Phase I/Ib Study of Olaparib and Carboplatin in BRCA1 or BRCA2 Mutation-Associated Breast or Ovarian Cancer With Biomarker Analyses

Lee, Jung Min; Hays, John L.; Annunziata, Christina M.; Noonan, Anne; Minasian, Lori M.; Zujewski, Jo Anne; Yu, Minshu; Gordon, Nicolas; Ji, Jiuping; Sissung, Tristan M.; Figg, William D.; Azad, Nilofer S.; Wood, Bradford J.; Doroshow, James H.; Kohn, Elise C.

doi:10.1093/jnci/dju089

Cited by 163 publications

(136 citation statements)

References 59 publications

(71 reference statements)

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“…One solution was to combine multiple drugs that act synergistically. A number of ongoing clinical trials are investigating the effects of combined therapy against different types of cancer (25)(26)(27). In our experimental system, the effect of combined treatment with SAHA and PJ34 on TXNIP expression was associated with variation in cell viability and apoptosis.…”

Section: Discussionmentioning

confidence: 98%

Epigenetic bivalent marking is permissive to the synergy of HDAC and PARP inhibitors on TXNIP expression in breast cancer cells

et al. 2015

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Abstract. Studies on stem cell differentiation led to the identification of paused genes, characterized by the contemporary presence of both activator and repressor epigenetic markers (bivalent marking). TXNIP is an oncosuppressor gene the expression of which was reduced in breast cancer. In the present study, we evaluated whether the concept of epigenetic bivalent marking can be applied to TXNIP gene in breast cancer cells. Using chromatin immunoprecipitation (ChIP), three histone modifications were investigated: two associated with transcriptional activation, lysines 9-14 acetylation of H3 histone (H3K9K14ac) and lysine 4 trimethylation of H3 histone (H3K4me3), and one associated with transcriptional silencing, lysine 27 trimethylation of H3 histone (H3K27me3). According to the bivalent marking model, TXNIP gene appears to be paused in MDA157 cells (markers of active and repressed transcription are present), but are definitively silenced in MDA468 cells (presence of only markers of transcription repression). This was proven by evaluating TXNIP mRNA and protein levels after the treatment of cell lines with a histone deacetylase inhibitor (SAHA) and a poly-ADPribose polymerases inhibitor (PJ34). In MDA157 cells, SAHA and PJ34 showed a synergistic effect: a large increment was observed in TXNIP mRNA and protein levels. By contrast, in MDA468 cells, synergy between the two compounds was not observed. Therefore, the pausing epigenetic signature was permissive for synergy between SAHA and PJ34 on TXNIP gene expression. The synergy between SAHA and PJ34 on TXNIP expression was associated with variation in cell viability and apoptosis. In MDA157 cells, but not in MDA468 cells, combined treatment of SAHA and PJ34 induced a decrease in cell viability and an increase of apoptosis. Thus, our data support the hypothesis that TXNIP is an effective target for the treatment of breast cancer.

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Section: Discussionmentioning

confidence: 98%

Epigenetic bivalent marking is permissive to the synergy of HDAC and PARP inhibitors on TXNIP expression in breast cancer cells

et al. 2015

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“…Several PARP inhibitors are currently in development for the treatment of patients with tumors harboring HRD, including those with a BRCA1/2 mutation (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Single-agent olaparib is approved in the United States for the treatment of patients with advanced germline BRCA1/2-mutated ovarian cancer who have received three or more lines of chemotherapy (27,28).…”

Section: Introductionmentioning

confidence: 99%

A Phase I–II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors

Kristeleit

Shapiro

Burris

et al. 2017

Clinical Cancer Research

214

160

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Purpose: Rucaparib is a potent, oral, small-molecule PARP inhibitor. This phase I-II study was the first to evaluate singleagent oral rucaparib at multiple doses.Experimental Design: Part 1 (phase I) sought to determine the MTD, recommended phase II dose (RP2D), and pharmacokinetics of oral rucaparib administered in 21-day continuous cycles in patients with advanced solid tumors. Part 2A (phase II) enrolled patients with platinum-sensitive, high-grade ovarian carcinoma (HGOC) associated with a germline BRCA1/2 mutation who received two to four prior regimens and had a progression-free interval of 6 months or more following their most recent platinum therapy. The primary endpoint was investigator-assessed objective response rate (ORR) by RECIST version 1.1.Results: In part 1, 56 patients received oral rucaparib (40 to 500 mg once daily and 240 to 840 mg twice daily). No MTD was identified per protocol-defined criteria; 600 mg twice daily was selected as the RP2D based on manageable toxicity and clinical activity. Pharmacokinetics were approximately doseproportional across all dose levels. In part 2A, 42 patients with germline BRCA1/2-mutated HGOC received rucaparib 600 mg twice daily. Investigator-assessed ORR was 59.5%. The most common treatment-emergent adverse events (all grades) were asthenia/fatigue (85.7%; 36/42), nausea (83.3%; 35/42), anemia (71.4%; 30/42), alanine transaminase and/or aspartate transaminase elevations (57.1%; 24/42), and vomiting (54.8%; 23/42). Among 98 patients, 5 (5.1%) discontinued because of an adverse event (excluding disease progression).Conclusions: Rucaparib was tolerable and had activity in patients with platinum-sensitive germline BRCA1/2-mutated HGOC. Clin Cancer Res; 23(15); 4095-106. Ó2017 AACR.

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“…The concept of synthetic lethality (35) has led to effective use of PARP inhibitors in other BRCA-related cancers (18,37,38). In pancreatic cancer, pre-clinical studies have reaffirmed comparable observations.…”

Section: Homologous Recombination Defect As a Molecular Target With Pmentioning

confidence: 94%

“…This concept is commonly known as synthetic lethality (35). Clinically, the effect of synthetic lethality is more frequently observed in BRCA1/2-mutated cancers treated with PARP inhibitors (18,37,38).…”

Section: Brca1 and Brca2-role In Dna Damage Response And Repairmentioning

confidence: 99%

Is it time to split strategies to treat homologous recombinant deficiency in pancreas cancer?

Teo¹,

O'Reilly²

2016

J. Gastrointest. Oncol.

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Pancreatic cancer is a highly lethal malignancy which tends to present with late stage disease.To date, identification of oncogenic drivers and aberrations has not led to effective targeted therapy.Approximately 5-15% of pancreatic cancer has an inheritable component. In fact, pancreatic adenocarcinoma is now recognized as a BRCA1/2-related cancer. Germline BRCA1/2 mutations can be found in up to 3.6-7% of unselected pancreatic cancer patients although the rates are significantly higher amongst patients with Ashkenazi Jewish ancestry. Germline mutations of other components of DNA repair and homologous recombination have also been identified although at much lower frequency. Large sequencing efforts have further identified somatic mutations in these genes in a small subset of pancreatic cancers. Small series and case reports have suggested that pancreatic cancers harboring BRCA1/2 or other homologous repair gene mutations demonstrate enhanced response to platinum-based chemotherapy although this has not been prospectively validated. Clinical trials with poly (ADP-ribose) polymerase (PARP) inhibitors as monotherapy or in combination with chemotherapy in different clinical settings are currently on-going. A subtype of pancreatic adenocarcinoma as characterized by deficiency in homologous recombination exists although the optimal management strategy remains to be fully elucidated.

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Phase I/Ib Study of Olaparib and Carboplatin in BRCA1 or BRCA2 Mutation-Associated Breast or Ovarian Cancer With Biomarker Analyses

Abstract: Olaparib capsules 400mg every 12 hours on days 1 to 7/carboplatin AUC5 is safe and has activity in gBRCAm BrCa/OvCa patients. Exploratory translational studies indicate pretreatment tissue FOXO3a expression may be predictive for response to therapy, requiring prospective validation.

Cited by 163 publications

References 59 publications

Epigenetic bivalent marking is permissive to the synergy of HDAC and PARP inhibitors on TXNIP expression in breast cancer cells

Epigenetic bivalent marking is permissive to the synergy of HDAC and PARP inhibitors on TXNIP expression in breast cancer cells

A Phase I–II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors

Is it time to split strategies to treat homologous recombinant deficiency in pancreas cancer?

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