roles in tumorigenesis. In fact, specific methylation profiles in the HOX gene sequence or in HOX-associated histones are recognized as potential biomarkers in several cancers, helping in the prediction of disease outcomes and adding information for decisions regarding the patient’s treatment. The methylation of some HOX genes can be associated with chemotherapy resistance, and its identification may suggest the use of other treatment options. The use of epigenetic drugs affecting generalized or specific DNA methylation profiles, an approach that now deserves much attention, seems likely to be a promising weapon in cancer therapy in the near future. In this review, we summarize these topics, focusing particularly on how the regulation of epigenetic processes may be used in cancer therapy.

Possibilities of epigenetic therapy of acute myeloid leukemias in children

The results of the treatment of acute myeloid leukemia (AML) in pediatric patients remain poor. The modern programs of treatment allow achieving long-term survival in only 6570% of patients and the event-free survival rates are lower and make up approximately 55%. The development of protocols for high-intensity therapy, which are based on the block principle, followed by long-term maintenance therapy has led to the significant progress in the treatment of AML. As supportive care has improved, it became possible to escalate the doses of chemotherapy, which contributed to the increase of the treatment effectiveness. So far, doses and drugs administration regimens have approached the tolerated level, which necessitates the research into new therapeutic targets. An investifation of the epigenetic processes underlying leukemogenesis made it possible to identify those targets DNA methylation and histone deacetylation. This review presents the results of the use of epigenetic drugs in the treatment of AML in children. The possibilities of including epigenetic agents in standard polychemotherapy protocols are presented.

The Potential Role of Epigenetic Drugs in the Treatment of Anxiety Disorders.

There is increasing evidence that abnormalities in epigenetic mechanisms of gene expression contribute to the pathogenesis of anxiety disorders (ADs). This article discusses the role of epigenetic mechanisms of gene expression in the pathogenesis of ADs. It also discusses the data so far obtained from preclinical and clinical trials on the use of epigenetic drugs for treating ADs. Most drug trials investigating the use of epigenetic drugs for treating ADs have used histone deacetylase inhibitors (HDACi). HDACi are showing favorable results in both preclinical and clinical drug trials for treating ADs. However, at present the mode of action of HDACi in ADs is not clear. More work needs to be done to elucidate how epigenetic dysregulation contributes to the pathogenesis of ADs. More work also needs to be done on the mode of action of HDACi in alleviating the signs and symptoms of ADs.

HDAC Inhibitors in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a hematological malignancy characterized by uncontrolled proliferation, differentiation arrest, and accumulation of immature myeloid progenitors. Although clinical advances in AML have been made, especially in young patients, long-term disease-free survival remains poor, making this disease an unmet therapeutic challenge. Epigenetic alterations and mutations in epigenetic regulators contribute to the pathogenesis of AML, supporting the rationale for the use of epigenetic drugs in patients with AML. While hypomethylating agents have already been approved in AML, the use of other epigenetic inhibitors, such as histone deacetylases (HDAC) inhibitors (HDACi), is under clinical development. HDACi such as Panobinostat, Vorinostat, and Tricostatin A have been shown to promote cell death, autophagy, apoptosis, or growth arrest in preclinical AML models, yet these inhibitors do not seem to be effective as monotherapies, but rather in combination with other drugs. In this review, we discuss the rationale for the use of different HDACi in patients with AML, the results of preclinical studies, and the results obtained in clinical trials. Although so far the results with HDACi in clinical trials in AML have been modest, there are some encouraging data from treatment with the HDACi Pracinostat in combination with DNA demethylating agents.

Targeting Chromatin Remodeling for Cancer Therapy.

Background:Epigenetic alterations comprise key regulatory events that dynamically alter gene expression and their deregulation is commonly linked to the pathogenesis of various diseases, including cancer. Unlike DNA mutations, epigenetic alterations involve modifications to proteins and nucleic acids that regulate chromatin structure without affecting the underlying DNA sequence, altering the accessibility of the transcriptional machinery to the DNA, thus modulating gene expression. In cancer cells, this often involves the silencing of tumor suppressor genes or the increased expression of genes involved in oncogenesis. Advances in laboratory medicine have made it possible to map critical epigenetic events, including histone modifications and DNA methylation, on a genome-wide scale. Like the identification of genetic mutations, mapping of changes to the epigenetic landscape has increased our understanding of cancer progression. However, in contrast to irreversible genetic mutations, epigenetic modifications are flexible and dynamic, thereby making them promising therapeutic targets. Ongoing studies are evaluating the use of epigenetic drugs in chemotherapy sensitization and immune system modulation. With the preclinical success of drugs that modify epigenetics, along with the FDA approval of epigenetic drugs including the DNA methyltransferase 1 (DNMT1) inhibitor 5-azacitidine and the histone deacetylase (HDAC) inhibitor vorinostat, there has been a rise in the number of drugs that target epigenetic modulators over recent years.Conclusion:We provide an overview of epigenetic modulations, particularly those involved in cancer, and discuss the recent advances in drug development that target these chromatin-modifying events, primarily focusing on novel strategies to regulate the epigenome.

Epigenetic therapy inhibits growth of ovarian cancer cells and reverses chemoresistant properties acquired from metastatic omental adipose-derived stem cells

Objective: 1. To examine the cytotoxicity of epigenetic drugs as single agents and in combination with paclitaxel/cisplatin 2. To investigate the ability of ovarian cancer cells to acquire chemoresistance in different omental microenvironments and whether the use of epigenetic drugs is able to counteract this chemoresistance.

Epigenetic drugs as new therapy for tumor necrosis factor-α-compromised bone healing.

Impaired bone regeneration by excess inflammation leads to failure of bone healing. Current therapies display limited benefits making new treatments imperative. Our recent discoveries of the anti-inflammatory characteristics of bromodomain and extra terminal domain (BET) inhibitors, N-methylpyrrolidone (NMP) and N,N-Dimethylacetamide (DMA), implicate possible therapeutic use of epigenetic drugs in inflammation-impaired bone healing. Here, we investigated the effects of NMP and DMA on osteogenesis in vitro and ex vivo under the influence of TNFα, a key cytokine responsible for impaired fracture healing. NMP and DMA pre-treatment recovered TNFα-inhibited expression of essential osteoblastic genes, Alp, Runx2, and Osterix as well as mineralization in multipotent stem cells, but not in pre-osteoblasts and calvarial osteoblasts. The mechanism of action involves the recovery of TNFα-suppressed BMP-induced Smad signaling and the reduction of TNFα-triggered ERK pathway. In addition, ERK inhibitor treatment diminished the effect of TNFα on osteogenesis, which reinforces the role of ERK pathway in the adverse effect of TNFα. Furthermore, endochondral ossification was analyzed in an ex vivo bone culture model. TNFα largely abrogated BMP-promoted growth of mineralized bone while pre-treatment of NMP and DMA prevented the deleterious effect of TNFα. Taken together, these data shed light on developing low- affinity epigenetic drugs as new therapies for inflammation-compromised bone healing.

Highlights of This Issue

Increased SPINK1 levels associate with poor clinical outcome and represent the second-largest molecular subtype of prostate cancer. Bhatia and colleagues deciphered the mechanism of SPINK1 upregulation and established a regulatory model, showing the functional interplay between SPINK1, miRNA-338-5p/miRNA-421 and EZH2. In this study, the authors show that overexpression of miRNA-338-5p/miRNA-421 in SPINK1-positive cancer cells attenuates its oncogenic properties, tumorigenesis, and metastases. In agreement, SPINK1-postive prostate cancer patients show epigenetic silencing of miRNA-338-5p/miRNA-421 due to increased levels of EZH2. This study opens avenues for the use of epigenetic drugs or synthetic mimics of miRNA-338-5p/miRNA-421 as an adjuvant therapy for SPINK1-positive malignancies.Fibroblast growth factor receptors (FGFR), in their function as upstream tyrosine kinases activating the MAPK and the PI3K signaling pathways, can regulate cellular growth and have established roles in human tumorigenesis. In that setting, increased kinase signaling can be brought about by a variety of genetic alterations which can be detected in patient tumor samples, identifying those patients most likely to benefit from FGFR-directed therapy. In the present phase I trial, Voss and colleagues investigate the safety and efficacy of Debio 1347, a highly selective orally available FGFR 1-3 inhibitor, in a target population of patients that screened positive for harboring activating FGFR1-3 alterations in their tumors. This approach proved to be feasible with promising tolerability and efficacy results.Because of the development of resistance and high-relapse rates with currently available therapies, mixed-lineage leukemia (MLL leukemia) is frequently associated with a poor prognosis; therefore, novel therapeutic targets are urgently needed. Wang and colleagues discovered that LAMP5 is a novel autophagic suppressor, is specifically expressed in MLL leukemia, and serves as a bodyguard for fusion proteins to evade degradation. Suppressing LAMP5 expression effectively released MLL fusions from its defence system and extended survival in vivo. This effect was particularly strong when combining DOT1L inhibitors and LAMP5 knockdown. The finding highlights the potential of LAMP5 as a therapeutic target.Aberrant overexpression of stratifin (SFN) can be detected in lung adenocarcinoma from an early stage, playing a role in oncogenesis and progression. Shiba-Ishii and colleagues identify SKP1 as an SFN binding partner and demonstrate that SFN-SKP1 binding causes dysfunction of a specific ubiquitin ligase, SCFFBW7, allowing several oncoproteins to evade ubiquitination and degradation. In silico drug screening selected aprepitant and ticagrelor as potential SFN inhibitors that dose-dependently reduced SFN-SKP1 binding and tumor progression. Because SFN is widely expressed from an early stage, these drugs would be promising candidates for nonsurgical treatment of advanced and early-stage tumors.

Epigenetic drugs and their molecular targets in testicular germ cell tumours.

Current treatment regimens for type II testicular germ cell tumours (TGCTs) achieve cure rates of ≥95%; however, 1-5% of TGCTs develop resistance to standard platinum-based chemotherapy. Patients with recurrent TGCT typically receive high-dose chemotherapy, but this treatment results in severe adverse effects and cytotoxicity. Thus, alternative treatment options should be considered to improve patient well-being and quality of life. Epigenetic drugs could be feasible options for TGCT treatment. Several compounds have already been tested in TGCT cell lines and xenograft models with promising results. These compounds include DNA demethylating agents (such as SGI-110), histone demethylase inhibitors (such as the lysine-specific histone demethylase 1A (LSD1) inhibitor CBB3001), histone deacetylase (HDAC) inhibitors (such as romidepsin) and bromodomain inhibitors (such as JQ1). Despite the diversity in their molecular effects, most epigenetic compounds show strong overlap in their genetic response. The use of epigenetic drugs in TGCTs triggers a cellular stress response, induction of differentiation and downregulation of genes associated with pluripotency, leading to growth arrest and apoptosis. Additive effects are seen using a combination of JQ1 and romidepsin. The availability of dual drugs (such as LSD1-HDAC1 hybrid inhibitors) could additionally take advantage of drug synergy effects. Thus, epigenetic drugs are novel tools that could be combined with standard therapy approaches to improve treatment of TGCTs.