Utilisation of semiconductor sequencing for the detection of predictive biomarkers in glioblastoma

AbstractThe standard treatment for glioblastoma involves a combination of surgery, radiation and chemotherapy but have limited impact on survival. The exponential increase in targeted agents directed at pivotal oncogenic pathways now provide new therapeutic opportunities for this tumour type. However, lack of comprehensive precision oncology testing at diagnosis means such therapeutic opportunities are potentially overlooked.To investigate the role of semiconductor sequencing for detection of predictive biomarkers in routine glioblastoma samples we have undertaken analysis of test trending data generated by a clinically validated next generation sequencing platform designed to capture 764 of the leading anti-cancer targeted agents/combinations and immunotherapies via analysis of actionable genomic variants distributed across 505 genes. Analysis was performed across a cohort of 55 glioblastoma patients.Analysis of trending data has revealed a complex and rich actionable mutational landscape in which 166 actionable mutations were detected across 36 genes linked to 17 off label targeted therapy protocols and 111 clinical trials. The majority of patients harboured three or more actionable mutations affecting key cancer related regulatory networks including the PI3K/AKT/MTOR and RAS/RAF/MEK/MAPK signalling pathways, DNA-damage repair pathways and cell cycle checkpoints. Linkage with immunotherapy and PARP inhibitors was identified in 44% of glioblastoma patients as a consequence of alterations in DNA-damage repair genes.Taken together our data indicates that precision oncology testing utilising semiconductor sequencing can be used to identify a broad therapeutic armamentarium of targeted therapies and immunotherapies that can be potentially employed for the improved clinical management of glioblastoma patients.

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Targeting DNA Replication Stress and DNA Double-Strand Break Repair for Optimizing SCLC Treatment

Cancers ◽

10.3390/cancers11091289 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1289 ◽

Cited By ~ 4

Author(s):

Xing Bian ◽

Wenchu Lin

Keyword(s):

Lung Cancer ◽

Dna Damage ◽

Dna Replication ◽

Dna Damage Repair ◽

Predictive Biomarkers ◽

Replication Stress ◽

Genotoxic Stress ◽

Repair System ◽

Damage Repair ◽

Repair Pathways

Small cell lung cancer (SCLC), accounting for about 15% of all cases of lung cancer worldwide, is the most lethal form of lung cancer. Despite an initially high response rate of SCLC to standard treatment, almost all patients are invariably relapsed within one year. Effective therapeutic strategies are urgently needed to improve clinical outcomes. Replication stress is a hallmark of SCLC due to several intrinsic factors. As a consequence, constitutive activation of the replication stress response (RSR) pathway and DNA damage repair system is involved in counteracting this genotoxic stress. Therefore, therapeutic targeting of such RSR and DNA damage repair pathways will be likely to kill SCLC cells preferentially and may be exploited in improving chemotherapeutic efficiency through interfering with DNA replication to exert their functions. Here, we summarize potentially valuable targets involved in the RSR and DNA damage repair pathways, rationales for targeting them in SCLC treatment and ongoing clinical trials, as well as possible predictive biomarkers for patient selection in the management of SCLC.

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Cell Cycle Checkpoints and DNA Damage Repair

Cellular Signaling in Health and Disease - Biological and Medical Physics, Biomedical Engineering ◽

10.1007/978-0-387-98173-4_10 ◽

2009 ◽

pp. 201-225

Author(s):

Martin Beckerman

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Dna Damage Repair ◽

Cell Cycle Checkpoints ◽

Damage Repair

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DNA damage repair as a target in pancreatic cancer: state-of-the-art and future perspectives

Gut ◽

10.1136/gutjnl-2019-319984 ◽

2020 ◽

pp. gutjnl-2019-319984 ◽

Cited By ~ 2

Author(s):

Lukas Perkhofer ◽

Johann Gout ◽

Elodie Roger ◽

Fernando Kude de Almeida ◽

Carolina Baptista Simões ◽

...

Keyword(s):

Pancreatic Cancer ◽

Dna Damage ◽

Dna Repair ◽

Dna Damage Repair ◽

Predictive Biomarkers ◽

Progression Free Survival ◽

Dna Double Strand Breaks ◽

Dismal Prognosis ◽

Damage Repair ◽

Personalised Treatment

Complex rearrangement patterns and mitotic errors are hallmarks of most pancreatic ductal adenocarcinomas (PDAC), a disease with dismal prognosis despite some therapeutic advances in recent years. DNA double-strand breaks (DSB) bear the greatest risk of provoking genomic instability, and DNA damage repair (DDR) pathways are crucial in preserving genomic integrity following a plethora of damage types. Two major repair pathways dominate DSB repair for safeguarding the genome integrity: non-homologous end joining and homologous recombination (HR). Defective HR, but also alterations in other DDR pathways, such as BRCA1, BRCA2, ATM and PALB2, occur frequently in both inherited and sporadic PDAC. Personalised treatment of pancreatic cancer is still in its infancy and predictive biomarkers are lacking. DDR deficiency might render a PDAC vulnerable to a potential new therapeutic intervention that increases the DNA damage load beyond a tolerable threshold, as for example, induced by poly (ADP-ribose) polymerase inhibitors. The Pancreas Cancer Olaparib Ongoing (POLO) trial, in which olaparib as a maintenance treatment improved progression-free survival compared with placebo after platinum-based induction chemotherapy in patients with PDAC and germline BRCA1/2 mutations, raised great hopes of a substantially improved outcome for this patient subgroup. This review summarises the relationship between DDR and PDAC, the prevalence and characteristics of DNA repair mutations and options for the clinical management of patients with PDAC and DNA repair deficiency.

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Targeting DNA Damage Repair for Immune Checkpoint Inhibition: Mechanisms and Potential Clinical Applications

Frontiers in Oncology ◽

10.3389/fonc.2021.648687 ◽

2021 ◽

Vol 11 ◽

Author(s):

Wei Sun ◽

Qing Zhang ◽

Runkun Wang ◽

Yang Li ◽

Yue Sun ◽

...

Keyword(s):

Dna Damage ◽

Immune Checkpoint ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Dna Damage Repair ◽

Predictive Biomarkers ◽

High Sensitivity ◽

Parp Inhibitors ◽

Combination Strategies ◽

Damage Repair

DNA damage repair (DDR) pathways play an essential role in maintaining genomic integrity. DDR dysfunction leads to accumulated DNA damage, predisposition to cancer, and high sensitivity to chemotherapy and radiotherapy. Recent studies have demonstrated that DDR status is associated with response to immune checkpoint inhibitors (ICIs). Among the DDR pathways, mismatch repair is one of the most recognized predictive biomarkers for ICIs. Furthermore, preclinical and early clinical studies suggest the rationale of combining agents targeting the DDR pathways, such as poly (ADP-ribose) polymerase (PARP) inhibitors, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, and ataxia telangiectasia and rad3-related (ATR) kinase inhibitors, with ICIs. In the present review, we describe the predictive role of DDR pathways in ICIs and summarize the advances in potential combination strategies of novel agents targeting DDR with ICIs for cancer treatment.

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