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Circulation Research May 2021Often considered a rare disease, cardiac amyloidosis is increasingly recognized by practicing clinicians. The increased rate of diagnosis is in part due the aging of the... (Review)
Review
Often considered a rare disease, cardiac amyloidosis is increasingly recognized by practicing clinicians. The increased rate of diagnosis is in part due the aging of the population and increasing incidence and prevalence of cardiac amyloidosis with advancing age, as well as the advent of noninvasive methods using nuclear scintigraphy to diagnose transthyretin cardiac amyloidosis due to either variant or wild type transthyretin without a biopsy. Perhaps the most important driver of the increased awareness is the elucidation of the biologic mechanisms underlying the pathogenesis of cardiac amyloidosis which have led to the development of several effective therapies with differing mechanisms of actions. In this review, the mechanisms underlying the pathogenesis of cardiac amyloidosis due to light chain (AL) or transthyretin (ATTR) amyloidosis are delineated as well as the rapidly evolving therapeutic landscape that has emerged from a better pathophysiologic understanding of disease development.
Topics: Aging; Alkylating Agents; Amyloid; Amyloid Neuropathies, Familial; Amyloidosis; Antibodies, Monoclonal; Benzoates; Benzoxazoles; Bridged Bicyclo Compounds, Heterocyclic; Cardiomyopathies; Catechol O-Methyltransferase Inhibitors; Heart Transplantation; Humans; Immunomodulating Agents; Oligonucleotides; Proteasome Inhibitors; Protein Folding; Pyrazoles; RNA, Small Interfering; Stem Cell Transplantation; Sulfonamides; Tolcapone
PubMed: 33983835
DOI: 10.1161/CIRCRESAHA.121.318187 -
Science (New York, N.Y.) Jul 2022Approximately half of glioblastoma and more than two-thirds of grade II and III glioma tumors lack the DNA repair protein O-methylguanine methyl transferase (MGMT)....
Approximately half of glioblastoma and more than two-thirds of grade II and III glioma tumors lack the DNA repair protein O-methylguanine methyl transferase (MGMT). MGMT-deficient tumors respond initially to the DNA methylation agent temozolomide (TMZ) but frequently acquire resistance through loss of the mismatch repair (MMR) pathway. We report the development of agents that overcome this resistance mechanism by inducing MMR-independent cell killing selectively in MGMT-silenced tumors. These agents deposit a dynamic DNA lesion that can be reversed by MGMT but slowly evolves into an interstrand cross-link in MGMT-deficient settings, resulting in MMR-independent cell death with low toxicity in vitro and in vivo. This discovery may lead to new treatments for gliomas and may represent a new paradigm for designing chemotherapeutics that exploit specific DNA repair defects.
Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Cell Line, Tumor; DNA Methylation; DNA Modification Methylases; DNA Repair; DNA Repair Enzymes; Dacarbazine; Drug Design; Drug Resistance, Neoplasm; Glioblastoma; Humans; Temozolomide; Tumor Suppressor Proteins
PubMed: 35901163
DOI: 10.1126/science.abn7570 -
Theranostics 2022The concentration and duration of intracellular drugs have always been the key factors for determining the efficacy of the treatment. Efflux of chemotherapeutic drugs...
The concentration and duration of intracellular drugs have always been the key factors for determining the efficacy of the treatment. Efflux of chemotherapeutic drugs or anticancer agents is a major reason for multidrug resistance generation in cancer cells. The high expression of polymerase I and transcript release factor (PTRF) is correlated with a worse prognosis in glioma patients. However, the importance of PTRF on temozolomide (TMZ) resistance in glioblastoma (GBM) is poorly understood. TCGA data analysis, CGGA data analysis, transmission electron microscopy (TEM), scanning electron microscopy (SEM), clone formation, cell counting kit-8 (cck-8), western blot (WB), immunofluorescence (IF), immunohistochemistry (IHC) and flow cytometry assays were performed to investigate the underlying mechanism and effect of PTRF on TMZ-resistance in a variety of GBM cell lines and GBM patient-derived xenograft (PDX) models. Clone formation, WB, IF, IHC and flow cytometry assays were performed to examine the efficacy of sequential therapy of TMZ followed by CQ in GBM cells and PDX models. The prognosis of GBM patients treated with TMZ was negatively correlated with PTRF expression. Our results reveal that PTRF knockdown significantly decrease proliferation and increase apoptosis in GBM after TMZ treatment. Moreover, PTRF contribute to TMZ-resistance by increasing TMZ efflux through extracellular vesicles (EVs). Furthermore, our results demonstrate that sequential therapy of TMZ followed by CQ significantly promotes the TMZ efficacy against GBM by increasing intracellular TMZ concentration ([TMZ]i). This study highlights that PTRF can act as an independent biomarker to predict the prognosis of GBM patients after TMZ treatment and describes a new mechanism contributing to TMZ-resistance. In addition, this study may provide a novel idea for GBM therapy.
Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Extracellular Vesicles; Glioblastoma; Humans; Temozolomide; Xenograft Model Antitumor Assays
PubMed: 35673568
DOI: 10.7150/thno.71763 -
Clinical Cancer Research : An Official... Jun 2022In a post hoc analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with IDH1/2 wildtype (wt)... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
In a post hoc analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with IDH1/2 wildtype (wt) anaplastic astrocytomas with molecular features of glioblastoma [redesignated as glioblastoma, isocitrate dehydrogenase-wildtype (IDH-wt) in the 2021 World Health Organization (WHO) classification of central nervous system tumors].
PATIENTS AND METHODS
From the randomized phase III CATNON study examining the addition of adjuvant and concurrent temozolomide to radiotherapy in anaplastic astrocytomas, we selected a subgroup of IDH1/2wt and H3F3Awt tumors with presence of TERT promoter mutations and/or EGFR amplifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including MGMT promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis.
RESULTS
Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. A total of 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, IDH-wt. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival [HR, 1.19; 95% confidence interval (CI), 0.82-1.71] or progression-free survival (HR, 0.87; 95% CI, 0.61-1.24). MGMT promoter methylation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival.
CONCLUSIONS
In this cohort of patients with glioblastoma, IDH-wt temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of MGMT promoter status. These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population.
Topics: Antineoplastic Agents, Alkylating; Astrocytoma; Brain Neoplasms; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Dacarbazine; Glioblastoma; Humans; Isocitrate Dehydrogenase; Prospective Studies; Temozolomide
PubMed: 35275197
DOI: 10.1158/1078-0432.CCR-21-4283 -
Journal of Experimental & Clinical... Feb 2022Glioblastoma (GB) is the most common and highly malignant brain tumor characterized by aggressive growth and resistance to alkylating chemotherapy. Autophagy induction...
BACKGROUND
Glioblastoma (GB) is the most common and highly malignant brain tumor characterized by aggressive growth and resistance to alkylating chemotherapy. Autophagy induction is one of the hallmark effects of anti-GB therapies with temozolomide (TMZ). However, the non-classical form of autophagy, autophagy-based unconventional secretion, also called secretory autophagy and its role in regulating the sensitivity of GB to TMZ remains unclear. There is an urgent need to illuminate the mechanism and to develop novel therapeutic targets for GB.
METHODS
Cancer genome databases and paired-GB patient samples with or without TMZ treatment were used to assess the relationship between HMGB1 mRNA levels and overall patient survival. The relationship between HMGB1 protein level and TMZ sensitivity was measured by immunohistochemistry, ELISA, Western blot and qRT-PCR. GB cells were engineered to express a chimeric autophagic flux reporter protein consisting of mCherry, GFP and LC3B. The role of secretory autophagy in tumor microenvironment (TME) was analyzed by intracranial implantation of GL261 cells. Coimmunoprecipitation (Co-IP) and Western blotting were performed to test the RAGE-NFκB-NLRP3 inflammasome pathway.
RESULTS
The exocytosis of HMGB1 induced by TMZ in GB is dependent on the secretory autophagy. HMGB1 contributed to M1-like polarization of tumor associated macrophages (TAMs) and enhanced the sensitivity of GB cells to TMZ. Mechanistically, RAGE acted as a receptor for HMGB1 in TAMs and through RAGE-NFκB-NLRP3 inflammasome pathway, HMGB1 enhanced M1-like polarization of TAMs. Clinically, the elevated level of HMGB1 in sera may serve as a beneficial therapeutic-predictor for GB patients under TMZ treatment.
CONCLUSIONS
We demonstrated that enhanced secretory autophagy in GB facilitates M1-like polarization of TAMs to enhance TMZ sensitivity of GB cells. HMGB1 acts as a key regulator in the crosstalk between GB cells and tumor-suppressive M1-like TAMs in GB microenvironment and may be considered as an adjuvant for the chemotherapeutic agent TMZ.
Topics: Animals; Antineoplastic Agents, Alkylating; Apoptosis; Autophagy; Cell Line, Tumor; Glioblastoma; Humans; Macrophages; Male; Mice; Temozolomide; Tumor Microenvironment
PubMed: 35193644
DOI: 10.1186/s13046-022-02291-8 -
Ophthalmology Dec 2021To compare the effectiveness and safety of the MicroShunt versus trabeculectomy in patients with primary open-angle glaucoma (POAG). (Comparative Study)
Comparative Study Randomized Controlled Trial
PURPOSE
To compare the effectiveness and safety of the MicroShunt versus trabeculectomy in patients with primary open-angle glaucoma (POAG).
DESIGN
One-year results from a 2-year, prospective, randomized, multicenter, noninferiority study (NCT01881425) conducted in the United States and Europe.
PARTICIPANTS
Eligible patients were aged 40-85 years with intraocular pressure (IOP) ≥15 and ≤40 mmHg and mild-to-severe POAG inadequately controlled on maximum tolerated medical therapy.
METHODS
Patients were randomized 3:1 to undergo stand-alone MicroShunt implantation or trabeculectomy, both performed with adjunctive mitomycin C (0.2 mg/ml for 2 minutes).
MAIN OUTCOME MEASURES
The primary effectiveness end point was surgical success, defined as ≥20% reduction in mean diurnal IOP from baseline (no medication washout) at year 1 without increasing the number of glaucoma medications. Secondary effectiveness end points at year 1 were the mean IOP change from baseline and requirement for postoperative intervention. Additional end points included glaucoma medication use and adverse events.
RESULTS
Overall, 395 (MicroShunt) and 132 (trabeculectomy) patients were randomized (mean Humphrey visual field mean deviation, -12.34 decibels [dB]). At year 1, probability of success was lower in the MicroShunt group compared with the trabeculectomy group (53.9% vs. 72.7%, respectively; P < 0.01). In the MicroShunt group, mean IOP ± standard deviation decreased from 21.1 ± 4.9 mmHg at baseline to 14.3 ± 4.3 mmHg (-29.1%; P < 0.01) at year 1, with a mean of 0.6 ± 1.1 glaucoma medications (baseline 3.1 ± 1.0; P < 0.01). In the trabeculectomy group, mean IOP decreased from 21.1 ± 5.0 mmHg to 11.1 ± 4.3 mmHg (-45.4%; P < 0.01), with a mean of 0.3 ± 0.9 glaucoma medications (baseline 3.0 ± 0.9; P < 0.01). Postoperative interventions, including laser suture lysis, were reported in 40.8% (MicroShunt) versus 67.4% (trabeculectomy) of patients (P < 0.01). Reported incidence of transient hypotony was higher in the trabeculectomy group versus the MicroShunt group (49.6% vs. 28.9%; P < 0.01). Vision-threatening complications were uncommon and reported in 1.0% of MicroShunt versus 0.8% of trabeculectomy patients.
CONCLUSIONS
Probability of success was lower with MicroShunt compared with trabeculectomy. Although reductions in IOP and glaucoma medications over 1 year were observed in both groups, the trabeculectomy group had a lower mean IOP on fewer medications.
Topics: Adult; Aged; Aged, 80 and over; Alkylating Agents; Antihypertensive Agents; Female; Follow-Up Studies; Glaucoma Drainage Implants; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Mitomycin; Prospective Studies; Prosthesis Implantation; Single-Blind Method; Tonometry, Ocular; Trabeculectomy; Treatment Outcome; Visual Acuity; Visual Fields
PubMed: 34051211
DOI: 10.1016/j.ophtha.2021.05.023 -
Neuro-oncology May 2023Temozolomide (TMZ) resistance has become an important obstacle affecting its therapeutic benefits. O6-methylguanine DNA methyltransferase (MGMT) is primarily responsible...
BACKGROUND
Temozolomide (TMZ) resistance has become an important obstacle affecting its therapeutic benefits. O6-methylguanine DNA methyltransferase (MGMT) is primarily responsible for the TMZ resistance in Glioblastoma multiforme (GBM) patients. In addition, active DNA damage repair pathways can also lead to TMZ resistance. Here, we reported a novel small-molecule inhibitor EPIC-0412 that improved the therapeutic efficacy of TMZ by inhibiting the DNA damage repair pathway and MGMT in GBM via epigenetic pathways.
METHODS
The small-molecule compound EPIC-0412 was obtained through high-throughput screening. RNA immunoprecipitation (RIP), chromatin isolation by RNA purification (ChIRP), and chromatin immunoprecipitation (ChIP) assays were used to verify the effect of EPIC-0412. Co-immunoprecipitation (Co-IP) was used to elucidate the interactions of transcription factors at the MGMT promoter region. Animal experiments using a mouse model were performed to verify the efficacy of EPIC-0412 in sensitizing GBM cells to TMZ.
RESULTS
EPIC-0412 physically interrupts the binding of HOTAIR and EZH2, leading to the upregulation of CDKN1A and BBC3, causing cell cycle arrest and apoptosis in GBM cells. EPIC-0412 inhibits DNA damage response in GBM cells through the p21-E2F1 DNA damage repair axis. EPIC-0412 epigenetically silences MGMT through its interaction with the ATF3-p-p65-HADC1 axis at the MGMT promoter region. The application of EPIC-0412 restored the TMZ sensitivity in GBM in vivo experiments.
CONCLUSION
This study discovered a small-molecule inhibitor EPIC-0412, which enhanced the chemotherapeutic effect of TMZ by acting on the p21-E2F1 DNA damage repair axis and ATF3-p-p65-MGMT axis, providing evidence for combining epigenetic drugs to increase the sensitization toward TMZ in GBM patients.
Topics: Animals; Temozolomide; Glioblastoma; Antineoplastic Agents, Alkylating; DNA Repair; DNA Repair Enzymes; Drug Resistance, Neoplasm; DNA Modification Methylases; RNA; Cell Line, Tumor
PubMed: 36272139
DOI: 10.1093/neuonc/noac242 -
Neuro-oncology Dec 2020The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide (TMZ) chemotherapy in preclinical glioblastoma models but brain...
BACKGROUND
The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide (TMZ) chemotherapy in preclinical glioblastoma models but brain penetration was poor. Clinically, PARP inhibitors exacerbate the hematological side effects of TMZ. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib and assess the safety and tolerability of its combination with TMZ.
METHODS
Preclinical pharmacokinetic studies evaluated olaparib tissue distribution in rats and tumor-bearing mice. Adult patients with recurrent glioblastoma received various doses and schedules of olaparib and low-dose TMZ in a 3 + 3 design. Suitable patients received olaparib prior to neurosurgical resection; olaparib concentrations in plasma, tumor core and tumor margin specimens were measured by mass spectrometry. A dose expansion cohort tested tolerability and efficacy of the recommended phase II dose (RP2D). Radiosensitizing effects of olaparib were measured by clonogenic survival in glioblastoma cell lines.
RESULTS
Olaparib was a substrate for multidrug resistance protein 1 and showed no brain penetration in rats but was detected in orthotopic glioblastoma xenografts. Clinically, olaparib was detected in 71/71 tumor core specimens (27 patients; median, 496 nM) and 21/21 tumor margin specimens (9 patients; median, 512.3 nM). Olaparib exacerbated TMZ-related hematological toxicity, necessitating intermittent dosing. RP2D was olaparib 150 mg (3 days/week) with TMZ 75 mg/m2 daily for 42 days. Fourteen (36%) of 39 evaluable patients were progression free at 6 months. Olaparib radiosensitized 6 glioblastoma cell lines at clinically relevant concentrations of 100 and 500 nM.
CONCLUSION
Olaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better preclinical models.
Topics: Adult; Animals; Antineoplastic Agents, Alkylating; Glioblastoma; Humans; Mice; Phthalazines; Piperazines; Rats; Temozolomide
PubMed: 32347934
DOI: 10.1093/neuonc/noaa104 -
Cancer Discovery Jul 2022The majority of metastatic colorectal cancers (mCRC) are mismatch repair (MMR) proficient and unresponsive to immunotherapy, whereas MMR-deficient (MMRd) tumors often... (Clinical Trial)
Clinical Trial
UNLABELLED
The majority of metastatic colorectal cancers (mCRC) are mismatch repair (MMR) proficient and unresponsive to immunotherapy, whereas MMR-deficient (MMRd) tumors often respond to immune-checkpoint blockade. We previously reported that the treatment of colorectal cancer preclinical models with temozolomide (TMZ) leads to MMR deficiency, increased tumor mutational burden (TMB), and sensitization to immunotherapy. To clinically translate these findings, we designed the ARETHUSA clinical trial whereby O6-methylguanine-DNA-methyltransferase (MGMT)-deficient, MMR-proficient, RAS-mutant mCRC patients received priming therapy with TMZ. Analysis of tissue biopsies and circulating tumor DNA (ctDNA) revealed the emergence of a distinct mutational signature and increased TMB after TMZ treatment. Multiple alterations in the nucleotide context favored by the TMZ signature emerged in MMR genes, and the p.T1219I MSH6 variant was detected in ctDNA and tissue of 94% (16/17) of the cases. A subset of patients whose tumors displayed the MSH6 mutation, the TMZ mutational signature, and increased TMB achieved disease stabilization upon pembrolizumab treatment.
SIGNIFICANCE
MMR-proficient mCRCs are unresponsive to immunotherapy. We provide the proof of concept that inactivation of MMR genes can be achieved pharmacologically with TMZ and molecularly monitored in the tissue and blood of patients with mCRC. This strategy deserves additional evaluation in mCRC patients whose tumors are no longer responsive to standard-of-care treatments. See related commentary by Willis and Overman, p. 1612. This article is highlighted in the In This Issue feature, p. 1599.
Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Cell Line, Tumor; Colorectal Neoplasms; DNA Mismatch Repair; DNA-Binding Proteins; Dacarbazine; Humans; Mutation; O(6)-Methylguanine-DNA Methyltransferase; Temozolomide
PubMed: 35522273
DOI: 10.1158/2159-8290.CD-21-1434 -
Theranostics 2020: Glioma is the most common primary malignant brain tumor in adults. Chemoresistance of temozolomide (TMZ), the first-line chemotherapeutic agent, is a major issue in...
: Glioma is the most common primary malignant brain tumor in adults. Chemoresistance of temozolomide (TMZ), the first-line chemotherapeutic agent, is a major issue in the management of patients with glioma. Alterations of alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene constitute one of the most prevalent genetic abnormalities in gliomas. Therefore, elucidation of the role of ATRX contributing to TMZ resistance in glioma is urgently needed. : We performed the bioinformatics analysis of gene expression, and DNA methylation profiling, as well as RNA and ChIP-seq data sets. CRISPR-Cas9 gene editing system was used to achieve the ATRX knockout in TMZ resistant cells. In vitro and in vivo experiments were carried out to investigate the role of ATRX contributing to TMZ resistance in glioma. : We found that ATRX expression was upregulated via DNA demethylation mediated by STAT5b/TET2 complex and strengthened DNA damage repair by stabilizing PARP1 protein in TMZ resistant cells. ATRX elicited PARP1 stabilization by the down-regulating of FADD expression via the H3K27me3 enrichment, which was dependent on ATRX/EZH2 complex in TMZ resistant cells. Magnetic resonance imaging (MRI) revealed that the PARP inhibitor together with TMZ inhibited glioma growth in ATRX wild type TMZ resistant intracranial xenograft models. : The present study further illustrated the novel mechanism of the ATRX/PARP1 axis contributing to TMZ resistance. Our results provided substantial new evidence that PARP inhibitor might be a potential adjuvant agent in overcoming ATRX mediated TMZ resistance in glioma.
Topics: Animals; Antineoplastic Agents, Alkylating; Brain Neoplasms; CRISPR-Cas Systems; DNA Damage; DNA Methylation; DNA Repair; DNA, Neoplasm; DNA-Binding Proteins; Dioxygenases; Drug Resistance, Neoplasm; Enhancer of Zeste Homolog 2 Protein; Fas-Associated Death Domain Protein; Gene Editing; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; Glioma; Histone Code; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Proteins; Poly (ADP-Ribose) Polymerase-1; Promoter Regions, Genetic; Proto-Oncogene Proteins; STAT5 Transcription Factor; Temozolomide; Tumor Stem Cell Assay; Up-Regulation; X-linked Nuclear Protein; Xenograft Model Antitumor Assays
PubMed: 32194873
DOI: 10.7150/thno.41219