Glioblastoma Therapy: Past, Present and Future

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(5), С. 2529 - 2529

Опубликована: Фев. 21, 2024

Glioblastoma (GB) stands out as the most prevalent and lethal form of brain cancer. Although great efforts have been made by clinicians researchers, no significant improvement in survival has achieved since Stupp protocol became standard care (SOC) 2005. Despite multimodality treatments, recurrence is almost universal with rates under 2 years after diagnosis. Here, we discuss recent progress our understanding GB pathophysiology, particular, importance glioma stem cells (GSCs), tumor microenvironment conditions, epigenetic mechanisms involved growth, aggressiveness recurrence. The discussion on therapeutic strategies first covers SOC treatment targeted therapies that shown to interfere different signaling pathways (pRB/CDK4/RB1/P16

Язык: Английский

---

The Role of PARPs in Inflammation—And Metabolic—Related Diseases: Molecular Mechanisms and Beyond

Cells, Год журнала: 2019, Номер 8(9), С. 1047 - 1047

Опубликована: Сен. 6, 2019

Poly(ADP-ribosyl)ation (PARylation) is an essential post-translational modification catalyzed by poly(ADP-ribose) polymerase (PARP) enzymes. Poly(ADP-ribose) 1 (PARP1) a well-characterized member of the PARP family. PARP1 plays crucial role in multiple biological processes and activation contributes to development various inflammatory malignant disorders, including lung cardiovascular disease, ovarian cancer, breast diabetes. In this review, we will focus on molecular mechanisms PARPs enzymes inflammation- metabolic-related diseases. Specifically, discuss signaling pathways that associated with regulation pathogenesis. Recently, increasing evidence suggests inhibition promising strategy for intervention some Thus, our in-depth understanding mechanism how are activated their downstream effecters can provide more potential therapeutic targets treatment related diseases future crucial.

Язык: Английский

---

A Systematic Review of Glioblastoma-Targeted Therapies in Phases II, III, IV Clinical Trials

Cancers, Год журнала: 2021, Номер 13(8), С. 1795 - 1795

Опубликована: Апрель 9, 2021

Glioblastoma (GBM), the most frequent and aggressive glial tumor, is currently treated as first line by Stupp protocol, which combines, after surgery, radiotherapy chemotherapy. For recurrent GBM, in absence of standard treatment or available clinical trials, various protocols including cytotoxic drugs and/or bevacizumab are applied. Despite these heavy treatments, mean overall survival patients under 18 months. Many studies underway. Based on clinicaltrials.org conducted up to 1 April 2020, this review lists, not only main, but all targeted therapies phases II-IV 257 trials adults with newly diagnosed GBMs for last twenty years. It does involve immunotherapies targeting tumor cell metabolism, that well documented other reviews. Without surprise, frequently reported those (i) EGFR (40 trials), more generally tyrosine kinase receptors (85 trials) (ii) VEGF/VEGFR (75 53 involving bevacizumab). But many targets interest. They listed thoroughly described, an one-on-one basis, four sections related GBM stem cells pathways, growth autonomy migration, (iii) cycle escape death, (iv) angiogenesis.

Язык: Английский

---

A Review of Approaches to Potentiate the Activity of Temozolomide against Glioblastoma to Overcome Resistance

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(6), С. 3217 - 3217

Опубликована: Март 12, 2024

A glioblastoma (GBM) is one of the most aggressive, infiltrative, and treatment-resistant malignancies central nervous system (CNS). The current standard care for GBMs include maximally safe tumor resection, followed by concurrent adjuvant radiation treatment chemotherapy with DNA alkylating agent temozolomide (TMZ), which was approved FDA in 2005 based on a marginal increase (~2 months) overall survival (OS) levels. This approach, while initially successful containing treating GBM, almost invariably fails to prevent recurrence. In addition limited therapeutic benefit, TMZ also causes debilitating adverse events (AEs) that significantly impact quality life GBM patients. Some common AEs hematologic (e.g., thrombocytopenia, neutropenia, anemia) non-hematologic nausea, vomiting, constipation, dizziness) toxicities. Recurrent are often resistant other DNA-damaging agents. Thus, there an urgent need devise strategies potentiate activity, overcome drug resistance, reduce dose-dependent AEs. Here, we analyze major mechanisms resistance-mediated intracellular signaling activation repair pathways overexpression transporters. We review some approaches investigated counteract these resistance TMZ, including use chemosensitizers delivery enhance tumoral exposure.

Язык: Английский

---

PARP-1–Targeted Radiotherapy in Mouse Models of Glioblastoma

Journal of Nuclear Medicine, Год журнала: 2018, Номер 59(8), С. 1225 - 1233

Опубликована: Март 23, 2018

The DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP-1) is overexpressed in glioblastoma, with overall low expression healthy brain tissue. Paired the availability of specific small molecule inhibitors, PARP-1 a near-ideal target to develop novel radiotherapeutics induce damage and apoptosis cancer cells, while sparing Methods: We synthesized an ¹³¹I-labeled therapeutic investigated its pharmacology vitro vivo. A subcutaneous tumor model was used quantify retention times efficacy. potential clinical scenario, intratumoral convection-enhanced delivery, mimicked using orthotopic glioblastoma combined implanted osmotic pump system study local administration ¹³¹I-PARPi (PARPi PARP inhibitor). Results:¹³¹I-PARPi 1(2H)-phthalazinone, similar structure Food Drug Administration–approved inhibitor AZD-2281. In studies have shown that AZD-2281 share pharmacologic profiles. delivered 134.1 cGy/MBq injected activity. Doses nontarget tissues, including liver kidney, were significantly lower. Radiation cell death treated tumors by p53 activation U87-MG cells transfected p53-bioluminescent reporter. Treated mice showed longer survival than receiving vehicle (29 vs. 22 d, P < 0.005) model. Convection-enhanced delivery demonstrated efficient tumors, quickly clearing from Conclusion: Our results demonstrate ¹³¹I-PARPi's high as highlight PARP's relevance for radionuclide therapy. plays integral role therapy, radiolabeled therapeutics could ultimately lead improvements standard care.

Язык: Английский

---

Validation of genomic and transcriptomic models of homologous recombination deficiency in a real-world pan-cancer cohort

BMC Cancer, Год журнала: 2022, Номер 22(1)

Опубликована: Май 28, 2022

With the introduction of DNA-damaging therapies into standard care cancer treatment, there is a growing need for predictive diagnostics assessing homologous recombination deficiency (HRD) status across tumor types. Following strong clinical evidence utility DNA-sequencing-based HRD testing in ovarian cancer, and breast we present analytical validation Tempus HRD-DNA test. We further developed, validated, explored HRD-RNA model, which uses gene expression data from 16,750 RNA-seq samples to predict formalin-fixed paraffin-embedded numerous types.Genomic transcriptomic profiling was performed using next-generation sequencing xT, xO, xE, RS, RS.v2 assays on 48,843 samples. Samples were labeled based their BRCA1, BRCA2 selected Homologous Recombination Repair pathway (CDK12, PALB2, RAD51B, RAD51C, RAD51D) mutational train validate HRD-DNA, genome-wide loss-of-heterozygosity biomarker, HRD-RNA, logistic regression model trained expression.In sample 2058 1216 tumors, BRCA predicted by with F1-scores 0.98 0.96, respectively. Across an independent set 1363 solid types, prostate, pancreatic, non-small cell lung 0.88, 0.69, 0.62, respectively.We HRD-positive patients many types believe both models may generalize other mechanisms outside loss. complements DNA-based detection methods, especially indications low prevalence alterations.

Язык: Английский

---

Synergic pro-apoptotic effects of Ferulic Acid and nanostructured lipid carrier in glioblastoma cells assessed through molecular and Delayed Luminescence studies

Scientific Reports, Год журнала: 2020, Номер 10(1)

Опубликована: Март 13, 2020

Abstract Herein, we assessed the effect of Ferulic Acid (FA), a natural antioxidant with anti-cancer effect, on human glioblastoma cells through molecular and Delayed Luminescence (DL) studies. DL, phenomenon ultra-week emission optical photons, was used to monitor mitochondrial assessment. The FA loaded in nanostructured lipid carriers (NLCs) also assessed. To validate NLCs as drug delivery system for treatment, particular attention focused their effect. We found that free induced significant decrease c-Myc Bcl-2 expression levels accompanied by apoptotic pathway activation. Blank NLCs, even if they did not induce cytotoxicity caspase-3 cleavage, decreased Bcl-2, ERK1/2, activating PARP-1 cleavage. changes DL intensity kinetics highlighted possible nanoparticle matrix mitochondria, involvement NADH pool ROS production that, turn, activates ERK1/2 pathways. All effects protein activation appeared more evident when were exposed NLCs. demonstrated observed are due synergic pro-apoptotic influence exerted FA, whose bio-availability increases cells, formulation.

Язык: Английский

---

Molecular targeted therapy: A new avenue in glioblastoma treatment (Review)

Oncology Letters, Год журнала: 2022, Номер 25(2)

Опубликована: Дек. 15, 2022

Glioblastoma, also referred to as glioblastoma multiforme (GBM), is grade IV astrocytoma characterized by being fast-growing and the most aggressive brain tumor. In adults, it prevalent type of malignant Despite advancements in both diagnosis tools therapeutic treatments, GBM still associated with poor survival rate without any statistically significant improvement past three decades. Patient's genome signature one key factors causing development this tumor, addition previous radiation exposure other environmental factors. Researchers have identified genomic subsequent molecular alterations affecting core pathways that trigger phenotype Targeting intrinsically altered molecules seen a novel avenue treatment. The present review shed light on signaling implicated development. It discussed main challenges impeding successful treatment, such blood barrier tumor microenvironment (TME), plasticity heterogeneity TME stem cells. presented current targeted therapy clinical trials. Profound comprehensive understanding participants opens doors for innovative, more personalized modalities.

Язык: Английский

---

Prognostic value of PARP1 and PARP2 copy number alterations in prostate cancer

Laboratory Investigation, Год журнала: 2025, Номер unknown, С. 104171 - 104171

Опубликована: Апрель 1, 2025

Язык: Английский

---

NAMPT as a Dedifferentiation-Inducer Gene: NAD+ as Core Axis for Glioma Cancer Stem-Like Cells Maintenance

Frontiers in Oncology, Год журнала: 2019, Номер 9

Опубликована: Май 2, 2019

Glioma Cancer Stem-Like Cells (GSCs) are a small subset of CD133+ cells with self-renewal properties and capable to initiate new tumors contributing progression, maintenance, hierarchy complexity. GSCs highly resistant chemo radiotherapy. These believed be responsible for tumor relapses patients' fatal outcome after developing recurrent Glioblastoma (GBM) or High Grade (HGG). under replicative stress high demands on NAD+ supply repair DNA, maintain capacity induce plasticity. feeds Poly-ADP polymerases (PARP) NAD+-dependent deacetylases (SIRTUINS) GSC phenotype. This energetic core axis is mainly controlled by the rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT), an important oncogene dedifferentiation. Targeting depicts frontier in therapy; hence NAMPT could represent key regulator maintenance. Its inhibition may attenuate decreasing supply, consequently better together current therapies control.

Язык: Английский

---