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Molecular Therapy. Oncology Mar 2024The high rates of protein synthesis and processing render multiple myeloma (MM) cells vulnerable to perturbations in protein homeostasis. The induction of proteotoxic...
The high rates of protein synthesis and processing render multiple myeloma (MM) cells vulnerable to perturbations in protein homeostasis. The induction of proteotoxic stress by targeting protein degradation with proteasome inhibitors (PIs) has revolutionized the treatment of MM. However, resistance to PIs is inevitable and represents an ongoing clinical challenge. Our first-in-human study of the selective inhibitor of RNA polymerase I transcription of ribosomal RNA genes, CX-5461, has demonstrated a potential signal for anti-tumor activity in three of six heavily pre-treated MM patients. Here, we show that CX-5461 has potent anti-myeloma activity in PI-resistant MM preclinical models and . In addition to inhibiting ribosome biogenesis, CX-5461 causes topoisomerase II trapping and replication-dependent DNA damage, leading to G2/M cell-cycle arrest and apoptotic cell death. Combining CX-5461 with PI does not further enhance the anti-myeloma activity of CX-5461 . In contrast, CX-5461 shows synergistic interaction with the histone deacetylase inhibitor panobinostat in both the Vk∗MYC and the 5T33-KaLwRij mouse models of MM by targeting ribosome biogenesis and protein synthesis through distinct mechanisms. Our findings thus provide strong evidence to facilitate the clinical development of targeting the ribosome to treat relapsed and refractory MM.
PubMed: 38596309
DOI: 10.1016/j.omton.2024.200771 -
Atypical Teratoid Rhabdoid Tumours Are Susceptible to Panobinostat-Mediated Differentiation Therapy.Cancers Oct 2021Atypical teratoid rhabdoid tumour (ATRT) is a rare but highly aggressive undifferentiated solid tumour arising in the central nervous system and predominantly affecting...
Atypical teratoid rhabdoid tumour (ATRT) is a rare but highly aggressive undifferentiated solid tumour arising in the central nervous system and predominantly affecting infants and young children. ATRT is exclusively characterized by the inactivation of , a member of the SWI/SNF chromatin remodelling complex that is essential for the regulation of large sets of genes required for normal development and differentiation. Histone deacetylase inhibitors (HDACi) are a promising anticancer therapy and are able to mimic the normal acetylation functions of SMARCB1 in -deficient cells and drive multilineage differentiation in extracranial rhabdoid tumours. However, the potential efficacy of HDACi in ATRT is unknown. Here, we show that human ATRT cells are highly responsive to the HDACi panobinostat and that sustained treatment leads to growth arrest, increased cell senescence, decreased clonogenicity and induction of a neurogenesis gene-expression profile. Furthermore, in an orthotopic ATRT xenograft model, continuous panobinostat treatment inhibits tumour growth, increases survival and drives neuronal differentiation as shown by the expression of the neuronal marker, TUJ1. Collectively, this preclinical study supports the therapeutic potential of panobinostat-mediated differentiation therapy for ATRT.
PubMed: 34680294
DOI: 10.3390/cancers13205145 -
International Journal of Cancer Nov 2020Overall survival rates for patients with advanced osteosarcoma have remained static for over three decades. An in vitro analysis of osteosarcoma cell lines for...
Overall survival rates for patients with advanced osteosarcoma have remained static for over three decades. An in vitro analysis of osteosarcoma cell lines for sensitivity to an array of approved cancer therapies revealed that panobinostat, a broad spectrum histone deacetalyase (HDAC) inhibitor, is highly effective at triggering osteosarcoma cell death. Using in vivo models of orthotopic and metastatic osteosarcoma, here we report that panobinostat impairs the growth of primary osteosarcoma in bone and spontaneous metastasis to the lung, the most common site of metastasis for this disease. Further, pretreatment of mice with panobinostat prior to tail vein inoculation of osteosarcoma prevents the seeding and growth of lung metastases. Additionally, panobinostat impaired the growth of established lung metastases and improved overall survival, and these effects were also manifest in the lung metastatic SAOS2-LM7 model. Mechanistically, the efficacy of panobinostat was linked to high expression of HDAC1 and HDAC2 in osteosarcoma, and silencing of HDAC1 and 2 greatly reduced osteosarcoma growth in vitro. In accordance with these findings, treatment with the HDAC1/2 selective inhibitor romidepsin compromised the growth of osteosarcoma in vitro and in vivo. Analysis of patient-derived xenograft osteosarcoma cell lines further demonstrated the sensitivity of the disease to panobinostat or romidepsin. Collectively, these studies provide rationale for clinical trials in osteosarcoma patients using the approved therapies panobinostat or romidepsin.
Topics: Animals; Bone Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Depsipeptides; Gene Expression Regulation, Neoplastic; Histone Deacetylase 1; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Humans; Lung Neoplasms; Mice; Osteosarcoma; Panobinostat; Survival Analysis; Xenograft Model Antitumor Assays
PubMed: 32599665
DOI: 10.1002/ijc.33046 -
Breast Cancer Research : BCR Dec 2019CGRRF1 is a growth suppressor and consists of a transmembrane domain and a RING-finger domain. It functions as a RING domain E3 ubiquitin ligase involved in endoplasmic...
BACKGROUND
CGRRF1 is a growth suppressor and consists of a transmembrane domain and a RING-finger domain. It functions as a RING domain E3 ubiquitin ligase involved in endoplasmic reticulum-associated degradation. The expression of CGRRF1 is decreased in cancer tissues; however, the role of CGRRF1 in breast cancer and the mechanism(s) of its growth suppressor function remain to be elucidated.
METHODS
To investigate whether CGRRF1 inhibits the growth of breast cancer, we performed MTT assays and a xenograft experiment. Tumors harvested from mice were further analyzed by reverse phase protein array (RPPA) analysis to identify potential substrate(s) of CGRRF1. Co-immunoprecipitation assay was used to verify the interaction between CGRRF1 and its substrate, followed by in vivo ubiquitination assays. Western blot, subcellular fractionation, and reverse transcription quantitative polymerase chain reaction (qRT-PCR) were performed to understand the mechanism of CGRRF1 action in breast cancer. Publicly available breast cancer datasets were analyzed to examine the association between CGRRF1 and breast cancer.
RESULTS
We show that CGRRF1 inhibits the growth of breast cancer in vitro and in vivo, and the RING-finger domain is important for its growth-inhibitory activity. To elucidate the mechanism of CGRRF1, we identified EGFR as a new substrate of CGRRF1. CGRRF1 ubiquitinates EGFR through K48-linked ubiquitination, which leads to proteasome degradation. In addition to regulating the stability of EGFR, knockout of CGRRF1 enhances AKT phosphorylation after EGF stimulation. By analyzing the breast cancer database, we found that patients with low CGRRF1 expression have shorter survival. As compared to normal breast tissues, the mRNA levels of CGRRF1 are lower in breast carcinomas, especially in HER2-positive and basal-like breast cancers. We further noticed that CGRRF1 promoter methylation is increased in breast cancer as compared to that in normal breast tissue, suggesting that CGRRF1 is epigenetically modified in breast cancer. Treatment of 5-azactidine and panobinostat restored CGRRF1 expression, supporting that the promoter of CGRRF1 is epigenetically modified in breast cancer. Since 5-azactidine and panobinostat can increase CGRRF1 expression, they might be potential therapies for breast cancer treatment.
CONCLUSION
We demonstrated a tumor-suppressive function of CGRRF1 in breast cancer and identified EGFR as its target.
Topics: Animals; Breast Neoplasms; Cell Line, Tumor; DNA Methylation; Disease Models, Animal; ErbB Receptors; Female; Gene Expression; Gene Knockdown Techniques; Heterografts; Humans; Intracellular Signaling Peptides and Proteins; Mice; Mutation; Phosphorylation; Promoter Regions, Genetic; Protein Binding; Protein Interaction Domains and Motifs; Protein Transport; Proto-Oncogene Proteins c-akt; Tumor Suppressor Proteins; Ubiquitination
PubMed: 31801577
DOI: 10.1186/s13058-019-1212-2 -
Biomedicine & Pharmacotherapy =... Nov 2022Approximately 20% of meningiomas are not benign (higher grade) and tend to relapse after surgery and radiation therapy. Malignant (anaplastic) meningioma (MM) is a minor...
Approximately 20% of meningiomas are not benign (higher grade) and tend to relapse after surgery and radiation therapy. Malignant (anaplastic) meningioma (MM) is a minor subset of high-grade meningioma that is lethal with no effective treatment options currently. Oncolytic herpes simplex virus (oHSV) is a powerful anti-cancer modality that induces both direct cell death and anti-tumor immunity, and has shown activity in preclinical models of MM. However, clinically meaningful efficacy will likely entail rational mechanistic combination approaches. We here show that epigenome modulator histone deacetylase inhibitors (HDACi) increase anti-cancer effects of oHSV in human MM models, IOMM-Lee (NF2 wild-type) and CH157 (NF2 mutant). Minimally toxic, sub-micromolar concentrations of pan-HDACi, Trichostatin A and Panobinostat, substantively increased the infectability and spread of oHSV G47Δ within MM cells in vitro, resulting in enhanced oHSV-mediated killing of target cells when infected at low multiplicity of infection (MOI). Transcriptomics analysis identified selective alteration of mRNA processing and splicing modules that might underlie the potent anti-MM effects of combining HDACi and oHSV. In vivo, HDACi treatment increased intratumoral oHSV replication and boosted the capacity of oHSV to control the growth of human MM xenografts. Thus, our work supports further translational development of the combination approach employing HDACi and oHSV for the treatment of MM.
Topics: Humans; Meningioma; Histone Deacetylase Inhibitors; Panobinostat; Neoplasm Recurrence, Local; Simplexvirus; Herpes Simplex; Meningeal Neoplasms; RNA, Messenger
PubMed: 36271587
DOI: 10.1016/j.biopha.2022.113843 -
Cancers Nov 2021Novel therapies for multiple myeloma (MM) promise to improve outcomes but are also associated with substantial increasing costs. Evidence regarding cost-effectiveness of... (Review)
Review
BACKGROUND
Novel therapies for multiple myeloma (MM) promise to improve outcomes but are also associated with substantial increasing costs. Evidence regarding cost-effectiveness of novel treatments is necessary, but a comprehensive up-to-date overview of the cost-effectiveness evidence of novel treatments is currently lacking.
METHODS
We searched Embase, Medline via Ovid, Web of Science and EconLIT ProQuest to identify all cost-effectiveness evaluations of novel pharmacological treatment of MM reporting cost per quality-adjusted life year (QALY) and cost per life year (LY) gained since 2005. Quality and completeness of reporting was assessed using the Consolidated Health Economic Evaluation Reporting Standards.
RESULTS
We identified 13 economic evaluations, comprising 32 comparisons. Our results show that novel agents generate additional LYs (range: 0.311-3.85) and QALYs (range: 0.1-2.85) compared to backbone regimens and 0.02 to 1.10 LYs and 0.01 to 0.91 QALYs for comparisons between regimens containing two novel agents. Lifetime healthcare costs ranged from USD 60,413 to 1,434,937 per patient. The cost-effectiveness ratios per QALY gained ranged from dominating to USD 1,369,062 for novel agents compared with backbone therapies and from dominating to USD 618,018 for comparisons between novel agents.
CONCLUSIONS
Cost-effectiveness ratios of novel agents were generally above current willingness-to-pay thresholds. To ensure access, cost-effectiveness should be improved or cost-effectiveness ratios above current thresholds should be accepted.
PubMed: 34830761
DOI: 10.3390/cancers13225606 -
Cells Dec 2019In the last decades CD38 has emerged as an attractive target for multiple myeloma (MM). CD38 is a novel multifunctional glycoprotein that acts as a receptor, adhesion... (Review)
Review
In the last decades CD38 has emerged as an attractive target for multiple myeloma (MM). CD38 is a novel multifunctional glycoprotein that acts as a receptor, adhesion molecule interacting with CD31 and as an ectoenzyme. As an ectoenzyme, CD38 functions as a metabolic sensor catalyzing the extracellular conversion of NAD+ to the immunosuppressive factor adenosine (ADO). Other ectoenzymes, CD73 and CD203a, together with CD38, are also involved in the alternative axis of extracellular production of ADO, bypassing the canonical pathway mediated by CD39. CD38 is ubiquitously expressed in the bone marrow microenvironment; however, only MM cells display a very high surface density, which lead to the development of several anti-CD38 monoclonal antibodies (mAbs). The efficacy of anti-CD38 mAbs depends from the presence of CD38 on the surface of MM and immune-microenvironment cells. Interestingly, it has been reported that several drugs like lenalidomide, panobinostat, the all-trans retinoic acid and the DNA methyltransferase inhibitors may increase the expression of CD38. Hence, the possibility to modulate CD38 by increasing its expression on MM cells is the pre-requisite to potentiate the clinical efficacy of the anti-CD38 mAbs and to design clinical trials with the combination of anti-CD38 mAbs and these drugs.
Topics: ADP-ribosyl Cyclase 1; Animals; Antibodies, Monoclonal; Bone Marrow; Humans; Multiple Myeloma
PubMed: 31847204
DOI: 10.3390/cells8121632 -
Cancer Nov 2020Novel therapies are urgently needed for pediatric patients with relapsed acute myeloid leukemia (AML).
BACKGROUND
Novel therapies are urgently needed for pediatric patients with relapsed acute myeloid leukemia (AML).
METHODS
To determine whether the histone deacetylase inhibitor panobinostat could be safely given in combination with intensive chemotherapy, a phase 1 trial was performed in which 17 pediatric patients with relapsed or refractory AML received panobinostat (10, 15, or 20 mg/m ) before and in combination with fludarabine and cytarabine.
RESULTS
All dose levels were tolerated, with no dose-limiting toxicities observed at any dose level. Pharmacokinetic studies demonstrated that exposure to panobinostat was proportional to the dose given, with no associations between pharmacokinetic parameters and age, weight, or body surface area. Among the 9 patients who had sufficient (>2%) circulating blasts on which histone acetylation studies could be performed, 7 demonstrated at least 1.5-fold increases in acetylation. Although no patients had a decrease in circulating blasts after single-agent panobinostat, 8 of the 17 patients (47%), including 5 of the 6 patients treated at dose level 3, achieved complete remission. Among the 8 complete responders, 6 (75%) attained negative minimal residual disease status.
CONCLUSIONS
Panobinostat can be safely administered with chemotherapy and results in increased blast histone acetylation. This suggests that it should be further studied in AML.
Topics: Adolescent; Adult; Child; Female; Humans; Leukemia, Myeloid, Acute; Male; Neoplasm Recurrence, Local; Panobinostat; Young Adult
PubMed: 32809242
DOI: 10.1002/cncr.33156 -
American Journal of Cancer Research 2022Early stage estrogen receptor α (ERα, ESR1)-positive breast cancer patients can develop more aggressive endocrine-resistant tumors that express constitutively active...
Early stage estrogen receptor α (ERα, ESR1)-positive breast cancer patients can develop more aggressive endocrine-resistant tumors that express constitutively active mutant forms of ERα including ERα-Y537S and ERα-D538G. These patients are treated with selective ER down regulators (SERDs) such as the ERα antagonist fulvestrant. Previous studies show that histone deacetylase (HDAC) inhibitors downregulate ERα and since some dietary derived short chain fatty acids (butyrate, propionate and acetate) exhibit HDAC inhibitory activity we investigated their effects as SERDs in MCF-7 and T47D cells expressing wild-type and mutant ERα-D538G and ERα-Y537S. The SCFAs exhibited SERD-like activity in both cell lines expressing wild-type and mutant ERα. The results for propionate and butyrate correlated with parallel induction of histone acetylation and this was also observed for the HDAC inhibitors Panobinostat, Vorinostat and Entinostat which also downregulated wild-type and mutant ERα and induced histone acetylation. Although acetate induced ERα degradation the mechanisms may be independent of the HDAC inhibitory activity of this compound. These results suggest that high fibre diets that induce formation of SCFAs may have some clinical efficacy for treating ER-positive endocrine resistant breast cancer patients and this is currently being investigated.
PubMed: 35968335
DOI: No ID Found -
Indian Journal of Hematology & Blood... Apr 2023Multiple myeloma is a B cell neoplasm characterized by bone marrow infiltration with malignant plasma cells. The Overexpression of histone deacetylase prevents apoptosis...
Multiple myeloma is a B cell neoplasm characterized by bone marrow infiltration with malignant plasma cells. The Overexpression of histone deacetylase prevents apoptosis of myeloma cells by different mechanisms. The combination of Panobinostat with a BH3 mimetic, S63845, has demonstrated significant antitumor activity in multiple myeloma. We examined the impact of Panobinostat combined with MCL-1 inhibitor on multiple myeloma cell lines and as well as on fresh human myeloma cells. Our study shows that MCL-1 remains a major resistant factor to cell death induced by Panobinostat. Therefore, the inhibition of the MCL-1 member is considered a therapeutic strategy to kill the myeloma cells. We examined that the MCL-1 inhibitor (S63845) enhanced the cytotoxic effect of Panobinostat and decreased the viability of human cell lines and primary myeloma patient cells. Mechanistically, Panobinostat/S63845 control cell death via an intrinsic pathway. Given these data, the combination can be a promising therapeutic target for myeloma patients and should be further explored in clinical trials.
PubMed: 37006981
DOI: 10.1007/s12288-022-01584-4