Tackling DNA damage repair mechanisms—a promising molecular informed therapeutic approach in pancreatic ductal adenocarcinoma

2020 ◽  
Vol 13 (4) ◽  
pp. 380-384 ◽  
Author(s):  
Bernhard Doleschal
Keyword(s):  
Dna Damage ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Therapeutic Approach ◽  
Dna Damage Repair ◽  
Ductal Adenocarcinoma ◽  
Damage Repair ◽  
Repair Mechanisms

scholarly journals DNA Damage Repair Deficiency in Pancreatic Ductal Adenocarcinoma: Preclinical Models and Clinical Perspectives

2021 ◽  
Vol 9 ◽  
Author(s):  
Jojanneke Stoof ◽  
Emily Harrold ◽  
Sarah Mariottino ◽  
Maeve A. Lowery ◽  
Naomi Walsh
Keyword(s):  
Dna Damage ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Dna Damage Repair ◽  
Genetically Engineered ◽  
Ductal Adenocarcinoma ◽  
Therapeutic Drug ◽  
Preclinical Models ◽  
Preclinical Research ◽  
Damage Repair ◽  
Genetically Engineered Mouse Model

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide, and survival rates have barely improved in decades. In the era of precision medicine, treatment strategies tailored to disease mutations have revolutionized cancer therapy. Next generation sequencing has found that up to a third of all PDAC tumors contain deleterious mutations in DNA damage repair (DDR) genes, highlighting the importance of these genes in PDAC. The mechanisms by which DDR gene mutations promote tumorigenesis, therapeutic response, and subsequent resistance are still not fully understood. Therefore, an opportunity exists to elucidate these processes and to uncover relevant therapeutic drug combinations and strategies to target DDR deficiency in PDAC. However, a constraint to preclinical research is due to limitations in appropriate laboratory experimental models. Models that effectively recapitulate their original cancer tend to provide high levels of predictivity and effective translation of preclinical findings to the clinic. In this review, we outline the occurrence and role of DDR deficiency in PDAC and provide an overview of clinical trials that target these pathways and the preclinical models such as 2D cell lines, 3D organoids and mouse models [genetically engineered mouse model (GEMM), and patient-derived xenograft (PDX)] used in PDAC DDR deficiency research.

scholarly journals The germline/somatic DNA damage repair gene mutations modulate the therapeutic response in Chinese patients with advanced pancreatic ductal adenocarcinoma

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lin Shui ◽  
Xiaofen Li ◽  
Yang Peng ◽  
Jiangfang Tian ◽  
Shuangshuang Li ◽  
...  
Keyword(s):  
Dna Damage ◽  
Retrospective Study ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Dna Damage Repair ◽  
Chinese Patients ◽  
Biological Behavior ◽  
Ductal Adenocarcinoma ◽  
Damage Repair ◽  
Platinum Based Chemotherapy

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with molecular heterogeneity, inducing differences in biological behavior, and therapeutic strategy. NGS profiles of pathogenic alterations in the Chinese PDAC population are limited. We conducted a retrospective study to investigate the predictive role of DNA damage repair (DDR) mutations in precision medicine. Methods The NGS profiles were performed on resected tissues from 195 Chinese PDAC patients. Baseline clinical or genetic characteristics and survival status were collected. The Kaplan–Meier survival analyses were performed by the R version 3.6.1. Results The main driver genes were KRAS, TP53, CDKN2A, and SMAD4. Advanced patients with KRAS mutation showed a worse OS than KRAS wild-type (p = 0.048). DDR pathogenic deficiency was identified in 30 (15.38%) of overall patients, mainly involving BRCA2 (n = 9, 4.62%), ATM (n = 8, 4.10%) and RAD50 genes (n = 3, 1.54%). No significance of OS between patients with or without DDR mutations (p = 0.88). But DDR mutation was an independent prognostic factor for survival analysis of advanced PDAC patients (p = 0.032). For DDR mutant patients, treatment with platinum-based chemotherapy (p = 0.0096) or olaparib (p = 0.018) respectively improved the overall survival. No statistical difference between tumor mutation burden (TMB) and DDR mutations was identified. Treatment of PD-1 blockades did not bring significantly improved OS to DDR-mutated patients than the naive DDR group (p = 0.14). Conclusions In this retrospective study, we showed the role of germline and somatic DDR mutation in predicting the efficacy of olaparib and platinum-based chemotherapy in Chinese patients. However, the value of DDR mutation in the prediction of hypermutation status and the sensitivity to the PD-1 blockade needed further investigation.

scholarly journals DNA Damage Repair Defects and Survival Outcomes for Patients With Resected Pancreatic Ductal Adenocarcinoma

Pancreas ◽  
2021 ◽  
Vol 50 (5) ◽  
pp. e50-e52
Author(s):  
Amy E. Chang ◽  
Marc R. Radke ◽  
David B. Zhen ◽  
Kelsey K. Baker ◽  
Andrew L. Coveler ◽  
...  
Keyword(s):  
Dna Damage ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Dna Damage Repair ◽  
Ductal Adenocarcinoma ◽  
Survival Outcomes ◽  
Damage Repair

scholarly journals Targeting DNA Damage Repair Mechanisms in Pancreas Cancer

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4259
Author(s):  
Lukas Perkhofer ◽  
Talia Golan ◽  
Pieter-Jan Cuyle ◽  
Tamara Matysiak-Budnik ◽  
Jean-Luc Van Laethem ◽  
...  
Keyword(s):  
Dna Damage ◽  
Current Knowledge ◽  
Parp Inhibitor ◽  
Dna Damage Repair ◽  
Significant Proportion ◽  
Ductal Adenocarcinoma ◽  
Damage Repair ◽  
Expert Meeting ◽  
Repair Mechanisms ◽  
Key Issues

Impaired DNA damage repair (DDR) is increasingly recognised as a hallmark in pancreatic ductal adenocarcinoma (PDAC). It is estimated that around 14% of human PDACs harbour mutations in genes involved in DDR, including, amongst others, BRCA1/2, PALB2, ATM, MSH2, MSH6 and MLH1. Recently, DDR intervention by PARP inhibitor therapy has demonstrated effectiveness in germline BRCA1/2-mutated PDAC. Extending this outcome to the significant proportion of human PDACs with somatic or germline mutations in DDR genes beyond BRCA1/2 might be beneficial, but there is a lack of data, and consequently, no clear recommendations are provided in the field. Therefore, an expert panel was invited by the European Society of Digestive Oncology (ESDO) to assess the current knowledge and significance of DDR as a target in PDAC treatment. The aim of this virtual, international expert meeting was to elaborate a set of consensus recommendations on testing, diagnosis and treatment of PDAC patients with alterations in DDR pathways. Ahead of the meeting, experts completed a 27-question survey evaluating the key issues. The final recommendations herein should aid in facilitating clinical practice decisions on the management of DDR-deficient PDAC.

Germline and somatic DNA damage repair gene mutations potentially predict the efficacy of relevant treatment in Chinese patients with pancreatic ductal adenocarcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16732-e16732
Author(s):  
Lin Shui ◽  
Yang Peng ◽  
Shuangshuang Li ◽  
Jiangfang Tian ◽  
Dan Cao
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Chinese Patients ◽  
Ductal Adenocarcinoma ◽  
Molecular Heterogeneity ◽  
Genetic Characteristics ◽  
Damage Repair ◽  
Potential Biomarker ◽  
Platinum Based Chemotherapy

e16732 Background: PDAC is a fatal disease with molecular heterogeneity, inducing differences in biological behaviour and therapeutic strategy. We conducted a study to reveal the mutation landscape of Chinese PDAC patients, and investigate the predictive role of germline and somatic DNA damage repair (DDR) status in precise treatment. Methods: 195 PDAC patients were enrolled from multiple medical centers of China between Jan 2016 to Nov 2019. Baseline clinical or genetic characteristics, and survival status were collected. NGS were performed on paraffin-embedded resected tissues or peripheral blood using a panel of 417 genes, including 50 DDR-related genes. Survival analysis was conducted using Kaplan-Meier, and Cox proportional hazard regression model. Results: The main driver genes were KRAS, TP53, CDKN2A, and SMAD4. Patients with KRAS mutation showed worse OS than those without (p = 0.048). DDR deficiency were identified in 15.38% of overall patients, mainly occurred in BRCA2 (4.62%), ATM (4.10%), RAD50 (1.54%) and MLH1 genes (1.03%). No significant improvement of OS existed between patients with or without DDR mutations (p = 0.88). Treatment with olaparib (adjusted HR, 0.2550; P = 0.0720) or platinum-based chemotherapy (adjusted HR, 0.1308; P = 0.0185) respectively decreased hazard of death in patients with DDR mutation. Besides BRCA gene, ATM mutant patients treated with olaparib harbored prolonged median OS than those without olaparib treatment (22.25 vs 15.2 month). Despite a little higher PD-L1 expression rate were seen in DDR mutant patients (29.17% vs 20.51%), no statistical correlation between tumor mutation burden level and DDR mutation was identified. And in patients treated with PD-1 blockade, 2 patients of DDR wild-type group both had SD, whereas of the remaining 5 patients with DDR deficiency, 1 was evaluated as PR, 3 as SD, and 1 as PD (ORR, 0 wt vs 20% mut). Conclusions: In this multi-center retrospective study, we deciphered the intra-tumoral genetic heterogeneity in Chinese PDAC population, which differs from western patients cohort to some extent. We found the potential role of germline and somatic DDR mutation status in predicting the response to olaparib and platinum-based chemotherapy, especially with BRCA or ATM mutation. However, DDR alteration was limited in prediction of hypermutational status and sensitivity to PD-1 blockade. Our study may provide a valuable evidence for clinical application of DDR mutation as a potential biomarker for precise treatment.

Dealing with transcription-blocking DNA damage: repair mechanisms, RNA polymerase II processing and human disorders

DNA Repair ◽  
2021 ◽  
pp. 103192
Author(s):  
Nan Jia ◽  
Chaowan Guo ◽  
Yuka Nakazawa ◽  
Diana van den Heuvel ◽  
Martijn S. Luijsterburg ◽  
...  
Keyword(s):  
Dna Damage ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Dna Damage Repair ◽  
Damage Repair ◽  
Repair Mechanisms ◽  
Human Disorders

scholarly journals DNA Damage/Repair Management in Cancers

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1050 ◽  
Author(s):  
Jehad F. Alhmoud ◽  
John F. Woolley ◽  
Ala-Eddin Al Moustafa ◽  
Mohammed Imad Malki
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Repair ◽  
Critical Factor ◽  
Dna Lesions ◽  
Cancer Development ◽  
Dna Damaging Agents ◽  
Damage Repair ◽  
Repair Mechanisms ◽  
Dna Strand

DNA damage is well recognized as a critical factor in cancer development and progression. DNA lesions create an abnormal nucleotide or nucleotide fragment, causing a break in one or both chains of the DNA strand. When DNA damage occurs, the possibility of generated mutations increases. Genomic instability is one of the most important factors that lead to cancer development. DNA repair pathways perform the essential role of correcting the DNA lesions that occur from DNA damaging agents or carcinogens, thus maintaining genomic stability. Inefficient DNA repair is a critical driving force behind cancer establishment, progression and evolution. A thorough understanding of DNA repair mechanisms in cancer will allow for better therapeutic intervention. In this review we will discuss the relationship between DNA damage/repair mechanisms and cancer, and how we can target these pathways.

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