Homologous recombination research is heating up and ready for therapy

Powell, Simon N.; Kachnic, Lisa A.

doi:10.1073/pnas.1106456108

Cited by 8 publications

(8 citation statements)

References 22 publications

(23 reference statements)

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“…There is growing evidence that mild hyperthermia can enhance CP-induced genotoxicity [56,57]. MHT can increase CP membrane permeability and subsequent penetration into the nucleosome [58], and accelerate the rate of CP hydrolysis to its active diaquo form [59].…”

Section: Discussionmentioning

confidence: 99%

Synergistic Effects of Cisplatin Chemotherapy and Gold Nanorod-Mediated Hyperthermia on Ovarian Cancer Cells and Tumors

Mehtala

Torregrosa-Allen²,

Elzey

et al. 2014

Nanomedicine (Lond.)

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Aim The synergistic effects of gold nanorod (GNR)-mediated mild hyperthermia (MHT; 42–43°C) and cisplatin (CP) activity was evaluated against chemoresistant SKOV3 cells in vitro and with a tumor xenograft model. Materials & methods In vitro studies were performed using CP at cytostatic concentrations (5 μM) and polyethylene glycol-stabilized GNRs, using near-infrared laser excitation for MHT. Results The amount of polyethylene glycol-GNRs used for environmental MHT was 1 μg/ml, several times lower than the loadings used in tumor tissue ablation. GNR-mediated MHT increased CP-mediated cytotoxicity by 80%, relative to the projected additive effect, and flow cytometry analysis suggested MHT also enhanced CP-induced apoptosis. In a pilot in vivo study, systemically administered polyethylene glycol-GNRs generated sufficient levels of MHT to enhance CP-induced reductions in tumor volume, despite their heterogeneous distribution in tumor tissue. Conclusion These studies imply that effective chemotherapies can be developed in combination with low loadings of nanoparticles for localized MHT.

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Section: Discussionmentioning

confidence: 99%

Synergistic Effects of Cisplatin Chemotherapy and Gold Nanorod-Mediated Hyperthermia on Ovarian Cancer Cells and Tumors

Mehtala

Torregrosa-Allen²,

Elzey

et al. 2014

Nanomedicine (Lond.)

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“…There is solid evidence that one target of hyperthermia is the HRR pathway via the heatinduced degradation of the breast cancer susceptibility gene 2 (BRCA2) protein [32]. This seminal report opened a new window for the potential use of hyperthermia in the sensitisation of tumours to biologically targeted therapies [33]. BRCA2 is the major player in HRR because it mediates the localisation and functional activation of the key protein in HRR, RAD51, to sites of function in human cells in response to DSBs.…”

Section: Hyperthermia and Dna Repairmentioning

confidence: 99%

Hallmarks of hyperthermia in driving the future of clinical hyperthermia as targeted therapy: translation into clinical application

Issels

Kampmann

Kanaar

et al. 2016

International Journal of Hyperthermia

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Regional hyperthermia is described as a targeted therapy and the definitions of six hallmarks of hyperthermia are proposed, representing the pleiotropic effect of this therapeutic modality to counteract tumour growth and progression. We recommend the considerations of these hallmarks in the design of clinical trials involving regional hyperthermia as targeted therapy. Randomised clinical studies using loco-regional hyperthermia as an adjuvant to radiotherapy or to chemotherapy for locally advanced tumours demonstrate the benefit of the combination compared to either of the standard treatments alone for tumour response, disease control, and patient survival outcome. These impressive results were obtained from proof-of-concept trials for superficial or deep-seated malignancies in unselected patients. None of these trials was designed as tailored approaches for the treatment of specified targets or to select potentially more sensitive subpopulations of patients using eligibility criteria. Based upon clinical examples of targeted chemotherapy, some guidelines are described for the successful development of targeted therapeutic combinations. We also retrospectively analyse the stepwise process of generating an ongoing new clinical trial using hyperthermia as targeted therapy to evade DNA repair in combination with a DNA damaging anticancer agent to implement this new vision.

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“…In our study, we demonstrate the role of BRCA2 as the major responsible heat target. However, more challenging molecular experiments beyond the scope of our investigations are needed to exclude other potentially heat‐sensitive candidates which might be also involved in the mechanisms . Xian et al .…”

Section: Discussionmentioning

confidence: 99%

“…However, more challenging molecular experiments beyond the scope of our investigations are needed to exclude other potentially heat-sensitive candidates which might be also involved in the mechanisms. 45 Xian et al reported that BRCA1, a further HRR protein, is also degraded after hyperthermia. 17 In another study, BRCA1 depletion in U2OS cells resulted only in a modest reduction of BRCA2-and RAD51-positive repair foci, but occurrence of repair foci was strongly dependent upon PALB2 expression.…”

Section: Discussionmentioning

confidence: 99%

Hyperthermia adds to trabectedin effectiveness and thermal enhancement is associated with BRCA2 degradation and impairment of DNA homologous recombination repair

Harnicek

Kampmann

Lauber

et al. 2016

Intl Journal of Cancer

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The tetrahydroisoquinoline trabectedin is a marine compound with approved activity against human soft-tissue sarcoma. It exerts antiproliferative activity mainly by specific binding to the DNA and inducing DNA double-strand breaks (DSB). As homologous recombination repair (HRR)-deficient tumors are more susceptible to trabectedin, hyperthermia-mediated on-demand induction of HRR deficiency represents a novel and promising strategy to boost trabectedin treatment. For the first time, we demonstrate enhancement of trabectedin effectiveness in human sarcoma cell lines by heat and characterize cellular events and molecular mechanisms related to heat-induced effects. Hyperthermic temperatures (41.8 or 438C) enhanced significantly trabectedin-related clonogenic cell death and G2/M cell cycle arrest followed by cell type-dependent induction of apoptosis or senescence. Heat combination increased accumulation of cH2AX foci as key marker of DSBs. Expression of BRCA2 protein, an integral protein of the HRR machinery, was significantly decreased by heat. Consequently, recruitment of downstream RAD51 to cH2AX-positive repair foci was almost abolished indicating relevant impairment of HRR by heat. Accordingly, enhancement of trabectedin effectiveness was significantly augmented in BRCA2-proficient cells by hyperthermia and alleviated in BRCA2 knockout or siRNA-transfected BRCA2 knockdown cells. In peripheral blood mononuclear cells isolated from sarcoma patients, increased numbers of nuclear cH2AX foci were detected after systemic treatment with trabectedin and hyperthermia of the tumor region. The findings establish BRCA2 degradation by heat as a key factor for a novel treatment strategy that allows targeted chemosensitization to trabectedin and other DNA damaging antitumor drugs by on-demand induction of HRR deficiency.Trabectedin (Yondelis V R ) is a DNA-intercalating anticancer drug originally isolated from the sea squirt Ecteinascidia turbinata. The drug is established for the treatment of advanced soft-tissue sarcoma after failure of anthracyclines and ifosfamide as well as for the treatment of platinum-sensitive ovarial carcinoma in combination with liposomal doxorubicin. In sarcoma, trabectedin usually induces high rates of tumor growth arrest. In a worldwide-expanded access program investigating 1,895 patients, stable disease was reported in 43% and overall survival was 11.9 months. Unfortunately, treatment response with relevant tumor shrinkage was only seen in 5%. 1 Given the worse prognosis of advanced sarcoma, there is urgent need to improve treatment. Enhancing antitumor efficacy of trabectedin by a local treatment seems to be a promising strategy.

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Homologous recombination research is heating up and ready for therapy

Cited by 8 publications

References 22 publications

Synergistic Effects of Cisplatin Chemotherapy and Gold Nanorod-Mediated Hyperthermia on Ovarian Cancer Cells and Tumors

Synergistic Effects of Cisplatin Chemotherapy and Gold Nanorod-Mediated Hyperthermia on Ovarian Cancer Cells and Tumors

Hallmarks of hyperthermia in driving the future of clinical hyperthermia as targeted therapy: translation into clinical application

Hyperthermia adds to trabectedin effectiveness and thermal enhancement is associated with BRCA2 degradation and impairment of DNA homologous recombination repair

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