DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy

Signal Transduction and Targeted Therapy, Год журнала: 2021, Номер 6(1)

Опубликована: Июль 9, 2021

Abstract Genomic instability is the hallmark of various cancers with increasing accumulation DNA damage. The application radiotherapy and chemotherapy in cancer treatment typically based on this property cancers. However, adverse effects including normal tissues injury are also accompanied by chemotherapy. Targeted therapy has potential to suppress cells’ damage response through tailoring patients lacking specific functions. Obviously, understanding broader role repair became a basic attractive strategy for targeted therapy, particular, raising novel hypothesis or theory field basis previous scientists’ findings would be important future promising druggable emerging targets. In review, we first illustrate timeline steps roles promotion developed, then summarize mechanisms regarding associated highlighting proteins behind targeting that initiate functioning abnormally duo extrinsic harm environmental factors, also, baseline drift leads harmful intrinsic therapy. addition, clinical therapeutic drugs effects, as well scheme relative trials were intensive discussed. Based background, suggest two hypotheses, namely “environmental gear selection” describe pathway evolution, “DNA drift”, which may play magnified mediating during treatment. This new shed light provide much better more comprehensive holistic view promote development research direction overcoming strategies patients.

Язык: Английский

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AND Logic Gate-Regulated DNAzyme Nanoflower for Monitoring the Activity of Multiple DNA Repair Enzymes

Analytical Chemistry, Год журнала: 2024, Номер 96(5), С. 2117 - 2123

Опубликована: Янв. 25, 2024

Despite the progress that has been made in diverse DNA-based nanodevices to situ monitor activity of DNA repair enzymes living cells, significance improving both sensitivity and specificity remained largely neglected understudied. Herein, we propose a regulatable nanodevice specifically for early evaluation cancer mediated by genomic instability. Concretely, an AND logic gate-regulated DNAzyme nanoflower was rationally designed self-assembly duplex modified with apurinic/apyrimidinic (AP) site methyl lesion site. The could be reconfigured under AP sites O6-methylguanine endonuclease 1 (APE1) methyltransferase (MGMT) produce fluorescent signal, realizing sensitive monitoring APE1 MGMT. Compared free duplex, response increased 60%, due effective enrichment probes structure. More importantly, have demonstrated dual-enzyme activated strategy allows imaging specific cells gate manner using MCF-7 as cell model, imaging. This multifunctional provides simple tool simultaneously visualizing multiple enzymes, holding great potential clinical diagnosis drug discovery.

Язык: Английский

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Homologous Recombination Deficiency in Pancreatic Cancer: A Systematic Review and Prevalence Meta-Analysis

Journal of Clinical Oncology, Год журнала: 2021, Номер 39(23), С. 2617 - 2631

Опубликована: Июль 1, 2021

To analyze the prevalence of homologous recombination deficiency (HRD) in patients with pancreatic ductal adenocarcinoma (PDAC).

Язык: Английский

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Systemic Therapy for Metastatic Pancreatic Cancer

Current Treatment Options in Oncology, Год журнала: 2021, Номер 22(11)

Опубликована: Окт. 19, 2021

Opinion statement Pancreatic cancer is mainly diagnosed at an advanced, often metastatic stage and still has a poor prognosis. Over the last decades, chemotherapy of pancreatic (mPDAC) proven to be superior mere supportive treatment with respect both survival quality life. Recently, even sequential mPDAC could established. Options for first-line are combination regimens such as FOLFIRINOX gemcitabine plus nab-paclitaxel when performance status patient good. For patients poorer status, single-agent valid option. PARP inhibitor olaparib been demonstrated improve progression-free used maintenance in subgroup BRCA1/-2 germ line mutation having received least 16 weeks platinum-based chemotherapy. This group also benefits from combinations. Therefore, stats should examined early occurrence these mutations only about 5% general Caucasian population. After failure treatment, offered second-line if their ECOG permits further treatment. Here, 5-FU/FA nanoliposomal irinotecan shown alone overall survival. Immune checkpoint inhibitors like PD1/PD-L1 mAbs particularly efficacious tumors high microsatellite instability (MSI-h). Limited data mPDACs shows that part already small MSI-H (frequency 1%) appears benefit substantially The identification subgroups, e.g., DNA damage repair deficiency, gene fusions, well novel approaches tumor-organoid-informed decisions, may therapeutic efficacy.

Язык: Английский

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Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma: A Physiopathologic and Pharmacologic Review

Cancers, Год журнала: 2022, Номер 14(10), С. 2486 - 2486

Опубликована: Май 18, 2022

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with poor prognosis and inadequate response to treatment. Many factors contribute this therapeutic failure: lack of symptoms until the reaches an advanced stage, leading late diagnosis; early lymphatic hematic spread; age patients; important development pro-tumoral hyperfibrotic stroma; high genetic metabolic heterogeneity; vascular supply; highly acidic matrix; extreme hypoxia; resistance available options. In most cases, disease silent for long time, andwhen it does become symptomatic, too ablative surgery; one major reasons explaining short survival associated disease. Even when surgery possible, relapsesare frequent, andthe causes devastating picture are low efficacy ofand all known chemotherapeutic treatments. Thus, imperative analyze roots in order improve benefits therapy. PDAC chemoresistance final product different, but some extent, interconnected factors. Surgery, being adequate treatment pancreatic cancer only that few selected cases can achieve longer survival, possible less than 20% patients. burden relies on chemotherapy mostcases. While FOLFIRINOX scheme has slightly overall also produces many more adverse eventsso gemcitabine still considered first choice treatment, especially combination other compounds/agents. This review discusses multiple PDAC.

Язык: Английский

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Facts and Hopes in Immunotherapy of Pancreatic Cancer

Clinical Cancer Research, Год журнала: 2022, Номер 28(21), С. 4606 - 4617

Опубликована: Июль 1, 2022

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging cancers to treat. For patients with advanced and metastatic disease, chemotherapy has yielded only modest incremental benefits, which are not durable. Immunotherapy revolutionized treatment other solid tumors by leading cures where none existed a decade ago, yet it made few inroads PDAC. A host trials promising preclinical data have failed, except for in small minority selected biomarkers. There is, however, glimmer hope, we seek cultivate. In this review, discuss recent advances understanding uniquely immunosuppressive tumor microenvironment (TME) PDAC, learnings from completed checkpoint inhibitors, TME modifiers, cellular vaccine therapies, oncolytic viruses, novel approaches. We go on our expectations improved models immunotherapy new approaches modifying including myeloid compartment, emerging biomarkers better select who may benefit immunotherapy. also improvements clinical trial design specific that will help us measure success when find it. Finally, urgent imperative execute bold, but rational, combination agents designed cure

Язык: Английский

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MRNIP condensates promote DNA double-strand break sensing and end resection

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Май 12, 2022

Abstract The rapid recognition of DNA double-strand breaks (DSBs) by the MRE11/RAD50/NBS1 (MRN) complex is critical for initiation damage response and DSB end resection. Here, we show that MRN interacting protein (MRNIP) forms liquid-like condensates to promote homologous recombination-mediated repair. intrinsically disordered region essential MRNIP condensate formation. Mechanically, compartmentalized concentrated into in nucleus. After formation, move damaged rapidly accelerate binding complex, therefore inducing autophosphorylation ATM subsequent activation signaling. Meanwhile, condensates-enhanced loading further promotes In addition, data from xenograft models clinical samples confirm a correlation between radioresistance. Together, these results reveal an important role phase separation complex-mediated

Язык: Английский

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METTL16 antagonizes MRE11-mediated DNA end resection and confers synthetic lethality to PARP inhibition in pancreatic ductal adenocarcinoma

Nature Cancer, Год журнала: 2022, Номер 3(9), С. 1088 - 1104

Опубликована: Сен. 22, 2022

Язык: Английский

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Current Understanding of Microbiomes in Cancer Metastasis

Cancers, Год журнала: 2023, Номер 15(6), С. 1893 - 1893

Опубликована: Март 22, 2023

Cancer has been the first killer that threatens people’s lives and health. Despite recent improvements in cancer treatment, metastasis continues to be main reason for death from cancer. The functions of microbiome have studied recently, it is proved can influence tumor metastasis, as well positive or negative responses therapy. Here, we summarize mechanisms microorganisms affecting which include epithelial-mesenchymal transition (EMT), immunity, fluid shear stress (FSS), matrix metalloproteinases (MMPs). This review will not only give a further understanding relationship between but also provide new perspective microbiome’s application prevention, early detection, treatment.

Язык: Английский

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PRMT1 promotes pancreatic cancer development and resistance to chemotherapy

Cell Reports Medicine, Год журнала: 2024, Номер 5(3), С. 101461 - 101461

Опубликована: Март 1, 2024

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types cancer, and novel treatment regimens are direly needed. Epigenetic regulation contributes to development various cancer types, but its role in potential as a therapeutic target for PDAC underexplored. Here, we show that PRMT1 is highly expressed murine human pancreatic essential cell proliferation tumorigenesis. Deletion delays KRAS-dependent mouse model, multi-omics analyses reveal depletion leads global changes chromatin accessibility transcription, resulting reduced glycolysis decrease tumorigenic capacity. Pharmacological inhibition combination with gemcitabine has synergistic effect on tumor growth vitro vivo. Collectively, our findings implicate key regulator promising therapy.

Язык: Английский

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