Extent of radiosensitization by the PARP inhibitor olaparib depends on its dose, the radiation dose and the integrity of the homologous recombination pathway of tumor cells

Verhagen, Caroline V.M.; Haan, Rosemarie de; Hageman, Floor; Oostendorp, Tim P.D.; Carli, Annalisa L E; O’Connor, Mark J.; Jonkers, Jos; Verheij, Marcel; Brekel, Michiel W. M. van den; Vens, Conchita

doi:10.1016/j.radonc.2015.03.028

Cited by 96 publications

(90 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The development of PARP1 inhibitors has drawn closer the goal of combining these compounds with current therapies [2, 4–9]. Unfortunately, despite several preclinical data confirming an increased antitumor activity by combining PARP1 inhibitors with either chemotherapy or radiotherapy [10–16], dose escalation in phase 1 combination studies has been greatly hampered by the observed hematologic toxicities. These adverse events limited the possibility to exploit these combinations into clinical practice [4, 5, 9, 11, 17–27].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Focused-beam X-ray radiation produces localized double-stranded DNA breaks and thus would be expected to render cells more sensitive to PARP inhibition (19, 20). Olaparib has been shown to enhance the effect of radiation in both BRCA2-proficient and deficient prostate cancer cells (21). Several PARP inhibitors have been shown to have radiosensitizer activity in vivo (20, 22-25); however, these agents have not yet been demonstrated to provide radiosensitivity to radiation-resistant tumors.…”

Section: Introductionmentioning

confidence: 99%

Nanoformulation of Olaparib Amplifies PARP Inhibition and Sensitizes PTEN/TP53-Deficient Prostate Cancer to Radiation

Ven

Tangutoori

Baldwin

et al. 2017

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

The use of PARP inhibitors in combination with radiation therapy is a promising strategy to locally enhance DNA-damage in tumors. Here we show that radiation-resistant cells and tumors derived from a Pten/Trp53-deficient mouse model of advanced prostate cancer are rendered radiation-sensitive following treatment with NanoOlaparib, a lipid-based injectable nanoformulation of Olaparib. This enhancement in radiosensitivity is accompanied by radiation dose-dependent changes in γ-H2AX expression and is specific to NanoOlaparib alone. In animals, twice-weekly intravenous administration of NanoOlaparib results in significant tumor growth inhibition, whereas previous studies of oral Olaparib as monotherapy have shown no therapeutic efficacy. When NanoOlaparib is administered prior to radiation, a single dose of radiation is sufficient to triple the median mouse survival time compared to radiation only controls. Half of mice treated with NanoOlaparib + radiation achieved a complete response over the 13 week study duration. Using ferumoxytol as a surrogate nanoparticle, MRI studies revealed that NanoOlaparib enhances the intratumoral accumulation of systemically administered nanoparticles. NanoOlaparib-treated tumors showed up to 19-fold higher nanoparticle accumulation compared to untreated and radiation-only controls, suggesting that the in vivo efficacy of NanoOlaparib may be potentiated by its ability to enhance its own accumulation. Together, this data suggests that NanoOlaparib may be a promising new strategy for enhancing the radiosensitivity of radiation-resistant tumors lacking BRCA mutations, such as those with PTEN and TP53 deletions.

show abstract

“…Other anti-PDL1 agents in earlier stages of development for ovarian cancer treatment include the IgG1 monoclonal antibodies durvalumab and atezolizumab [28]. While side effects for this genre of drugs are common (about 40% of patients) they are generally not severe (only 5% using Common Terminology Criteria for Adverse Events), and include rash, pruritis, diarrhea, arthralgia, arthritis, myalgia, myositis, thyroiditis, hypothyroidism, hypophysitis, and infusion-related reactions [29,30].…”

Section: Molecular Chemotherapies In Gynecologicmentioning

confidence: 99%

Molecular Chemotherapies in Gynecologic

Kennedy¹,

Robinson²

2017

Chemotherapy

View full text Add to dashboard Cite

The development of chemotherapy agents that precisely target specific molecular structures in cancer cells has become a priority in oncology research. In principal, this method halts cancer cell proliferation while allowing normal function of healthy cells. These molecular-based chemotherapy agents target many types of molecules involved in the growth, spread, and survival of malignant cells. Several of these target molecules have been identified in female genital tract malignancies, and multiple agents targeted at those molecules have been developed as treatment.This review outlines three major types of targeted agents that have clinical relevance in the treatment of gynecologic cancer. The first group of drugs inhibits vascular endothelial growth factor (VEGF), which normally facilitates angiogenesis. The second group inhibits poly ADP ribose polymerase, a base-excision enzyme that repairs single-strand DNA breaks. The final category is a set of drugs that inhibit programmed-cell death protein 1, an immune checkpoint that normally prevents autoimmunity. Therapeutic benefit has been demonstrated for each of these drug types in gynecologic, and particularly ovarian, cancers.New agents and applications for these agents have been developing at a rapid pace in each of these categories. FDA approval has been accelerated for several of these agents in recent years, suggesting a significant change in the process by which new drugs enter the clinical armamentarium. In short, the development of molecularly-targeted drugs for the treatment of cancer is a promising and rapidly-moving field.

show abstract

Extent of radiosensitization by the PARP inhibitor olaparib depends on its dose, the radiation dose and the integrity of the homologous recombination pathway of tumor cells

Cited by 96 publications

References 36 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

Nanoformulation of Olaparib Amplifies PARP Inhibition and Sensitizes PTEN/TP53-Deficient Prostate Cancer to Radiation

Molecular Chemotherapies in Gynecologic

Contact Info

Product

Resources

About