Phase I modular study of AZD6738, a novel oral, potent and selective ataxia telangiectasia Rad3-related (ATR) inhibitor in combination (combo) with carboplatin, olaparib or durvalumab in patients (pts) with advanced cancers

Yap, Tami; Krebs, Matthew; Postel-Vinay, S.; Bang, Y.; El-Khoueiry, A.; Abida, Wassim; Harrington, Kevin; Sundar, Raghav; Carter, Louise; Castanon-Alvarez, E; Im, Sejin; Berges, Aliénor; Khan, Maryam I.; Stephens, C.; Ross, Gayle; Soria, Jean‐Charles

doi:10.1016/s0959-8049(16)32607-7

Cited by 43 publications

(41 citation statements)

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“…Several clinical trials are now underway to test the safety and efficacy of combinations of DNA repair-targeted agents with ICB agents in both DNA repair-deficient and DNA-repair proficient settings (Table 2). [184] As clinical experience with both DNA repair targeted agents and ICB agents grows, and as the multifaceted cellular interactions between DNA repair and the immune system come into focus, it is likely that combination approaches will continue to emerge.…”

Section: Combining Dna Damage and Repair-based Therapies With Immunotmentioning

confidence: 99%

DNA Damage and Repair Biomarkers of Immunotherapy Response

et al. 2017

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DNA damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the interaction of tumor DNA damage with the immune system has recently come into focus, and it is now clear that the tumor DNA repair landscape has an important role in driving response to immune checkpoint blockade. Here, we summarize the mechanisms by which DNA damage and genomic instability have been found to shape the anti-tumor immune response and describe clinical efforts to use DNA repair biomarkers to guide use of immune-directed therapies.

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Section: Combining Dna Damage and Repair-based Therapies With Immunotmentioning

confidence: 99%

DNA Damage and Repair Biomarkers of Immunotherapy Response

et al. 2017

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“…Greater clarity with respect to these key questions and others, such as the role of PARP inhibitor potency, will be important as clinical trials' read out, and as basic and translational science, continues to bring new insights with respect to the mechanism and activity of both PARP inhibition and ICB individually, and in combination. Finally, although we have focused here on PARP inhibitor and anti-PD-1/L1 combinations, other targeted agents against components of the DDR are being evaluated for combination with ICB, including ATR inhibitors (108), which were shown to combine safely with the anti-PD-L1 durvalumab, resulting in early signals of activity. There are also other promising immunotherapeutic agents in development, which should be considered for combination with DDR inhibitors.…”

Section: Future Perspectives and Conclusionmentioning

confidence: 99%

Development of PARP and Immune-Checkpoint Inhibitor Combinations

2018

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PARP inhibitors drive increased DNA damage, particularly in tumors with existing defects in DNA repair. This damage not only promotes immune priming through a range of molecular mechanisms, but also leads to adaptive upregulation of programmed death ligand 1 (PD-L1) expression. In this context, PARP inhibition and programmed cell death 1 (PD-1)/PD-L1-targeting antibodies represent a rationale combination. In this review, we detail the basic and translational science underpinning this promising new combination, summarize available clinical data, and discuss the key questions that remain to be addressed during future development. Cancer Res; 78(24); 6717-25. Ó2018 AACR.

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“…Novel agents currently in early phase clinical trial targeting the cell cycle was used to generate a therapeutic testing strategy ( Figure 4b) [34][35][36][37][38] . Based on these data, in-vitro sensitivity was assessed using cell viability assays after a selection of PDCLs were treated with increasing doses of inhibitors of CHK1 (AZD7762), CDK4/6 (Palbociclib) and PLK4 (CFI-400945) demonstrating differential sensitivity ( Supplementary Figure 4).…”

Section: Replication Stress Is Associated With Sensitivity To Cell Cymentioning

confidence: 99%

“…Based on these data, in-vitro sensitivity was assessed using cell viability assays after a selection of PDCLs were treated with increasing doses of inhibitors of CHK1 (AZD7762), CDK4/6 (Palbociclib) and PLK4 (CFI-400945) demonstrating differential sensitivity ( Supplementary Figure 4). Based on promising early clinical trial results in other cancer types [37][38][39][40][41][42] , more extensive testing using inhibitors of ATR (AZD6738) and WEE1 (AZD1775) was performed on 15 PDCLs defined as high and low replication stress based on the replication stress signature score ( Figure 3a, Supplementary Figure 4). This demonstrated that PDCLs with high replication stress were more sensitive to both ATR and WEE1 inhibition (Figure 4c-f).…”

Section: Replication Stress Is Associated With Sensitivity To Cell Cymentioning

confidence: 99%

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Dreyer

Upstill-Goddard

Paulus-Hock³

et al. 2019

Preprint

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Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting the DNA damage response (DDR) and replication stress. We show that patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum and PARP inhibitor therapy in vitro and in vivo. We generated a novel signature of replication stress with potential clinical utility in predicting response to ATR and WEE1 inhibitor treatment. Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy.

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Phase I modular study of AZD6738, a novel oral, potent and selective ataxia telangiectasia Rad3-related (ATR) inhibitor in combination (combo) with carboplatin, olaparib or durvalumab in patients (pts) with advanced cancers

Cited by 43 publications

References 0 publications

DNA Damage and Repair Biomarkers of Immunotherapy Response

DNA Damage and Repair Biomarkers of Immunotherapy Response

Development of PARP and Immune-Checkpoint Inhibitor Combinations

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

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