The role of patient-derived ovarian cancer organoids in the study of PARP inhibitors sensitivity and resistance: from genomic analysis to functional testing

Abstract

Epithelial ovarian cancer (EOC) harbors distinct genetic features such as homologous recombination repair (HRR) deficiency, and therefore may respond to poly ADP-ribose polymerase inhibitors (PARPi). Over the past few years, PARPi have been added to the standard of care for EOC patients in both front-line and recurrent settings. Next-generation sequencing (NGS) genomic analysis provides key information, allowing for the prediction of PARPi response in patients who are PARPi naïve. However, there are indeed some limitations in NGS analyses. A subset of patients can benefit from PARPi, despite the failed detection of the predictive biomarkers such as BRCA1/2 mutations or HRR deficiency. Moreover, in the recurrent setting, the sequencing of initial tumor does not allow for the detection of reversions or secondary mutations restoring proficient HRR and thus leading to PARPi resistance. Therefore, it becomes crucial to better screen patients who will likely benefit from PARPi treatment, especially those with prior receipt of maintenance PARPi therapy. Recently, patient-derived organoids (PDOs) have been regarded as a reliable preclinical platform with clonal heterogeneity and genetic features of original tumors. PDOs are found feasible for functional testing and interrogation of biomarkers for predicting response to PARPi in EOC. Hence, we review the strengths and limitations of various predictive biomarkers and highlight the role of patient-derived ovarian cancer organoids as functional assays in the study of PARPi response. It was found that a combination of NGS and functional assays using PDOs could enhance the efficient screening of EOC patients suitable for PARPi, thus prolonging their survival time.

Progress of research on tumor organoids: A bibliometric analysis of relevant publications from 2011 to 2021

“…The combined clinical trial data confirmed that the chemo-radiotherapy response of the patients was a very close match with the organoid response of the rectal cancer, with an accuracy of 84.43%, a sensitivity of 78.01% and a specificity of 91.97% ( 41 ). Organoids have also successfully predicted the sensitivity of colorectal cancer ( 42 ), gastric cancer ( 43 ), ovarian cancer ( 44 ) and prostate cancer ( 45 ) to drugs. It appears at the present time that extracting samples from patient tumor tissues, creating and culturing organoids, exposing patient-derived tumor organoids to various drugs to find the best drug or drug combination to treat patients, revealing potential weaknesses of individual treatments based on gene mutation profiles and treatment responses of organoids and determining the next treatment route when first-line treatment is ineffective will become the ultimate mode of treatment for cancer ( 46 , 47 ) 1 .…”

The disruption of the CCDC6 – PP4 axis induces a BRCAness like phenotype and sensitivity to PARP inhibitors in high-grade serous ovarian carcinoma

“…This finding may have therapeutic significance since it will promote the use of CCDC6 as a biomarker for early-individualized therapy employing targeted treatments. In addition, Patients-Derived Organoids, or PDOs, have also recently been thought to be practical for examining HGSOC's susceptibility to and resistance to PARPi [ 70 , 71 ].…”

Homologous Recombination Deficiency Score Determined by Genomic Instability in a Romanian Cohort

“…Cells with HIGH HRD values have been shown to be more sensitive to poly (ADPribose) polymerase (PARPi) inhibitors and platinum therapy [34].…”