Colorectal Cancer Metastasis: The DNA Repair Inhibitor Dbait Increases Sensitivity to Hyperthermia and Improves Efficacy of Radiofrequency Ablation

Devun, Flavien; Biau, J.; Huerre, Michel; Croset, Amelie; Sun, Jian‐Sheng; Denys, Alban; Dutreix, Marie

doi:10.1148/radiol.13130805

Cited by 22 publications

(19 citation statements)

References 41 publications

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“…These perceptions indicate the synergetic effect of combination use of radiotherapy and hyperthermia [7] . Moreover, additional use of DNA repair inhibitors was reported to further enhance its efficacy [84] .…”

Section: Combination Therapy With Radiotherapymentioning

confidence: 99%

Cancer immunity and therapy using hyperthermia with immunotherapy, radiotherapy, chemotherapy, and surgery

Yagawa¹,

Tanigawa²,

Kobayashi³

et al. 2017

JCMT

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Hyperthermia is a type of medical modality for cancer treatment using the biological effect of artificially induced heat. Even though the intrinsic effects of elevated body temperature in cancer tissues are poorly understood, increasing the temperature of the body has been recognized as a popular therapeutic method for tumorous lesions as well as infectious diseases since ancient times. Recently accumulated evidence has shown that hyperthermia amplifies immune responses in the body against cancer while decreasing the immune suppression and immune escape of cancer. It also shows that hyperthermia inhibits the repair of damaged cancer cells after chemotherapy or radiotherapy. These perceptions indicate that hyperthermia has potential for cancer therapy in conjunction with immunotherapy, chemotherapy, radiotherapy, and surgery. Paradoxically, the anticancer effect of hyperthermia alone has not yet been adequately exploited because deep heating techniques and devices to aggregate heat effects only in cancer tissues are difficult in practical terms. This review article focuses on the current understanding concerning cancer immunity and involvement of hyperthermia and the innate and adoptive immune system. The potential for combination therapy with hyperthermia and chemotherapy, radiotherapy, and surgery is also discussed. Key words:Hyperthermia, cancer immunity, chemosensitizer, radiosensitizer, combination cancer therapy, hyperthermic intraoperative peritoneal chemotherapy ABSTRACTArticle history:

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Section: Combination Therapy With Radiotherapymentioning

confidence: 99%

Cancer immunity and therapy using hyperthermia with immunotherapy, radiotherapy, chemotherapy, and surgery

Yagawa¹,

Tanigawa²,

Kobayashi³

et al. 2017

JCMT

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“…AsiDNA acts by hijacking and hyper-activating PARP1 (13) and the DNA-dependent protein kinase (DNA-PK) (14) which modify the chromatin and consequently inhibit the recruitment of many proteins involved in the HR and NHEJ pathways at the damage sites (14). This strategy sensitizes tumors to DNA damaging therapies such as radiotherapy and chemotherapy (15)(16)(17)(18). The first-in-human phase I trial, combining AsiDNA to radiotherapy to treat patients with skin metastases from melanoma showed encouraging results, with 30% of complete responses (19).…”

Section: Introductionmentioning

confidence: 99%

Drug-Driven Synthetic Lethality: Bypassing Tumor Cell Genetics with a Combination of AsiDNA and PARP Inhibitors

Jdey

Thierry

Russo

et al. 2017

Clinical Cancer Research

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Purpose Cancer treatments using tumor defects in DNA repair pathways have shown promising results but are restricted to small subpopulations of patients. The most advanced drugs in this field are Poly(ADP-Ribose) Polymerase (PARP) inhibitors (PARPi), which trigger synthetic lethality in tumors with Homologous Recombination (HR) deficiency. Using AsiDNA, an inhibitor of HR and Non Homologous End Joining, together with PARPi should allow bypassing the genetic restriction for PARPi efficacy. Experimental design We characterized the DNA repair inhibition activity of PARPi (olaparib) and AsiDNA by monitoring repair foci formation and DNA damage. We analyzed the cell survival to standalone and combined treatments of 21 tumor cells, and 3 non-tumor cells. In 12 Breast Cancer (BC) cell lines, correlation with sensitivity to each drug and transcriptome were statistically analyzed to identify resistance pathways. Results Molecular analyses demonstrate that olaparib and AsiDNA respectively prevent recruitment of XRCC1 and RAD51/53BP1 repair enzymes to damage sites. Combination of both drugs increases the accumulation of unrepaired damage resulting in an increase of cell death in all tumor cells. In contrast, non-tumor cells do not show an increase of DNA damage nor lethality. Analysis of multi-level omics data from BC cells highlighted different DNA repair and cell cycle molecular profiles associated with resistance to AsiDNA or olaparib, rationalizing combined treatment. Treatment synergy was also confirmed with 6 other PARPi in development. Conclusion Our results highlight the therapeutic interest of combining AsiDNA and PARPi to recapitulate synthetic lethality in all tumors independently of their HR status.

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“…21). This strategy sensitizes tumors to chemo-and radiotherapy (19,(22)(23)(24). The first phase I clinical trial combining AsiDNA to radiotherapy to treat patients with skin metastases of melanoma showed encouraging results, with a 30% complete response rate (25).…”

Section: Introductionmentioning

confidence: 99%

Micronuclei Frequency in Tumors Is a Predictive Biomarker for Genetic Instability and Sensitivity to the DNA Repair Inhibitor AsiDNA

et al. 2017

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Therapeutic strategies targeting DNA repair pathway defects have been widely explored, but often only benefit small numbers of patients. Here we characterized potential predictive biomarkers for treatment with AsiDNA, a novel first-in-class DNA repair inhibitor. We evaluated genetic instability and DNA repair defects by direct and indirect assays in 12 breast cancer cell lines to estimate the spontaneous occurrence of single-strand and double-strand breaks (DSB). For each cell line, we monitored constitutive PARP activation, spontaneous DNA damage by alkaline comet assay, basal micronuclei levels, the number of large-scale chromosomal rearrangements (LST), and the status of several DNA repair pathways by transcriptome and genome analysis. Sensitivity to AsiDNA was associated with a high spontaneous frequency of cells with micronuclei and LST and specific alterations in DNA repair pathways that essentially monitor DSB repair defects. A high basal level of micronuclei as a predictive biomarker for AsiDNA treatment was validated in 43 tumor cell lines from various tissues and 15 models of cell- and patient-derived xenografts. Micronuclei quantification was also possible in patient biopsies. Overall, this study identified genetic instability as a predictive biomarker for sensitivity to AsiDNA treatment. That micronuclei frequency can be measured in biopsies and does not reveal the same genetic instability as conventional genome assays opens new perspectives for refining the classification of tumors with genetic instability. .

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Colorectal Cancer Metastasis: The DNA Repair Inhibitor Dbait Increases Sensitivity to Hyperthermia and Improves Efficacy of Radiofrequency Ablation

Abstract: Combining Dbait with RFA sensitizes the tumor periphery to mild hyperthermia and increases RFA antitumor efficacy.

Cited by 22 publications

References 41 publications

Cancer immunity and therapy using hyperthermia with immunotherapy, radiotherapy, chemotherapy, and surgery

Cancer immunity and therapy using hyperthermia with immunotherapy, radiotherapy, chemotherapy, and surgery

Drug-Driven Synthetic Lethality: Bypassing Tumor Cell Genetics with a Combination of AsiDNA and PARP Inhibitors

Micronuclei Frequency in Tumors Is a Predictive Biomarker for Genetic Instability and Sensitivity to the DNA Repair Inhibitor AsiDNA

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