Defining and targeting wild-type BRCA high-grade serous ovarian cancer: DNA repair and cell cycle checkpoints

2019 ◽  
Vol 28 (9) ◽  
pp. 771-785 ◽  
Author(s):  
S. Percy Ivy ◽  
Charles A. Kunos ◽  
Fernanda I. Arnaldez ◽  
Elise C. Kohn
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Dna Repair ◽  
Cell Cycle Checkpoints ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Wild Type

scholarly journals Genomics and molecular mechanisms of high grade serous ovarian cancer: the 12th Biennial Rivkin Center Ovarian Cancer Research Symposium

2019 ◽  
Vol 29 (Suppl 2) ◽  
pp. s7-s11
Author(s):  
Erinn B Rankin
Keyword(s):  
Ovarian Cancer ◽  
Cancer Research ◽  
Dna Repair ◽  
Molecular Mechanisms ◽  
New Technologies ◽  
Serous Carcinoma ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Poster Presentations ◽  
Oral Presentations

ObjectiveThe aim of this study was to review current research efforts in genomics and molecular mechanisms of high grade serous ovarian cancer, presented at the 12th Biennial Rivkin Center Ovarian Cancer Research Symposium, held at the University of Washington.MethodsThe 12th Biennial Rivkin Center Ovarian Cancer Research Symposium brought together leaders in the field to discuss recent advances in ovarian cancer research and therapy.ResultsThe genomics and molecular mechanisms of ovarian cancer session featured invited speaker presentations by Dr Alan D’ Andrea on ‘Deoxyribonucleic acid (DNA) repair in ovarian cancer’ and Dr Kathleen Cho on ‘Modeling the genomics of high grade serous carcinoma in the mouse’. Eight additional oral presentations and 46 poster presentations were selected from the submitted abstracts that highlighted current research efforts in p53, DNA repair, genomic instability and modeling disease in mice, and organoids in high grade serous ovarian cancer.ConclusionsNew technologies utilizing clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (CAS9) approaches in mice, organoids, and cell based screens continue to advance our knowledge of key molecular drivers of ovarian cancer initiation, progression, and drug resistance. Improved understanding of the mechanisms of poly ADP ribose polymerase inhibitor resistance may lead to new therapeutic strategies to enhance outcomes in women with high grade serous ovarian cancer.

Whence High-Grade Serous Ovarian Cancer

2017 ◽  
pp. 443-448 ◽  
Author(s):  
Elise C. Kohn ◽  
S. Percy Ivy
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Rational Design ◽  
Driver Mutations ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Loss Of Function ◽  
Brca1 And Brca2 ◽  
Unique Type ◽  
Cellular Environment

Our understanding of epithelial ovarian cancer has blossomed, and we now recognize that it is a collection of varied histologic and molecularly different malignancies, many of which may not derive from a true ovarian anatomic precursor. High-grade serous ovarian cancer (HGSOC) is a unique type of epithelial cancer. It is characterized by nearly universal mutation in and dysfunction of p53, genomic instability rather than driver mutations, advanced stage at onset, and probable fallopian tube epithelium origin, with a serous tubal in situ carcinoma precursor. Germline deleterious mutations in BRCA1 and BRCA2, as well as other less prevalent genes involved in DNA repair, such as PALB2 and RAD51c, are associated with its carcinogenesis and may predict susceptibility to classes of treatment agents, including DNA-damaging agents and DNA repair inhibitors. Loss of function of these genes is associated with homologous recombination dysfunction (HRD). It is now recognized that there may be HGSOC with wild-type BRCA1 and BRCA2 with an identifiable HRD phenotype. Such HRD tumors also may be more susceptible to certain classes of treatments and may be phenotypically detectable with a composite molecular biomarker that has been shown to be predictive for response to PARP inhibitors. Use of this new knowledge of the anatomic and molecular background of HGSOC has led to the rational design of novel combinations of treatment classes to create an HRD-like cellular environment and thus drive treatment benefits.

scholarly journals Wild-Type Tumor Repressor Protein 53 (TRP53) Promotes Ovarian Cancer Cell Survival

Endocrinology ◽  
2012 ◽  
Vol 153 (4) ◽  
pp. 1638-1648 ◽  
Author(s):  
Lisa K. Mullany ◽  
Zhilin Liu ◽  
Erin R. King ◽  
Kwong-Kwok Wong ◽  
JoAnne S. Richards
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Ovarian Cancer ◽  
Dna Repair ◽  
Cell Survival ◽  
Cancer Cells ◽  
Ovarian Cancer Cells ◽  
Low Grade ◽  
Wild Type ◽  
Repressor Protein

Loss of Pten in the KrasG12D;Amhr2-Cre mutant mice leads to the transformation of ovarian surface epithelial (OSE) cells and rapid development of low-grade, invasive serous adenocarcinomas. Tumors occur with 100% penetrance and express elevated levels of wild-type tumor repressor protein 53 (TRP53). To test the functions of TRP53 in the Pten;Kras (Trp53+) mice, we disrupted the Trp53 gene yielding Pten;Kras(Trp53−) mice. By comparing morphology and gene expression profiles in the Trp53+ and Trp53− OSE cells from these mice, we document that wild-type TRP53 acts as a major promoter of OSE cell survival and differentiation: cells lacking Trp53 are transformed yet are less adherent, migratory, and invasive and exhibit a gene expression profile more like normal OSE cells. These results provide a new paradigm: wild-type TRP53 does not preferentially induce apoptotic or senescent related genes in the Pten;Kras(Trp53+) cancer cells but rather increases genes regulating DNA repair, cell cycle progression, and proliferation and decreases putative tumor suppressor genes. However, if TRP53 activity is forced higher by exposure to nutlin-3a (a mouse double minute-2 antagonist), TRP53 suppresses DNA repair genes and induces the expression of genes that control cell cycle arrest and apoptosis. Thus, in the Pten;Kras(Trp53+) mutant mouse OSE cells and likely in human TP53+ low-grade ovarian cancer cells, wild-type TRP53 controls global molecular changes that are dependent on its activation status. These results suggest that activation of TP53 may provide a promising new therapy for managing low-grade ovarian cancer and other cancers in humans in which wild-type TP53 is expressed.

scholarly journals Real-world treatment patterns and outcomes in platinum-sensitive recurrent high-grade serous ovarian cancer patients

2021 ◽  
Author(s):  
Carlota Moya-Alarcón ◽  
Guiomar Piera ◽  
Ángel Callejo ◽  
Amaya Gascó
Keyword(s):  
Ovarian Cancer ◽  
Treatment Outcomes ◽  
Cancer Patients ◽  
Negative Impact ◽  
Treatment Patterns ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Wild Type ◽  
Platinum Sensitive ◽  
Study Results

Aim: To describe the overall cancer-related healthcare utilization patterns, treatment patterns and outcomes in women diagnosed with platinum-sensitive recurrent high-grade serous ovarian cancer. Patients & methods: Subanalysis of the Spanish sample of a retrospective, noninterventional, multinational, observational study. Results: BRCA-mutated patients had better outcomes in terms of progression-free survival and overall survival than patients who were BRCA wild-type. It was observed that patients’ treatment outcomes after the first recurrence progressively worsened as the patient underwent subsequent chemotherapy lines. Healthcare resource utilization when accounting for the follow-up time did not substantially differ between BRCA1/ 2-mutated and BRCA wild-type patients. Conclusion: BRCA1/2 mutation carriers have better treatment outcomes, including longer survival, without a negative impact on the use of healthcare resources.

scholarly journals Role of BRCA Mutation and HE4 in Predicting Chemotherapy Response in Ovarian Cancer: A Retrospective Pilot Study

Biomedicines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 55
Author(s):  
Francesco Plotti ◽  
Corrado Terranova ◽  
Federica Guzzo ◽  
Carlo De Cicco Nardone ◽  
Daniela Luvero ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Brca Mutation ◽  
Predictive Marker ◽  
Chemotherapy Response ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Wild Type ◽  
Platinum Sensitive ◽  
Platinum Resistant

Even though 80% of patients with High-Grade Serous Ovarian Cancer respond to standard first-line chemotherapy, a majority of them could relapse in the following five years due to a resistance to platinum. Human Epididymis protein 4 (HE4) is one of the most promising markers in predicting platinum therapy response. This pilot study aims to evaluate the potential role of HE4 value in predicting chemotherapy response in BRCA mutated patients and in BRCA wild-type (non-mutated) ones. We selected 69 patients, affected by High-Grade Serous Ovarian Cancer, and optimally debulked and submitted to standard chemotherapy protocols. HE4 was dosed during every chemotherapy course. Patients were classified as platinum-resistant and platinum-sensitive. According to BRCA mutation test, patients were further divided into BRCA wild-type (53 patients), and BRCA mutated (16 patients). 35 patients out of 69 (52%) were platinum-sensitive (recurrence > 12 months), while 33 patients (48%) were platinum-resistant (recurrence < 12 months). Thus, in the total population, HE4 performed as a marker of chemosensitivity with a sensibility of 79% and a specificity of 97%. In the BRCA WT group, 23 patients out of 53 (43%) were platinum-sensitive, while 30 patients out of 53 (57%) were platinum-resistant. In the BRCA WT group, HE4 performed as a predictive marker of chemosensitivity with a sensibility of 80% and a specificity of 100%. In the BRCA mutated group, 13 patients out of 16 (82%) were platinum-sensitive, while 3 patients (18%) were platinum-resistant. In the BRCA mutated group, HE4 performed as a predictive marker of chemosensitivity in all patients. The ability to detect platinum-resistant patients before tumor relapse probably could open new therapeutic scenarios.

Abstract 1428: Single-cell transcriptomics reveals differential DNA repair signatures after chemotherapy in high-grade serous ovarian cancer

2017 ◽  
Author(s):  
Anniina Farkkila ◽  
Kaiyang Zhang ◽  
Katja Kaipio ◽  
Tarja Lamminen ◽  
Rainer Lehtonen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Single Cell ◽  
High Grade ◽  
Serous Ovarian Cancer
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