scholarly journals DNA damaging agents in ovarian cancer

2020 ◽  
Vol 15 ◽  
pp. 67-72
Author(s):  
Maria-Pilar Barretina-Ginesta
Oncotarget ◽  
2017 ◽  
Vol 8 (16) ◽  
pp. 27380-27392 ◽  
Author(s):  
Noa Rabinowicz ◽  
Lingegowda S. Mangala ◽  
Kevin R. Brown ◽  
Cintia Checa-Rodriguez ◽  
Asher Castiel ◽  
...  

Oncotarget ◽  
2018 ◽  
Vol 9 (14) ◽  
pp. 11592-11603 ◽  
Author(s):  
Francesca Vena ◽  
Ruochen Jia ◽  
Arman Esfandiari ◽  
Juan J. Garcia-Gomez ◽  
Manuel Rodriguez-Justo ◽  
...  

2019 ◽  
Vol 29 (Suppl 2) ◽  
pp. s16-s21 ◽  
Author(s):  
Dmitriy Zamarin

Here we review the latest pre-clinical and clinical developments for treatment of ovarian cancer, presented at the American Association of Cancer Research/Rivkin Center Ovarian Cancer Research Symposium held at the University of Washington in September 2018. Abstracts and presentations pertaining to the 'Novel Therapeutics' session were reviewed and are summarized here. The session featured a keynote presentation from Dr Ursula Matulonis, who summarized the current state of the art of treatment of ovarian cancer, including recent clinical trials incorporating the use of novel agents, including poly-ADP-ribose polymerase (PARP) inhibitors, other DNA-damaging agents, vascular endothelial growth factor receptor inhibitors, mirvetuximab soravtansine, and immune checkpoint blockade. Dr Jung-Min Lee then summarized the rationale and the results of early studies for targeting cell cycle checkpoint kinases for anti-cancer therapy. Eight submissions were selected for oral presentations, and 36 abstracts were presented as posters. The topics covered a range of clinical and pre-clinical strategies and biomarkers, including immunotherapy, mechanisms of chemotherapy, and PARP inhibitor resistance, DNA-damaging agents, and other novel therapeutic strategies. Key studies have highlighted that resistance to chemotherapy and PARP inhibitors remain a major challenge in therapy of ovarian cancer. Cancer stem cells represent an important mechanism of chemoresistance and strategies to target these cells may be a pathway to prevention of ovarian cancer relapse. Advancement of novel therapeutics targeting DNA damage, cell metabolism, and endoplasmic reticulum present some of the novel strategies in the pipeline. Emerging compelling pre-clinical data with novel antibody-drug conjugates targeting various surface receptors in ovarian cancer alone and in combination with immune checkpoint blockade generate a strong enthusiasm for rapid translation of these strategies to clinic.


Author(s):  
Emad Matanes ◽  
Tahira Baloch ◽  
David Octeau ◽  
Roy Kessous ◽  
Liron Kogan ◽  
...  

2020 ◽  
Vol 159 ◽  
pp. 137
Author(s):  
E. Matanes ◽  
L. Kogan ◽  
V. López-Ozuna ◽  
C. Mitric ◽  
O. Raban ◽  
...  

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 119 ◽  
Author(s):  
Giovanna Damia ◽  
Massimo Broggini

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. It is initially responsive to cisplatin and carboplatin, two DNA damaging agents used in first line therapy. However, almost invariably, patients relapse with a tumor resistant to subsequent treatment with platinum containing drugs. Several mechanisms associated with the development of acquired drug resistance have been reported. Here we focused our attention on DNA repair mechanisms, which are fundamental for recognition and removal of platinum adducts and hence for the ability of these drugs to exert their activity. We analyzed the major DNA repair pathways potentially involved in drug resistance, detailing gene mutation, duplication or deletion as well as polymorphisms as potential biomarkers for drug resistance development. We dissected potential ways to overcome DNA repair-associated drug resistance thanks to the development of new combinations and/or drugs directly targeting DNA repair proteins or taking advantage of the vulnerability arising from DNA repair defects in EOCs.


2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Hannah C. Wise ◽  
Gopakumar V. Iyer ◽  
Kathleen Moore ◽  
Sarah M. Temkin ◽  
Sarah Gordon ◽  
...  

AbstractDNA-dependent protein kinase (DNA-PK) has been shown to play a crucial role in repair of DNA double-strand breaks, facilitating nonhomologous end-joining. DNA-PK inhibitors have the potential to block DNA repair and therefore enhance DNA-damaging agents. M3814 is a DNA-PK inhibitor that has shown preclinical activity in combination with DNA-damaging agents, including radiotherapy and topoisomerase II inhibitors. Here we evaluated the activity of M3814 in combination with multiple topoisomerase II inhibitors, doxorubicin, etoposide, and pegylated liposomal doxorubicin (PLD) in vivo, utilizing ovarian cancer xenografts. Using cell lines representative of P53 wild-type ovarian cancer (A2780), and P53 mutant ovarian cancer (SKOV3), cells were implanted in the flank of athymic nude female mice. Mice were treated with vehicle, M3814 alone, topoisomerase II inhibitor alone, and M3814 in combination with topoisomerase II inhibitor, and change in tumor volume over time was documented. The addition of M3814 was well tolerated. We demonstrated that M3814 shows limited efficacy as a single agent in ovarian cancer models. The combination of M3814 with PLD showed enhanced activity over PLD as a single agent. Further study of this combination is warranted.


2021 ◽  
Author(s):  
Jung Kyoon Choi

BRCA1/2 mutations account for only a small fraction of homologous recombination (HR) deficiency (HRD) cases. Recently developed genomic HRD (gHRD) tests suffer confounding factors causing low precision in predicting samples that will respond to poly (ADP-ribose) polymerase (PARP) inhibitors and DNA damaging agents. Here, we present molecular evidence and clinical utility of transcriptional HRD (tHRD) that is based on aberrant transcript usage (TU) of minor isoforms. Specifically, increased TU of non-functional isoforms of DNA repair genes was prevalent in breast and ovarian cancer with gHRD. Our functional assays validated its association with impaired HR activity. Remarkably, tHRD detection based on the TU pattern of key genes was superior to gHRD or BRCA1/2 screening in accuracy for predicting the responses of cell lines and cancer patients to PARP inhibitors and genotoxic drugs. In particular, this approach demonstrated the capability to reflect functional HR status, particularly when applied to our cohort of olaparib users with acquired platinum resistance in ovarian cancer. Hence, the tHRD-based diagnostic tests are expected to broaden the clinical utility of PARP inhibitors.


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