Combining DNA damaging therapeutics with immunotherapy: more haste, less speed

Brown, Jessica; Sundar, Raghav; Lopez, Juanita

doi:10.1038/bjc.2017.376

Cited by 194 publications

(172 citation statements)

References 90 publications

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“…Targeting PARP in Cancer DNA damage activates a complex range of processes, including DDR signaling, DNA repair, cell-cycle regulation, and potentially also an immunologic response, all of which have been extensively reviewed previously (6,7,(11)(12)(13)(14). Briefly, DNA single-strand breaks resulting from processes that remove misincorporated rNTP incorporation, dNTP mismatches, or bases following oxidative damage are the most common; however, DNA doublestrand breaks (DSB) are the most cytotoxic.…”

Section: Introductionmentioning

confidence: 99%

PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

Pilié

Byers

O’Connor

et al. 2019

Clinical Cancer Research

263

198

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A mounting body of evidence now indicates that PARP inhibitors have the potential to be used as a foundation for both monotherapy and combination strategies across a wide spectrum of molecular backgrounds and tumor types. Although PARP inhibitors as a class display many similarities, critical differences in structure can translate into differences in tolerability and antitumor activity that have important implications for the clinic. Furthermore, while PARP inhibitors have demonstrated a clear role in treating tumors with underlying homologous recombination deficiencies, there is now biological and early clinical evidence to support their use in other molecular subsets of cancer, including tumors associated with high levels of replication stress such as small-cell lung cancer. In this article, we highlight the key similarities and differences between individual PARP inhibitors and their implications for the clinic. We discuss data that currently support clinical strategies for extending the benefit of PARP inhibitors beyond BRCA-mutant cancers, toward broader populations of patients through the use of novel biomarkers of homologous recombination repair deficiency (HRD), as well as predictive biomarkers rooted in mechanisms of sensitivity outside of HRD. We also explore the potential application of PARP inhibitors in earlier treatment settings, including neoadjuvant, adjuvant, and even chemoprevention approaches. Finally, we focus on promising combination therapeutic strategies, such as those with other DNA damage response (DDR) inhibitors such as ATR inhibitors, immune checkpoint inhibitors, and non-DDR-targeted agents that induce "chemical BRCAness."

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Section: Introductionmentioning

confidence: 99%

PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

Pilié

Byers

O’Connor

et al. 2019

Clinical Cancer Research

263

198

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“…The scientific rationale between PARP inhibitors and immunotherapy is related to immune activation such that error‐prone repair may cause more point mutations leading to neoantigen formation but also that innate cytosolic DNA can lead to a type I immune‐activating response via the STING path. Furthermore, certain checkpoints such as ATM , ATR , and CHK1 can lead to upregulation of programmed death‐ligand 1 (PD‐L1) . Another example is that of ARID1 deficiency and synergy with immunotherapy .…”

Section: Introductionmentioning

confidence: 99%

Analysis of DNA Damage Response Gene Alterations and Tumor Mutational Burden Across 17,486 Tubular Gastrointestinal Carcinomas: Implications for Therapy

Parikh

He²,

Hong

et al. 2019

The Oncologist

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Background Alterations in the DNA damage response (DDR) pathway confer sensitivity to certain chemotherapies, radiation, and other DNA damage repair targeted therapies. BRCA1/2 are the most well‐studied DDR genes, but recurrent alterations are described in other DDR pathway members across cancers. Deleterious DDR alterations may sensitize tumor cells to poly (ADP‐ribose) polymerase inhibition, but there are also increasing data suggesting that there may also be synergy with immune checkpoint inhibitors. The relevance of DDR defects in gastrointestinal (GI) cancers is understudied. We sought to characterize DDR‐defective GI malignancies and to explore genomic context and tumor mutational burden (TMB) to provide a platform for future rational investigations. Materials and Methods Tumor samples from 17,486 unique patients with advanced colorectal, gastroesophageal, or small bowel carcinomas were assayed using hybrid‐capture‐based comprehensive genomic profiling including sequencing of 10 predefined DDR genes: ARID1A, ATM, ATR, BRCA1, BRCA2, CDK12, CHEK1, CHEK2, PALB2, and RAD51. TMB (mutations per megabase [mut/Mb]) was calculated from up to 1.14 Mb of sequenced DNA. Clinicopathologic features were extracted and descriptive statistics were used to explore genomic relationships among identified subgroups. Results DDR alterations were found in 17% of cases: gastric adenocarcinoma 475/1,750 (27%), small bowel adenocarcinoma 148/666 (22%), esophageal adenocarcinoma 467/2,501 (19%), and colorectal cancer 1,824/12,569 (15%). ARID1A (9.2%) and ATM (4.7%) were the most commonly altered DDR genes in this series, followed by BRCA2 (2.3%), BRCA1 (1.1%), CHEK2 (1.0%), ATR (0.8%), CDK12 (0.7%), PALB2 (0.6%), CHEK1 (0.1%) and RAD51 (0.1%). More than one DDR gene alteration was found in 24% of cases. High microsatellite instability (MSI‐H) and high TMB (TMB‐H, ≥20 mut/Mb) were found in 19% and 21% of DDR‐altered cases, respectively. Of DDR‐altered/TMB‐H cases, 87% were also MSI‐H. However, even in the microsatellite stable (MSS)/DDR‐wild‐type (WT) versus MSS/DDR‐altered, TMB‐high was seen more frequently (0.4% vs. 3.3%, P < .00001.) Median TMB was 5.4 mut/Mb in the MSS/DDR‐altered subset versus 3.8 mut/Mb in the MSS/DDR‐WT subset (P ≤ .00001), and ATR alterations were enriched in the MSS/TMB‐high cases. Conclusion This is the largest study to examine selected DDR defects in tubular GI cancers and confirms that DDR defects are relatively common and that there is an association between the selected DDR defects and a high TMB in more than 20% of cases. Microsatellite stable DDR‐defective tumors with elevated TMB warrant further exploration. Implications for Practice Deleterious DNA damage response (DDR) alterations may sensitize tumor cells to poly (ADP‐ribose) polymerase inhibition, but also potentially to immune checkpoint inhibitors, owing to accumulation of mutations in DDR‐defective tumors. The relevance of DDR defects in gastrointestinal (GI) cancers is understudied. This article characterizes DDR‐defective GI malignan...

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“…The tumor and the corresponding immune responses continuously evolve, making the identification of a single immunological blocker that could provide a universal therapeutic success nearly impossible. Therefore, there is a well‐founded opinion that future immunotherapy will use combinations of immune and more traditional agents, such as chemo‐ or radiotherapy . Additionally, direct intercellular contacts that do not involve immune cells may be discovered, and these might serve as efficient therapeutic targets.…”

Section: Brief Summary Of Immune Checkpointsmentioning

confidence: 99%

“…Therefore, there is a well-founded opinion that future immunotherapy will use combinations of immune and more traditional agents, such as chemo-or radiotherapy. [36,58,59] Additionally, direct intercellular contacts that do not involve immune cells may be discovered, and these might serve as efficient therapeutic targets.…”

Section: Immune Checkpoint Therapy-a New Paradigm Of Tumor Therapymentioning

confidence: 99%

Missed Druggable Cancer Hallmark: Cancer–Stroma Symbiotic Crosstalk as Paradigm and Hypothesis for Cancer Therapy

Sverdlov

2018

BioEssays

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During tumor evolution, cancer cells use the tumor-stroma crosstalk to reorganize the microenvironment for maximum robustness of the tumor. The success of immune checkpoint therapy foretells a new cancer therapy paradigm: an effective cancer treatment should not aim to influence the individual components of super complex intracellular interactomes (molecular targeting), but try to disrupt the intercellular interactions between cancer and stromal cells, thus breaking the tumor as a whole. Arguments are provided in favor of a hypothesis that such interactions include formation of synapse-like structures (interfaces) where the interacting cells are located at a distance of ∼10-15 nm. Within these interfaces, molecules initiating and strengthening the interaction are organized, and allow optimum cross-signaling; a very confined intercellular space facilitates the concentration of secreted cytokines, enhancing the paracrine cross-communication. These features of tumors form a druggable cancer hallmark the tumor-stroma symbiotic crosstalk-which represents a new target for efficient cancer drug discovery.

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Combining DNA damaging therapeutics with immunotherapy: more haste, less speed

Cited by 194 publications

References 90 publications

PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

Analysis of DNA Damage Response Gene Alterations and Tumor Mutational Burden Across 17,486 Tubular Gastrointestinal Carcinomas: Implications for Therapy

Missed Druggable Cancer Hallmark: Cancer–Stroma Symbiotic Crosstalk as Paradigm and Hypothesis for Cancer Therapy

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