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Biology-driven therapy advances in high-grade serous ovarian cancer
Yinu Wang, … , Mazhar Adli, Daniela Matei
Yinu Wang, … , Mazhar Adli, Daniela Matei
Published January 2, 2024
Citation Information: J Clin Invest. 2024;134(1):e174013. https://doi.org/10.1172/JCI174013.
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Review Article has an altmetric score of 213

Biology-driven therapy advances in high-grade serous ovarian cancer

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Abstract

Following a period of slow progress, the completion of genome sequencing and the paradigm shift relative to the cell of origin for high grade serous ovarian cancer (HGSOC) led to a new perspective on the biology and therapeutic solutions for this deadly cancer. Experimental models were revisited to address old questions, and improved tools were generated. Additional pathways emerging as drivers of ovarian tumorigenesis and key dependencies for therapeutic targeting, in particular, VEGF-driven angiogenesis and homologous recombination deficiency, were discovered. Molecular profiling of histological subtypes of ovarian cancer defined distinct genetic events for each entity, enabling the first attempts toward personalized treatment. Armed with this knowledge, HGSOC treatment was revised to include new agents. Among them, PARP inhibitors (PARPis) were shown to induce unprecedented improvement in clinical benefit for selected subsets of patients. Research on mechanisms of resistance to PARPis is beginning to discover vulnerabilities and point to new treatment possibilities. This Review highlights these advances, the remaining challenges, and unsolved problems in the field.

Authors

Yinu Wang, Alexander James Duval, Mazhar Adli, Daniela Matei

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Figure 1

Model of HGSOC initiation from the epithelium of the fallopian tube.

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Model of HGSOC initiation from the epithelium of the fallopian tube.
Fol...
Following initiating TP53 mutation, fallopian tube secretory epithelial cells proliferate and form secretory cell expansion with a TP53 signature. Follicular fluid released during ovulation contains ROS, which induces inflammation and can cause additional mutations and increased genetic instability. Mutated pathways include DNA repair processes, antiapoptotic pathways, and growth pathways. The secretory cells become irregular in size and shape, and the tissue becomes disordered as serous tubal intraepithelial carcinoma lesions develop. Finally, transformed cells begin to dissociate from the precursor lesion leading to metastasis. FT, fallopian tube; STIC, serous tubal intraepithelial carcinoma; SS-DNA, single-stranded DNA; DS-DNA, double-stranded DNA; MAPK, mitogen-activated protein kinase.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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