Synergistic Effect of Trabectedin and Olaparib Combination Regimen in Breast Cancer Cell Lines

Ávila-Arroyo, Sonia; Núñez, Gema Santamaría; García‐Fernández, Luis; Galmarini, Carlos M.

doi:10.4048/jbc.2015.18.4.329

Cited by 21 publications

(17 citation statements)

References 29 publications

(42 reference statements)

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“…Clearly, trabectedin synergized with both tested PARP1 inhibitors, but we found olaparib was significantly more potent than veliparib. Our result reflects the fact that veliparib is a pure catalytic inhibitor of PARP1 activation, whereas olaparib is a poisoning drug that blocks activated PARP1 enzyme at the site of damage (PARP1-trapping activity) impeding the subsequent recruitment of repairing machinery [11, 52, 55]. We studied the synergism of PARP1 inhibitors and trabectedin in a large set of different tumor cell lines and in in vivo models, demonstrating that PARP1 inhibition improved the antitumor activity of trabectedin in a cell-line dependent intensity, as previously shown in breast cancer and in Ewing’s sarcoma cell lines [44, 55].…”

Section: Discussionmentioning

confidence: 94%

“…Our result reflects the fact that veliparib is a pure catalytic inhibitor of PARP1 activation, whereas olaparib is a poisoning drug that blocks activated PARP1 enzyme at the site of damage (PARP1-trapping activity) impeding the subsequent recruitment of repairing machinery [11, 52, 55]. We studied the synergism of PARP1 inhibitors and trabectedin in a large set of different tumor cell lines and in in vivo models, demonstrating that PARP1 inhibition improved the antitumor activity of trabectedin in a cell-line dependent intensity, as previously shown in breast cancer and in Ewing’s sarcoma cell lines [44, 55]. Among the tested BSTS histotypes, Ewing’s sarcoma cells were the most sensitive to the combination, a result that might be explained by the known exquisite sensitivity of the pathognomonic fusion protein EWS/FLI1-expressing cells to both trabectedin and PARP1 inhibition [10, 56–59].…”

Section: Discussionmentioning

confidence: 94%

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PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models

et al. 2017

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BackgroundEnhancing the antitumor activity of the DNA-damaging drugs is an attractive strategy to improve current treatment options. Trabectedin is an isoquinoline alkylating agent with a peculiar mechanism of action. It binds to minor groove of DNA inducing single- and double-strand-breaks. These kinds of damage lead to the activation of PARP1, a first-line enzyme in DNA-damage response pathways. We hypothesized that PARP1 targeting could perpetuate trabectedin-induced DNA damage in tumor cells leading finally to cell death.MethodsWe investigated trabectedin and PARP1 inhibitor synergism in several tumor histotypes both in vitro and in vivo (subcutaneous and orthotopic tumor xenografts in mice). We searched for key determinants of drug synergism by comparative genomic hybridization (aCGH) and gene expression profiling (GEP) and validated their functional role.ResultsTrabectedin activated PARP1 enzyme and the combination with PARP1 inhibitors potentiated DNA damage, cell cycle arrest at G2/M checkpoint and apoptosis, if compared to single agents. Olaparib was the most active PARP1 inhibitor to combine with trabectedin and we confirmed the antitumor and antimetastatic activity of trabectedin/olaparib combination in mice models. However, we observed different degree of trabectedin/olaparib synergism among different cell lines. Namely, in DMR leiomyosarcoma models the combination was significantly more active than single agents, while in SJSA-1 osteosarcoma models no further advantage was obtained if compared to trabectedin alone. aCGH and GEP revealed that key components of DNA-repair pathways were involved in trabectedin/olaparib synergism. In particular, PARP1 expression dictated the degree of the synergism. Indeed, trabectedin/olaparib synergism was increased after PARP1 overexpression and reduced after PARP1 silencing.ConclusionsPARP1 inhibition potentiated trabectedin activity in a PARP1-dependent manner and PARP1 expression in tumor cells might be a useful predictive biomarker that deserves clinical evaluation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0652-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 94%

PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models

et al. 2017

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“…Various experimental studies have shown that trabectedin could decrease the recruitment and differentiation of monocytes to TAMs in tumor tissue; suggesting that trabectedin has potential cytotoxic effect against TAMs and can significantly decrease the production of CCL2 and IL‐6 [Germano et al, D'incalci et al, ]. Recently, Ávila‐Arroyo et al [] found in vitro study that combination of trabectedin and olaparib induced G2/M arrest and apoptotic cell death in BRCA1 ‐positive breast tumor cells. Targeting TAMs by some of already approved drugs are listed in Table .…”

Section: Tumor‐associated Macrophagesmentioning

confidence: 99%

Macrophage Polarization: Anti-Cancer Strategies to Target Tumor-Associated Macrophage in Breast Cancer

et al. 2017

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Tumor-associated macrophages (TAMs) are the most abundant inflammatory cells and orchestrate different stages of breast cancer development. TAMs participate in the tumor angiogenesis, matrix remodeling, invasion, immunosuppression, metastasis, and chemoresistance in breast cancer. Several clinical studies indicate the association between the high influx of TAMs in tumor with poor prognosis in hepatocellular, ovarian, cervical, and breast cancer. Previously developed hypotheses have proposed that TAMs participate in antitumor responses of the body, while recently many clinical and experimental studies have revealed that TAMs in tumor microenvironment predominantly resemble with M2-like polarized macrophages and produce a high amount of anti-inflammatory factors which are directly responsible for the development of tumor. Various studies have shown that TAMs in tumor either enhance or antagonize the anti-tumor efficacy of cytotoxic agents, antibodies-targeting cancer cells, and therapeutic agents depending on the nature of treatment. Thereby, multiple roles of TAMs suggests that it is very important to develop novel therapeutic strategies to target TAMs in breast tumor. In this review, we have discussed the functional role of TAMs in breast cancer and summarized available recent advances potential therapeutic strategies that effectively target to TAMs cells. J. Cell. Biochem. 118: 2484-2501, 2017. © 2017 Wiley Periodicals, Inc.

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“…Preclinical experiments support this concept [43–45]. Combination of olaparib and carboplatin has already been assessed in a Phase 1/1b study involving mixed population of patients with BRCA1/2 germ-line mutations, however only 1 out of 42 evaluable patients achieved complete response [46].…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic and targeted therapy for hereditary cancers

Iyevleva

Imyanitov

2016

Hered Cancer Clin Pract

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There is a number of drugs demonstrating specific activity towards hereditary cancers. For example, tumors in BRCA1/2 mutation carriers usually arise via somatic inactivation of the remaining BRCA allele, which makes them particularly sensitive to platinum-based drugs, PARP inhibitors (PARPi), mitomycin C, liposomal doxorubicin, etc. There are several molecular assays for BRCA-ness, which permit to reveal BRCA-like phenocopies among sporadic tumors and thus extend clinical indications for the use of BRCA-specific therapies. Retrospective data on high-dose chemotherapy deserve consideration given some unexpected instances of cure from metastatic disease among BRCA1/2-mutated patients. Hereditary non-polyposis colorectal cancer (HNPCC) is characterized by high-level microsatellite instability (MSI-H), increased antigenicity and elevated expression of immunosuppressive molecules. Recent clinical trial demonstrated tumor responses in HNPCC patients treated by the immune checkpoint inhibitor pembrolizumab. There are successful clinical trials on the use of novel targeted agents for the treatment or rare cancer syndromes, e.g. RET inhibitors for hereditary medullary thyroid cancer, mTOR inhibitors for tumors arising in patients with tuberous sclerosis (TSC), and SMO inhibitors for basal-cell nevus syndrome. Germ-line mutation tests will be increasingly used in the future for the choice of the optimal therapy, therefore turnaround time for these laboratory procedures needs to be significantly reduced to ensure proper treatment planning.

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Synergistic Effect of Trabectedin and Olaparib Combination Regimen in Breast Cancer Cell Lines

Cited by 21 publications

References 29 publications

PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models

PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models

Macrophage Polarization: Anti-Cancer Strategies to Target Tumor-Associated Macrophage in Breast Cancer

Cytotoxic and targeted therapy for hereditary cancers

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