Sensitizing thermochemotherapy with a PARP1-inhibitor

Oei, Arlene L.; Vriend, Lianne; Leeuwen, Caspar M. van; Rodermond, Hans M.; Cate, Rosemarie ten; Westermann, Anneke M.; Stalpers, Lukas J.A.; Crezee, J.; Kanaar, Roland; Kok, H. Petra; Krawczyk, Przemek M.; Franken, Nicolaas A.P.

doi:10.18632/oncotarget.11422

Cited by 18 publications

(29 citation statements)

References 51 publications

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“…This provides a possible explanation for hyperthermia's sensitising effects towards irradiation and chemotherapeutic compounds that induce double strand breaks, such as cisplatin [34,35] and Trabectedin [36]. Moreover, attenuation of HR by hyperthermia sensitises cultured cells and mouse tumours to PARPinhibitors [19,[37][38][39], a class of therapeutics that specifically target cells deficient in HR. PARP-inhibitors are currently available as personalised treatment to patients with ovarian cancer that harbour a BRCA-mutation and have relapsed after initial platinum-containing treatment [27].…”

Section: Discussionmentioning

confidence: 99%

“…To test this possibility, we took biopsies (designated biopsy A and B) from two macroscopically similar parts of the same cervical tumour during an examination under anaesthesia, and ex vivo incubated half of each biopsy at 37 C and the other half at 42 C. In both sample-sets, we observed BRCA2 degradation to an equal extent upon heat. However, the initial BRCA2-levels at 37 C were very different ( Figure 5). Theoretically, if biopsy B would have been the biopsy taken before hyperthermia in vivo, and if biopsy A was taken after hyperthermia, we would have found no differences in BRCA2-levels, while BRCA2 was in fact degraded by the heat treatment ( Figure 5).…”

Section: Brca2 Degradation As a Biomarker For Heat Depositionmentioning

confidence: 97%

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Heat-induced BRCA2 degradation in human tumours provides rationale for hyperthermia-PARP-inhibitor combination therapies

Tempel

Odijk

Holthe

et al. 2017

International Journal of Hyperthermia

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Purpose: Hyperthermia (40-44 C) effectively sensitises tumours to radiotherapy by locally altering tumour biology. One of the effects of heat at the cellular level is inhibition of DNA repair by homologous recombination via degradation of the BRCA2-protein. This suggests that hyperthermia can expand the group of patients that benefit from PARP-inhibitors, a drug exploiting homologous recombination deficiency. Here, we explore whether the molecular mechanisms that cause heat-mediated degradation of BRCA2 are conserved in cell lines from various origins and, most importantly, whether, BRCA2 protein levels can be attenuated by heat in freshly biopted human tumours. Experimental design: Cells from four established cell lines and from freshly biopsied material of cervical (15), head-and neck (9) or bladder tumours (27) were heated to 42 C for 60 min ex vivo. In vivo hyperthermia was studied by taking two biopsies of the same breast or cervical tumour: one before and one after treatment. BRCA2 protein levels were measured by immunoblotting. Results: We found decreased BRCA2-levels after hyperthermia in all established cell lines and in 91% of all tumours treated ex vivo. For tumours treated with hyperthermia in vivo, technical issues and intra-tumour heterogeneity prevented obtaining interpretable results. Conclusions: This study demonstrates that heat-mediated degradation of BRCA2 occurs in tumour material directly derived from patients. Although BRCA2-degradation may not be a practical biomarker for heat deposition in situ, it does suggest that application of hyperthermia could be an effective method to expand the patient group that could benefit from PARP-inhibitors. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 99%

Section: Brca2 Degradation As a Biomarker For Heat Depositionmentioning

confidence: 97%

Heat-induced BRCA2 degradation in human tumours provides rationale for hyperthermia-PARP-inhibitor combination therapies

Tempel

Odijk

Holthe

et al. 2017

International Journal of Hyperthermia

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“…Especially, the DNA damage repair pathway is tumor suppressive in normal cells, but it induces resistance of cancer cells to genotoxic anti-cancer therapies [23,24]. Based on these paradoxical roles of the molecules of the DNA damage repair pathway, inhibitors of this pathway, such as Poly (ADP-ribose) polymerase (PARP) inhibitors, have been developed as anticancer agents [11,21]. Therefore, when based on the role of SIRT6 in the DNA damage repair pathway [1,8,25], SIRT6 might be an inducer of therapeutic resistance [26].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of SIRT6 Potentiates the Anti-Tumor Effect of Doxorubicin through Suppression of the DNA Damage Repair Pathway in Osteosarcoma

Zhang

Moon

et al. 2020

Preprint

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Background SIRT6 has diverse roles in cells, and the role of SIRT6 in tumorigenesis is controversial. Considering the role of SIRT6 as an inducer of DNA damage repair, it might be involved in resistance to anti-cancer therapy. Methods We evaluated the prognostic significance of SIRT6 in 37 osteosarcomas and investigated the therapeutic efficacy of SIRT6 on the anticancer effects of doxorubicin, olaparib, and ATM inhibitor. Results Immunohistochemical expression of SIRT6 was significantly associated with shorter overall survival and relapse-free survival of osteosarcoma patients, especially in patients who received adjuvant chemotherapy. In U2OS and KHOS/NP osteosarcoma cells, knock-down of SIRT6 significantly potentiated apoptotic effects of doxorubicin and SIRT6 overexpression induced resistance to doxorubicin. Moreover, SIRT6 induced the DNA damage repair pathway and SIRT6-mediated resistance to doxorubicin was attenuated by blocking the DNA damage repair pathway with olaparib and ATM inhibitor. Conclusions This study suggests that suppression of SIRT6 in combination with doxorubicin might be an effective modality in the treatment of osteosarcoma patients, especially for osteosarcomas with shorter survival with high expression of SIRT6.

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“…BER as one of the DNA repair mechanisms, PARP1 may be one of the major genes involved in tumor cell recurrence and metastasis [10]. In vitro and in vivo studies have suggested that inhibition of PARP1 can reduce tumor cell repair function, thereby enhancing the therapeutic effect of radiotherapy and chemotherapy on tumors [11,12]. DSBR is the most common but most severe type of DNA damage in eukaryotic cells, and is mainly repaired in mammals through non-homologous end joining (NHEJ).…”

Section: Introductionmentioning

confidence: 99%

The Diagnostic Value of DNA Repair Gene in Breast Cancer Recurrence and Metastasis

Yang

Hao

et al. 2020

Preprint

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Background: DNA repair genes play a vital role in the treatment of many cancers, and DNA repair genes can be used in breast cancer recurrence and metastasis research. We found that the expression of DNA repair genes in breast cancer patients after recurrence and metastasis is abnormal, however, the clinical predictive significance of DNA repair genes is still elusive. Methods: The nested case-control method was used in patients with breast cancer recurrence and metastasis after surgery (n=109) and patients without recurrence and metastasis after surgery (n=109). The proteins and mRNA of DNA repair genes were detected by immunohistochemistry and Real-time PCR respectively. Results: PARP1(OR=1.485, 95%CI:1.279~1.725, P<0.05), XRCC4(OR= 1.419, 95%CI:1.217~ 1.656, P<0.05) and ERCC1 (OR=1.181, 95%CI: 1.032~1.353, P<0.05) were risk factors for postoperative recurrence and metastasis of breast cancer. Therefore, we used the ROC curve to study the optimal critical values of PARP1, XRCC4, and ERCC1, combined with the comprehensive judgment of clinical experience, we can conclude that PARP1 (cutoff value = 6, Se = 75.23%, Sp = 79.82%), XRCC4 (cutoff value = 6, Se = 78.9%0, Se = 79.82%), ERCC1 (cutoff value = 3, Se = 89.91%, Sp = 47.71%), suggesting that when the PARP1 score is higher than 6 or the XRCC4 score is higher than 6 or the ERCC1 score is higher than 3, the risk of recurrence and metastasis will increases (ORPARP1 = 14.941, 95% CIPARP1: 4.004~55.758, P <0.05; ORXRCC4 = 16.740, 95% CIXRCC4: 6.433 ~ 43.560, P <0.05; ORERCC1 = 5.285, 95% CIERCC1: 1.843 ~ 15.156, P <0.05). Due to PARP1, ERCC1 and XRCC4 belong to a part of DNA repair gene system, and the three proteins are positively correlated by correlation analysis (rPARP1-ERCC1=0.317; rPAPR1-XRCC4=0.329; rERCC1-XRCC4=0.377). The combined diagnosis of the PARR1,ERCC1 and XRCC4 have greater predictive value for the risk of recurrence and metastasis of breast cancer(Se = 88.99%, Sp = 82.57%；OR = 50.914, 95% CI: 10.918, 237.417, P <0.05).Conclusions: The recurrence and metastasis of breast cancer are predictive after PARP1>6, XRCC4>6, and ERCC1>3. The combined diagnosis of the three indicators have greater predictive value for the risk of recurrence and metastasis of breast cancer.

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Sensitizing thermochemotherapy with a PARP1-inhibitor

Cited by 18 publications

References 51 publications

Heat-induced BRCA2 degradation in human tumours provides rationale for hyperthermia-PARP-inhibitor combination therapies

Heat-induced BRCA2 degradation in human tumours provides rationale for hyperthermia-PARP-inhibitor combination therapies

Inhibition of SIRT6 Potentiates the Anti-Tumor Effect of Doxorubicin through Suppression of the DNA Damage Repair Pathway in Osteosarcoma

The Diagnostic Value of DNA Repair Gene in Breast Cancer Recurrence and Metastasis

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