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Molecular Therapy. Nucleic Acids Sep 2023Muscle-invasive urothelial cancer (MUC), characterized by high aggressiveness and significant heterogeneity, is currently lacking highly precise individualized treatment...
Muscle-invasive urothelial cancer (MUC), characterized by high aggressiveness and significant heterogeneity, is currently lacking highly precise individualized treatment options. We used a computational pipeline to synthesize multiomics data from MUC patients using 10 clustering algorithms, which were then combined with 10 machine learning algorithms to identify molecular subgroups of high resolution and develop a robust consensus machine learning-driven signature (CMLS). Through multiomics clustering, we identified three cancer subtypes (CSs) that are related to prognosis, with CS2 exhibiting the most favorable prognostic outcome. Subsequent screening enabled identification of 12 hub genes that constitute a CMLS with robust predictive power for prognosis. The low-CMLS group exhibited a more favorable prognosis and greater responsiveness to immunotherapy and was more likely to exhibit the "hot tumor" phenotype. The high-CMLS group had a poor prognosis and lower likelihood of benefitting from immunotherapy, but dasatinib and romidepsin may serve as promising treatments for them. Comprehensive analysis of multiomics data can offer important insights and further refine the molecular classification of MUC. Identification of CMLS represents a valuable tool for early prediction of patient prognosis and for screening potential candidates likely to benefit from immunotherapy, with broad implications for clinical practice.
PubMed: 37449047
DOI: 10.1016/j.omtn.2023.06.001 -
Cancer Nov 2023Cancer metastasis increases the complexity of the disease and escalates patient mortality. Traditional chemotherapy has been associated with low efficacy and marked side... (Review)
Review
Cancer metastasis increases the complexity of the disease and escalates patient mortality. Traditional chemotherapy has been associated with low efficacy and marked side effects. Studies pivot toward histone deacetylase (HDAC) enzymes and inhibitors because they are critical for chromatin structure, gene regulation, and cellular activities that are linked to metastasis and cancer progression. HDAC inhibitors (HDACi) can alter gene expression patterns and can lead to cell-cycle arrest and apoptosis in neoplastic cells. Several HDACi drugs like vorinostat, romidepsin, panobinostat, and belinostat are approved by the Food and Drug Administration. China and Japan have approved the use of tucidinostat, a new subtype-selective HDACi that inhibits class 1 HDAC1, HDAC2, HDAC3, as well as class 2b HDAC10. These drugs have shown promising results in the treatment of multiple carcinoma including cervical cancer, T-cell lymphoma, brain cancer, and breast cancer. This review highlights the HDACi classes, the mechanism of action of these inhibitors, their preclinical and clinical efficacy, and the latest clinical trials and patents used in cancer therapeutics. Overall, this review focuses on patents and clinical trials data from 2019 onward to give a better viewpoint on current trends in HDACis as chemotherapy agents.
PubMed: 37560925
DOI: 10.1002/cncr.34974 -
Clinical Epigenetics Aug 2023Peripheral T-cell lymphomas (PTCLs) are a group of highly aggressive malignancies with generally poor prognoses, and the first-line chemotherapy of PTCL has limited... (Review)
Review
Peripheral T-cell lymphomas (PTCLs) are a group of highly aggressive malignancies with generally poor prognoses, and the first-line chemotherapy of PTCL has limited efficacy. Currently, several novel targeted agents, including histone deacetylase inhibitors (HDACis), have been investigated to improve the therapeutic outcome of PTCLs. Several HDACis, such as romidepsin, belinostat, and chidamide, have demonstrated favorable clinical efficacy and safety in PTCLs. More novel HDACis and new combination therapies are undergoing preclinical or clinical trials. Mutation analysis based on next-generation sequencing may advance our understanding of the correlation between epigenetic mutation profiles and relevant targeted therapies. Multitargeted HDACis and HDACi-based prodrugs hold promising futures and offer further directions for drug design.
Topics: Humans; Lymphoma, T-Cell, Peripheral; Histone Deacetylase Inhibitors; DNA Methylation; Antineoplastic Agents; Combined Modality Therapy
PubMed: 37533111
DOI: 10.1186/s13148-023-01531-8 -
Neoplasia (New York, N.Y.) Sep 2023Constitutional mismatch repair deficiency (CMMRD) is a cancer predisposition syndrome associated with the development of hypermutant pediatric high-grade glioma, and...
Constitutional mismatch repair deficiency (CMMRD) is a cancer predisposition syndrome associated with the development of hypermutant pediatric high-grade glioma, and confers a poor prognosis. While therapeutic histone deacetylase (HDAC) inhibition of diffuse intrinsic pontine glioma (DIPG) has been reported; here, we use a clinically relevant biopsy-derived hypermutant DIPG model (PBT-24FH) and a CRISPR-Cas9 induced genetic model to evaluate the efficacy of HDAC inhibition against hypermutant DIPG. We screened PBT-24FH cells for sensitivity to a panel of HDAC inhibitors (HDACis) in vitro, identifying two HDACis associated with low nanomolar IC50s, quisinostat (27 nM) and romidepsin (2 nM). In vivo, quisinostat proved more efficacious, inducing near-complete tumor regression in a PBT-24FH flank model. RNA sequencing revealed significant quisinostat-driven changes in gene expression, including upregulation of neural and pro-inflammatory genes. To validate the observed potency of quisinostat in vivo against additional hypermutant DIPG models, we tested quisinostat in genetically-induced mismatch repair (MMR)-deficient DIPG flank tumors, demonstrating that loss of MMR function increases sensitivity to quisinostat in vivo. Here, we establish the preclinical efficacy of quisinostat against hypermutant DIPG, supporting further investigation of epigenetic targeting of hypermutant pediatric cancers with the potential for clinical translation. These findings support further investigation of HDAC inhibitors against pontine high-grade gliomas, beyond only those with histone mutations, as well as against other hypermutant central nervous system tumors.
Topics: Humans; Child; Diffuse Intrinsic Pontine Glioma; Histone Deacetylase Inhibitors; Histones; Hydroxamic Acids; Glioma
PubMed: 37603953
DOI: 10.1016/j.neo.2023.100921 -
Blood Advances Oct 2023Peripheral T-cell lymphomas (PTCLs) are associated with poor prognosis when treated with cytotoxic chemotherapy. We report the findings of a phase 2 study evaluating a...
Peripheral T-cell lymphomas (PTCLs) are associated with poor prognosis when treated with cytotoxic chemotherapy. We report the findings of a phase 2 study evaluating a chemotherapy-free combination of romidepsin plus lenalidomide as initial treatment for patients with PTCL who were aged >60 years or noncandidates for chemotherapy. Treatment was initiated with romidepsin 10 mg/m2 IV on days 1, 8, and 15 and lenalidomide 25 mg taken orally from days 1 to 21 of 28-day cycle for up to 1 year. The primary objective was overall response rate (ORR). Secondary objectives included safety and survival. The study enrolled 29 patients with a median age of 75 years, including 16 (55%) angioimmunoblastic T-cell lymphoma (AITL), 10 (34%) PTCL- not otherwise specified, 2 ATLL, and 1 EATL. Grade 3 to 4 hematologic toxicities included neutropenia (45%), thrombocytopenia (34%), and anemia (28%). Grade 3 to 4 nonhematologic toxicities included hyponatremia (45%), hypertension (38%), hypoalbuminemia (24%), fatigue (17%), hyperglycemia (14%), hypokalemia (14%), dehydration (10%), and infection (10%). At median follow-up of 15.7 months, 23 patients were evaluable and received a median treatment of 6 cycles. The ORR was 65.2% with complete response (CR) at 26.1%, including 78.6% ORR and 35.7% CR for AITL. Median duration of response was 10.7 months, with 27.1 months for patients achieving CR. The estimated 2-year progression-free survival was 31.5%, and 2-year overall survival was 49.5%. This study provides the first demonstration that the biologic combination of romidepsin and lenalidomide is feasible and effective as initial therapy for PTCL and warrants further evaluation. This trial was registered at www.clinicaltrials.gov as #NCT02232516.
Topics: Humans; Aged; Lymphoma, T-Cell, Peripheral; Lenalidomide; Treatment Outcome; Depsipeptides
PubMed: 37327113
DOI: 10.1182/bloodadvances.2023009767 -
Biomedicine & Pharmacotherapy =... Aug 2023Romidepsin, also known as NSC630176, FR901228, FK-228, FR-901228, depsipeptide, or Istodax®, is a natural molecule produced by the Chromobacterium violaceum bacterium... (Review)
Review
Romidepsin, also known as NSC630176, FR901228, FK-228, FR-901228, depsipeptide, or Istodax®, is a natural molecule produced by the Chromobacterium violaceum bacterium that has been approved for its anti-cancer effect. This compound is a selective histone deacetylase (HDAC) inhibitor, which modifies histones and epigenetic pathways. An imbalance between HDAC and histone acetyltransferase can lead to the down-regulation of regulatory genes, resulting in tumorigenesis. Inhibition of HDACs by romidepsin indirectly contributes to the anticancer therapeutic effect by causing the accumulation of acetylated histones, restoring normal gene expression in cancer cells, and promoting alternative pathways, including the immune response, p53/p21 signaling cascades, cleaved caspases, poly (ADP-ribose) polymerase (PARP), and other events. Secondary pathways mediate the therapeutic action of romidepsin by disrupting the endoplasmic reticulum and proteasome and/or aggresome, arresting the cell cycle, inducing intrinsic and extrinsic apoptosis, inhibiting angiogenesis, and modifying the tumor microenvironment. This review aimed to highlight the specific molecular mechanisms responsible for HDAC inhibition by romidepsin. A more detailed understanding of these mechanisms can significantly improve the understanding of cancer cell disorders and pave the way for new therapeutic approaches using targeted therapy.
Topics: Humans; Histones; Depsipeptides; Apoptosis; Neoplasms; Histone Deacetylases; Histone Deacetylase Inhibitors; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37224749
DOI: 10.1016/j.biopha.2023.114774 -
International Journal of Cancer Sep 2023BRAF mutations are the most common oncogenic alterations in melanoma cells, supporting proliferation, invasion, metastasis and immune evasion. In patients, these...
Reversing vemurafenib-resistance in primary melanoma cells by combined romidepsin and type I IFN treatment through blocking of tumorigenic signals and induction of immunogenic effects.
BRAF mutations are the most common oncogenic alterations in melanoma cells, supporting proliferation, invasion, metastasis and immune evasion. In patients, these aberrantly activated cellular pathways are inhibited by BRAFi whose potent antitumor effect and therapeutic potential are dampened by the development of resistance. Here, by using primary melanoma cell lines, generated from lymph node lesions of metastatic patients, we show that the combination of two FDA-approved drugs, the histone deacetylate inhibitor (HDCAi) romidepsin and the immunomodulatory agent IFN-α2b, reduces melanoma proliferation, long-term survival and invasiveness and overcomes acquired resistance to the BRAFi vemurafenib (VEM). Targeted resequencing revealed that each VEM-resistant melanoma cell line and the parental counterpart are characterized by a distinctive and similar genetic fingerprint, shaping the differential and specific antitumor modulation of MAPK/AKT pathways by combined drug treatment. By using RNA-sequencing and functional in vitro assays, we further report that romidepsin-IFN-α2b treatment restores epigenetically silenced immune signals, modulates MITF and AXL expression and induces both apoptosis and necroptosis in sensitive and VEM-resistant primary melanoma cells. Moreover, the immunogenic potential of drug-treated VEM-resistant melanoma cells results significantly enhanced, given the increased phagocytosis rate of these cells by dendritic cells, which in turn exhibit also a selective down-modulation of the immune checkpoint TIM-3. Overall, our results provide evidence that combined epigenetic-immune drugs can overcome VEM resistance of primary melanoma cells by oncogenic and immune pathways reprogramming, and pave the way for rapidly exploiting this combination to improve BRAFi-resistant metastatic melanoma treatment, also via reinforcement of immune checkpoint inhibitor therapy.
Topics: Humans; Vemurafenib; Drug Resistance, Neoplasm; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Melanoma; Interferon Type I; Cell Line, Tumor
PubMed: 37293858
DOI: 10.1002/ijc.34602 -
British Journal of Pharmacology May 2024Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by using herbal medicines. Currently, no therapies are available to treat or prevent...
BACKGROUND AND PURPOSE
Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by using herbal medicines. Currently, no therapies are available to treat or prevent aristolochic acid nephropathy. Histone deacetylase (HDAC) plays a crucial role in the development and progression of renal disease. We tested whether HDAC inhibitors could prevent aristolochic acid nephropathy and determined the underlying mechanism.
EXPERIMENTAL APPROACH
HDACs expression in the aristolochic acid nephropathy model was examined. The activation of PANoptosis of mouse kidney and renal tubular epithelial cell were assessed after exposure to HDAC1 and HDAC2 blockade. Kidney-specific knock-in of proline-serine-threonine-phosphatase-interacting protein 2 (PSTPIP2) mice were used to investigate whether PSTPIP2 affected the production of PANoptosome.
KEY RESULTS
Aristolochic acid upregulated the expression of HDAC1 and HDAC2 in the kidneys. Notably, the HDAC1 and HDAC2 specific inhibitor, romidepsin (FK228, depsipeptide), suppressed aristolochic acid-induced kidney injury, epithelial cell pyroptosis, apoptosis and necroptosis (PANoptosis). Moreover, romidepsin upregulated PSTPIP2 in renal tubular epithelial cells, which was enhanced by aristolochic acid treatment. Conditional knock-in of PSTPIP2 in the kidney protected against aristolochic acid nephropathy. In contrast, the knockdown of PSTPIP2 expression in PSTPIP2-knock-in mice restored kidney damage and PANoptosis. PSTPIP2 function was determined in vitro using PSTPIP2 knockdown or overexpression in mouse renal tubular epithelial cells (mTECs). Additionally, PSTPIP2 was found to regulate caspase 8 in aristolochic acid nephropathy.
CONCLUSION AND IMPLICATIONS
HDAC-mediated silencing of PSTPIP2 may contribute to aristolochic acid nephropathy. Hence, HDAC1 and HDAC2 specific inhibitors or PSTPIP2 could be valuable therapeutic agents for preventing aristolochic acid nephropathy.
Topics: Animals; Mice; Apoptosis; Aristolochic Acids; Histone Deacetylase 2; Histone Deacetylases; Kidney Diseases; Necroptosis; Pyroptosis
PubMed: 38073114
DOI: 10.1111/bph.16299 -
The Journal of Investigative Dermatology Jul 2024Cutaneous T-cell lymphomas are mature lymphoid neoplasias resulting from the malignant transformation of skin-resident T-cells. A distinctive clinical feature of...
Cutaneous T-cell lymphomas are mature lymphoid neoplasias resulting from the malignant transformation of skin-resident T-cells. A distinctive clinical feature of cutaneous T-cell lymphomas is their sensitivity to treatment with histone deacetylase inhibitors. However, responses to histone deacetylase inhibitor therapy are universally transient and noncurative, highlighting the need for effective and durable drug combinations. In this study, we demonstrate that the combination of romidepsin, a selective class I histone deacetylase inhibitor, with afatinib, an EGFR family inhibitor, induces strongly synergistic antitumor effects in cutaneous T-cell lymphoma models in vitro and in vivo through abrogation of Jak-signal transducer and activator of transcription signaling. These results support a previously unrecognized potential role for histone deacetylase inhibitor plus afatinib combination in the treatment of cutaneous T-cell lymphomas.
Topics: Depsipeptides; Lymphoma, T-Cell, Cutaneous; Humans; Animals; Mice; Afatinib; Signal Transduction; Drug Synergism; Skin Neoplasms; Cell Line, Tumor; Janus Kinases; Xenograft Model Antitumor Assays; Antineoplastic Combined Chemotherapy Protocols; Histone Deacetylase Inhibitors
PubMed: 38219917
DOI: 10.1016/j.jid.2023.12.010 -
Journal of Virus Eradication Sep 2023Understanding the clinical potency of latency-reversing agents (LRAs) on the HIV-1 reservoir is useful to deploy future strategies. This systematic review evaluated the... (Review)
Review
INTRODUCTION
Understanding the clinical potency of latency-reversing agents (LRAs) on the HIV-1 reservoir is useful to deploy future strategies. This systematic review evaluated the effects of LRAs in human intervention studies.
METHODS
A literature search was performed using medical databases focusing on studies with adults living with HIV-1 receiving LRAs. Eligibility criteria required participants from prospective clinical studies, a studied compound hypothesised as LRA, and reactivation or tolerability assessments. Relevant demographical data, LRA reactivation capacity, reservoir size, and adverse events were extracted. A study quality assessment with analysis of bias was performed by RoB 2 and ROBINS-I tools. The primary endpoints were HIV-1 reservoir reactivation after LRA treatment quantified by cell-associated unspliced HIV-1 RNA, and LRA tolerability defined by adverse events. Secondary outcomes were reservoir size and the effect of LRAs on analytical treatment interruption (ATI) duration.
RESULTS
After excluding duplicates, 5182 publications were screened. In total 45 publications fulfilled eligibility criteria including 26 intervention studies and 16 randomised trials. The risk of bias was evaluated as high. Chromatin modulators were the main investigated LRA class in 24 studies. Participants were mostly males (90.1%). Where reported, HIV-1 subtype B was most frequently observed. Reactivation after LRA treatment occurred in 78% of studies and was observed with nearly all chromatin modulators. When measured, reactivation mostly occurred within 24 h after treatment initiation. Combination LRA strategies have been infrequently studied and were without synergistic reactivation. Adverse events, where reported, were mostly low grade, yet occurred frequently. Seven studies had individuals who discontinued LRAs for related adverse events. The reservoir size was assessed by HIV-1 DNA in 80% of studies. A small decrease in reservoir was observed in three studies on immune checkpoint inhibitors and the histone deacetylase inhibitors romidepsin and chidamide. No clear effect of LRAs on ATI duration was observed.
CONCLUSION
This systematic review provides a summary of the reactivation of LRAs used in current clinical trials whilst highlighting the importance of pharmacovigilance. Highly heterogeneous study designs and underrepresentation of relevant patient groups are to be considered when interpreting these results. The observed reactivation did not lead to cure or a significant reduction in the size of the reservoir. Finding more effective LRAs by including well-designed studies are needed to define the required reactivation level to reduce the HIV-1 reservoir.
PubMed: 37663575
DOI: 10.1016/j.jve.2023.100342