PISARRO: A EUTROC phase Ib study of APR-246 in combination with carboplatin (C) and pegylated liposomal doxorubicin (PLD) in platinum sensitive relapsed high grade serous ovarian cancer (HGSOC).

Gourley, Charlie; Green, John; Gabra, Hani; Vergote, Ignace; Basu, Bristi; Brenton, James D.; Björklund, Ulf; Smith, Austin M.; Euler, Mikael von

doi:10.1200/jco.2016.34.15_suppl.5571

Cited by 15 publications

(7 citation statements)

References 3 publications

(3 reference statements)

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“…123 Wee-1 inhibitors and APR-246, targeting mutant TP53, have also shown positive results in cancer trials. 124,125 Since loss of STK11 results in activated mTOR (mammalian target of rapamycin), mTOR inhibitors may be effective against pancreatic cancer in Peutz-Jeghers syndrome patients. 126 CDK4/6 inhibitors targeting loss of CDKN2A, 127 and Wnt/β-catenin signaling inhibitors for APC proved to be effective in pancreatic cancer cell lines or mouse models, 128–130 both of which are being evaluated in clinical trials (NCT03065062; NCT01351103).…”

Section: Discussionmentioning

confidence: 99%

Germline Variants and Risk for Pancreatic Cancer

Zhan¹,

Shelton²,

Greer

et al. 2018

Pancreas

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Pancreatic cancer requires many genetic mutations. Combinations of underlying germline variants and environmental factors may increase the risk of cancer and accelerate the oncogenic process. We systematically reviewed, annotated, and classified previously reported pancreatic cancer-associated germline variants in established risk genes. Variants were scored using multiple criteria and binned by evidence for pathogenicity, then annotated with published functional studies and associated biological systems/pathways. Twenty-two previously identified pancreatic cancer risk genes and 337 germline variants were identified from 97 informative studies that met our inclusion criteria. Fifteen of these genes contained 66 variants predicted to be pathogenic (APC, ATM, BRCA1, BRCA2, CDKN2A, CFTR, CHEK2, MLH1, MSH2, NBN, PALB2, PALLD, PRSS1, SPINK1, TP53). Pancreatic cancer risk genes were organized into key biological mechanisms that promote pancreatic oncogenesis within an oncogenic model. Development of precision medicine approaches requires updated variant information within the framework of an oncogenic progression model. Complex risk modeling may improve interpretation of early biomarkers and guide pathway-specific treatment for pancreatic cancer in the future. Precision medicine is within reach.

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Section: Discussionmentioning

confidence: 99%

Germline Variants and Risk for Pancreatic Cancer

Zhan¹,

Shelton²,

Greer

et al. 2018

Pancreas

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“…Of the mutant p53-reactivating compounds described to date, the most thoroughly investigated and most clinically advanced is APR-246 (also known as PRIMA-1 MET ) [8] , [9] , [10] , [11] . APR-246 has previously been investigated in two phase I clinical trials [12] , [13] and is currently undergoing further clinical trials in patients with high-grade serous ovarian [14] , [15] and esophageal cancers ( NCT02999893 ) as well as in patients with myeloid neoplasms ( NCT03072043 ).…”

Section: Introductionmentioning

confidence: 99%

The Mutant p53-Targeting Compound APR-246 Induces ROS-Modulating Genes in Breast Cancer Cells

Synnott

Madden

Bykov

et al. 2018

Translational Oncology

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TP53 is the most frequently mutated gene in human cancer and thus an attractive target for novel cancer therapy. Several compounds that can reactive mutant p53 protein have been identified. APR-246 is currently being tested in a phase II clinical trial in high-grade serous ovarian cancer. We have used RNA-seq analysis to study the effects of APR-246 on gene expression in human breast cancer cell lines. Although the effect of APR-246 on gene expression was largely cell line dependent, six genes were upregulated across all three cell lines studied, i.e., TRIM16, SLC7A11, TXNRD1, SRXN1, LOC344887, and SLC7A11-AS1. We did not detect upregulation of canonical p53 target genes such as CDKN1A (p21), 14-3-3σ, BBC3 (PUMA), and PMAIP1 (NOXA) by RNA-seq, but these genes were induced according to analysis by qPCR. Gene ontology analysis showed that APR-246 induced changes in pathways such as response to oxidative stress, gene expression, cell proliferation, response to nitrosative stress, and the glutathione biosynthesis process. Our results are consistent with the dual action of APR-246, i.e., reactivation of mutant p53 and modulation of redox activity. SLC7A11, TRIM16, TXNRD1, and SRXN1 are potential new pharmacodynamic biomarkers for assessing the response to APR-246 in both preclinical and clinical studies.

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“…Novel cancer therapeutics that supposedly reactivate a variant tumour p53 protein include small molecule drug candidates (such as APR-246), presently in clinical development for myelodysplastic syndromes, acute myeloid leukemia, as well as solid tumours (NCT03268382) [32] . A phase Ib/II clinical trial in TP53 mutated high-risk hematological cancers is ongoing, combining APR-246 and azacytidine (NCT03931291).…”

Section: Discussionmentioning

confidence: 99%

Genetic markers and phosphoprotein forms of beta-catenin pβ-Cat552 and pβ-Cat675 are prognostic biomarkers of cervical cancer

et al. 2020

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BACKGROUND Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality world wide and constitutes the third most common malignancy in women. The RAIDs consortium ( http://www.raids-fp7.eu/ ) conducted a prospective European study [BioRAIDs (NCT02428842)] with the objective to stratify CC patients for innovative treatments. A “metagene” of genomic markers in the PI3K pathway and epigenetic regulators had been previously associated with poor outcome [2] . METHODS To detect new, more specific, targets for treatment of patients who resist standard chemo-radiation, a high-dimensional Cox model was applied to define dominant molecular variants, copy number variations, and reverse phase protein arrays (RPPA). FINDINGS Survival analysis on 89 patients with all omics data available, suggested loss-of-function (LOF) or activating molecular alterations in nine genes to be candidate biomarkers for worse prognosis in patients treated by chemo-radiation while LOF of ATRX, MED13 as well as CASP8 were associated with better prognosis. When protein expression data by RPPA were factored in, the supposedly low molecular weight and nuclear form, of beta-catenin, phosphorylated in Ser552 (pβ-Cat552), ranked highest for good prognosis, while pβ-Cat675 was associated with worse prognosis. INTERPRETATION These findings call for molecularly targeted treatments involving p53, Wnt pathway, PI3K pathway, and epigenetic regulator genes. Pβ-Cat552 and pβ-Cat675 may be useful biomarkers to predict outcome to chemo-radiation, which targets the DNA repair axis. FUNDING European Union's Seventh Program for research, technological development and demonstration (agreement N°304,810), the Fondation ARC pour la recherche contre le cancer.

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PISARRO: A EUTROC phase Ib study of APR-246 in combination with carboplatin (C) and pegylated liposomal doxorubicin (PLD) in platinum sensitive relapsed high grade serous ovarian cancer (HGSOC).

Cited by 15 publications

References 3 publications

Germline Variants and Risk for Pancreatic Cancer

Germline Variants and Risk for Pancreatic Cancer

The Mutant p53-Targeting Compound APR-246 Induces ROS-Modulating Genes in Breast Cancer Cells

Genetic markers and phosphoprotein forms of beta-catenin pβ-Cat552 and pβ-Cat675 are prognostic biomarkers of cervical cancer

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