Search

The antitumor antibiotic mithramycin A (MTA) binds to G/C-rich DNA sequences in the presence of dications. MTA inhibits transcription regulated by the Sp1 transcription factor, often enhanced during tumor development. It shows antitumor activity, but its clinical use was discontinued due to toxic side effects. However, recent observations have led to its use being reconsidered. The MTA biosynthetic pathways have been modified to produce mithramycin analogs (mithralogs) that encompass lower toxicity and improved pharmacological activity. Some mithralogs reduce gene expression in human ovarian and prostate tumors, among other types of cancer. They down-regulate gene expression in various cellular processes, including Sp1-responsive genes that control tumor development. Moreover, MTA and several mithralogs, such as EC-8042 (DIG-MSK) and EC-8105, effectively treat Ewing sarcoma by inhibiting transcription controlled by the oncogenic EWS-FLI1 transcription factor. [ABSTRACT FROM AUTHOR]

Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5 days/month), a transcriptional inhibitor of specificity protein 1 (Sp1)-regulated proteins, is 1,700 mg/day with median area under the plasma concentration-time curve (AUC) of 31.3 μg∗h/mL. Given potentially increased efficacy with sustained systemic exposure and challenging logistics of daily IV therapy, here we investigate oral terameprocol for rHGGs in a multicenter, phase 1 trial (GATOR). Using a 3 + 3 dose-escalation design, we enroll 20 patients, with median age 60 years (range 31-80), 70% male, and median one relapse (range 1-3). Fasting patients tolerate 1,200 mg/day (n = 3), 2,400 mg/day (n = 6), 3,600 mg/day (n = 3), and 6,000 mg/day (n = 2) oral doses without major toxicities. However, increased dosage does not lead to increased systemic exposure, including in fed state (6,000 mg/day, n = 4), with maximal AUC <5 μg∗h/mL. These findings warrant trials investigating approaches that provide sustained systemic levels of transcription inhibitors to exploit their therapeutic potential. This study was registered at ClinicalTrials.gov (NCT02575794)., Competing Interests: Declaration of interests M.S.A. – grants: Seagen, AstraZeneca, BMS, Bayer, Incyte, Pharmacyclics, Novocure, MimiVax, and Merck. Consultation fees: Bayer, Novocure, Kiyatec, Insightec, GSK, Xoft, Nuvation, Celularity, SDP Oncology, Apollomics, Prelude Therapeutics, Janssen, Tocagen, Voyager Therapeutics, ViewRay, Caris Life Sciences, Pyramid Biosciences, Varian Medical Systems, Cairn Therapeutics, AnHeart Therapeutics, Menarini Ricerche, Sumitomo Pharma Oncology, Autem therapeutics, GT Medical Technologies, Allovir, Equillium Bio., QV Bioelectronics, and Theraguix. Scientific Advisory Board memberships: Cairn Therapeutics, Pyramid Biosciences, Bugworks, and Modifi Biosciences. Data Safety and Monitoring Committee membership: VBI Vaccines. Stock shareholder: MimiVax, CytoDyn, Trisalus Lifesciences, and MedInnovate Advisors, LLC. D.M.P. – consulting or advisory role: Orbus Therapeutics, Sumitomo Dainippon Pharma Oncology, Inc., Stemline Therapeutics, and Novocure. Research funding: Pfizer (Inst), Novartis (Inst), NeOnc Technologies (Inst), Orbus Therapeutics (Inst), Bristol Myers Squibb (Inst), Genentech/Roche (Inst), Pharmacyclics (Inst), Bayer (Inst), Karyopharm Therapeutics (Inst), Apollomics (Inst), Vigeo Therapeutics (Inst), Global Coalition for Adaptive Research (Inst), MimiVax (Inst), Ono Pharmaceutical (Inst), and Mylan (Inst). Equity ownership/stock options: Pfizer (Pharmaceuticals) and Gilead (Pharmaceuticals). M.H. – Data Safety Monitoring Board member: Parexel and Advarra. Institutional research funding: Novartis and Vanquish. P.Y.W. – research support: AstraZeneca, Black Diamond, Bristol Meyers Squibb, Celgene, Chimerix, Eli Lily, Erasca, Genentech/Roche, Kazia, MediciNova, Merck, Novartis, Nuvation Bio, Servier, Vascular Biogenics, and VBI Vaccines. Advisory board/consultant: AstraZeneca, Black Diamond, Celularity, Chimerix, Day One Bio, Genenta, Glaxo Smith Kline, Merck, Mundipharma, Novartis, Novocure, Nuvation Bio, Prelude Therapeutics, Sapience, Servier, Sagimet, Vascular Biogenics, and VBI Vaccines. R.C.H. has patents related to the drug terameprocol and is affiliated with Erimos Pharmaceuticals, which holds rights to the drug. S.G. is an independent contractor/consultant to Erimos Pharmaceuticals, LLC with no ownership or other financial interest in Erimos Pharmaceuticals or its products., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Backgroud: Glioblastoma multiforme (GBM) is among the most aggressive cancers, with current treatments limited in efficacy. A significant hurdle in the treatment of GBM is the resistance to the chemotherapeutic agent temozolomide (TMZ). The methylation status of the MGMT promoter has been implicated as a critical biomarker of response to TMZ., Methods: To explore the mechanisms underlying resistance, we developed two TMZ-resistant GBM cell lines through a gradual increase in TMZ exposure. Transcriptome sequencing of TMZ-resistant cell lines revealed that alterations in histone post-translational modifications might be instrumental in conferring TMZ resistance. Subsequently, multi-omics analysis suggests a strong association between histone H3 lysine 9 acetylation (H3K9ac) levels and TMZ resistance., Results: We observed a significant correlation between the expression of H3K9ac and MGMT, particularly in the unmethylated MGMT promoter samples. More importantly, our findings suggest that H3K9ac may enhance MGMT transcription by facilitating the recruitment of the SP1 transcription factor to the MGMT transcription factor binding site. Additionally, by analyzing single-cell transcriptomics data from matched primary and recurrent GBM tumors treated with TMZ, we modeled the molecular shifts occurring upon tumor recurrence. We also noted a reduction in tumor stem cell characteristics, accompanied by an increase in H3K9ac, SP1, and MGMT levels, underscoring the potential role of H3K9ac in tumor relapse following TMZ therapy., Conclusions: The increase in H3K9ac appears to enhance the recruitment of the transcription factor SP1 to its binding sites within the MGMT locus, consequently upregulating MGMT expression and driving TMZ resistance in GBM., (© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

[Display omitted] • Context: Nucleic acid sequences containing guanine tracts can form G-quadruplexes (G4s), impacting gene regulation. • Principal results : HIVpro2 DNA sequence, derived from the HIV-1 promoter, forms a hybrid G4 structure with a single-nucleotide bulge. The structural interplay between HIVpro2 and other G4s can modulate SP1 binding sites architecture, potentially regulating viral transcription and latency. • Conceptual advance : Discovery of a G4 structure in HIVpro2 suggests a novel mechanism for HIV-1 gene regulation. • Significance : Understanding the structural switch between G4s and canonical duplexes may offer new strategies for HIV-1 therapy and latency control. Nucleic acid sequences containing guanine tracts are able to form non-canonical DNA or RNA structures known as G-quadruplexes (or G4s). These structures, based on the stacking of G-tetrads, are involved in various biological processes such as gene expression regulation. Here, we investigated a G4 forming sequence, HIVpro2, derived from the HIV-1 promoter. This motif is located 60 nucleotides upstream of the proviral Transcription Starting Site (TSS) and overlaps with two SP1 transcription factor binding sites. Using NMR spectroscopy, we determined that HIVpro2 forms a hybrid type G4 structure with a core that is interrupted by a single nucleotide bulge. An additional reverse-Hoogsteen AT base pair is stacked on top of the tetrad. SP1 transcription factor is known to regulate transcription activity of many genes through the recognition of Guanine-rich duplex motifs. Here, the formation of HIVpro2 G4 may modulate SP1 binding sites architecture by competing with the formation of the canonical duplex structure. Such DNA structural switch potentially participates to the regulation of viral transcription and may also interfere with HIV-1 reactivation or viral latency. [ABSTRACT FROM AUTHOR]

The development of sepsis can lead to many organ dysfunction and even death. Myocardial injury is one of the serious complications of sepsis leading to death. New evidence suggests that microRNAs (miRNAs) play a critical role in infection myocardial injury. However, the mechanism which miR-208a-5p regulates sepsis-induced myocardial injury remains unclear. To mimic sepsis-induced myocardial injury in vitro, rat primary cardiomyocytes were treated with LPS. Cell viability and apoptosis were tested by CCK-8 and flow cytometry, respectively. The secretion of inflammatory factors was analyzed by ELISA. mRNA and protein levels were detected by RT-qPCR and Western blotting. The interaction among SP1, XIAP and miR-208a-5p was detected using dual luciferase report assay. Ultrasonic analysis and HE staining was performed to observe the effect of miR-208a-5p in sepsis-induced rats. Our findings indicated that miR-208a-5p expression in primary rat cardiomyocytes was increased by LPS. MiR-208a-5p inhibitor reversed LPS-induced cardiomyocytes injury through inhibiting the apoptosis. Furthermore, the inflammatory injury in cardiomyocytes was induced by LPS, which was rescued by miR-208a-5p inhibitor. In addition, downregulation of miR-208a-5p improved LPS-induced sepsis myocardial injury in vivo. Mechanistically, XIAP might be a target gene of miR-208a-5p. SP1 promoted transcription of miR-208a by binding to the miR-208a promoter region. Moreover, silencing of XIAP reversed the regulatory of miR-208a-5p inhibitor on cardiomyocytes injury. To sum up, those findings revealed silencing of miR-208a-5p could alleviate sepsis-induced myocardial injury, which would grant a new process for the treatment of sepsis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)