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Trabectedin Promotes Oncolytic Virus Antitumor Efficacy, Viral Gene Expression, and Immune Effector Function in Models of Bone Sarcoma

ABSTRACT: We previously reported that the DNA alkylator and transcriptional-blocking chemotherapeutic agent trabectedin enhances oncolytic herpes simplex viroimmunotherapy in human sarcoma xenograft models, though the mechanism remained to be elucidated. Here we report trabectedin disrupts the intrinsic cellular antiviral response which increases viral transcript presence in the human tumor cells. We also extended our synergy findings to syngeneic murine sarcoma models, which are poorly susceptible to virus infection. In the absence of robust virus replication, we found trabectedin enhanced viroimmunotherapy efficacy by reducing infiltrating immunosuppressive CD4 T and myeloid cells and stimulating granzyme expression in infiltrating T and natural killer cells to cause immune-mediated tumor regressions. Thus, trabectedin enhances both the direct virus-mediated killing of tumor cells and the viral-induced activation of cytotoxic effector lymphocytes to cause tumor regressions across models. Our data provide a strong rationale for clinical translation as both mechanisms should be simultaneously active in human patients.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE260551 | GEO | 2024/10/11

REPOSITORIES: GEO

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Trabectedin Promotes Oncolytic Virus Antitumor Efficacy, Viral Gene Expression, and Immune Effector Function in Models of Bone Sarcoma

Project description:Trabectedin Promotes Oncolytic Virus Antitumor Efficacy, Viral Gene Expression, and Immune Effector Function in Models of Bone Sarcoma

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PARP1 expression drives the synergy between trabectedin and PARP1 inhibitors

Project description:Trabectedin is a DNA-damaging agent with a peculiar mechanism of action; it traps the DNA repair machinery leading to DNA single- and double-strand breaks, particularly in BRCA1/2-deficient tumors. We hypothesized that trabectedin-induced DNA damage might activate PARP1 (a DNA-repair machinery key player), and consequently, PARP1 inhibition would perpetuate trabectedin-induced DNA damage. In several tumor histotypes, we demonstrated a different degree of synergism between trabectedin and PARP1 inhibitors (PARP1-Is). Independent of BRCA1/2 status, PARP1 expression dictated the degree of synergism. Namely, silenced PARP1 reduced trabectedin-PARP1-Is synergism, whereas overexpressed PARP1 increased combination efficacy. High-PARP1 expression and specific gene signatures associated with DNA damage response and repair (DDR-R) were predictive of trabectedin+PARP1-I synergy. These findings pave the way for the clinical development of this novel combination therapy, as well as evaluation of PARP1 expression and DDR-R signatures in tumor samples as predictive biomarkers of response

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Doxorubicin Hydrochloride or Trabectedin in Treating Patients With Previously Untreated Advanced or Metastatic Soft Tissue Sarcoma

Project description:RATIONALE: Drugs used in chemotherapy, such as doxorubicin hydrochloride and trabectedin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether trabectedin is more effective than doxorubicin hydrochloride in treating patients with advanced or metastatic soft tissue sarcoma. PURPOSE: This randomized phase II/III trial is studying the safety of trabectedin compared with doxorubicin hydrochloride and to see how well they work in treating patients with advanced or metastatic soft tissue sarcoma.

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PARP1 expression predicts and determines synergy between PARP1 inhibitors and trabectedin.

2017-06-12 | GSE76981 | GEO

Effectiveness of irinotecan plus trabectedin in a desmoplastic small round cell tumor patient-derived xenograft

Project description:Desmoplastic small round cell tumor (DSRCT) is a rare and incurable malignancy characterized by the oncogenic EWSR1-WT1 transcription factor. This study exploited a novel DSRCT patient-derived xenograft (PDX), which reproduces histomorphological and molecular characteristics of the paired clinical tumor, to comparatively assess the activity of cytotoxic and targeted anticancer agents. Anti-tumor effect was moderate for single-agent doxorubicin, pazopanib and larotrectenib [maximum tumor volume inhibition (max TVI): 55-66%] while trabectedin had a higher effect (max TVI: 82%). Single-agent vinorelbine, irinotecan and eribulin achieved a nearly complete tumor growth inhibition (max TVI: 96-98%), although tumors started to re-growth after the end of treatment. Combination of irinotecan with either eribulin or trabectedin resulted in complete responses which were maintained until the end of the experiment for irinotecan plus trabectedin. Irinotecan-based combinations almost completely abrogated the expression of proteins involved in the G2/M checkpoint preventing cell entrance in mitosis and induced apoptotic and necroptotic cell death. This study emphasizes the importance of patient-derived pre-clinical models to explore new treatments in DSRCT and fosters clinical investigation in the activity of irinotecan plus trabectedin.

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Effectiveness of irinotecan plus trabectedin in a desmoplastic small round cell tumor patient-derived xenograft [II]

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Whole genome transcription profiling of the JN-DSCRT1 cell line treated with Trabectedin

Project description:The purpose of experiments consisted in studying the mode of action of Trabectedin in Desmoplastic Small Round Cell Tumor (DSRCT). In order to investigate the effects of Trabectedin in the expression of EWS-WT1 target genes in relation to the drug growth inhibitory effect, the JN-DSCRT-1 cell line was treated for 1 hour with 5 nM of Trabectedin. Samples were collected at 6, 12 and 24 hours after drug washout. Three biological replicates were used for each time point.

2017-01-27 | E-MTAB-4532 | biostudies-arrayexpress

Transcriptional profiling of patient-derived xenograft models of myxoid liposarcoma either responsive or resistant to trabectedin treatment.

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Trabectedin derails transcription-coupled nucleotide excision repair to induce DNA breaks in highly transcribed genes

Project description:Most genotoxic anticancer agents fail in tumors with intact DNA repair. Therefore, trabectedin, a unique agent more toxic to cells with active DNA repair, specifically transcription-coupled nucleotide excision repair (TC-NER), provides new therapeutic opportunities. To unlock the potential of trabectedin and inform its application in precision oncology, a full mechanistic understanding of the drug’s TC-NER-dependent toxicity is needed. Here, we determined that abortive TC-NER of trabectedin-DNA adducts forms persistent single-strand breaks (SSBs) by blocking the second of the two sequential NER incisions by XPG. We mapped the 3’-hydroxyl groups of SSBs originating from the first NER incision at trabectedin lesions, recording TC-NER on a genome-wide scale. We showed that trabectedin-induced SSBs primarily occur in transcribed strands of active genes and peak near transcription start sites. Frequent SSBs were also found outside gene bodies, revealing TC-NER connection to divergent transcription from promoters. This work advances trabectedin as a tool compound for precision oncology and for studying TC-NER and transcription.

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Trabectedin is a novel chemotherapy agent for diffuse large B cell lymphoma

Project description:Assess the efficacy of trabectedin in two DLBCL cell lines

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