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Evaluating carboplatin and PARP inhibitor combination efficacy using high-grade serous carcinoma spheroids and
Emily J Tomas1,2, Jennifer Davis1, Yudith Ramos Valdes1
1Cancer Research Laboratory Program, the Mary and John Knight Translational Ovarian Cancer Research Unit, Verspeeten Family Cancer Centre, London, Canada.
Background:
PARP inhibitors (PARPis) are new targeted agents that exploit homologous recombination DNA repair deficiencies (HRDs), which are present in 50% of high-grade serous carcinoma (HGSC) cases. Currently, olaparib is approved as maintenance therapy for BRCA1/2-mutated HGSC, and niraparib is approved for platinum-sensitive recurrent disease. However, research is currently expanding their potential as front-line agents or in combination with carboplatin, a standard HGSC chemotherapeutic.
Methods:
Immortalized ovarian cancer (iOvCa) cell lines, developed from HGSC patient ascites, were treated with carboplatin, olaparib and niraparib to determine their sensitivity. Immunofluorescence analysis of RAD51 was conducted for HRD testing of all the cell lines. The cell lines were cultured as three-dimensional organoids and spheroids to mimic tumor growth and metastasis, respectively, and then treated to assess the effects of different drug combinations.
Results:
The half-maximal inhibitory concentrations of olaparib and niraparib varied across our iOvCa cell lines, with iOvCa195 BRCA1-mutant line exhibiting the expected high sensitivity to both PARPis. Direct combination of carboplatin with olaparib or niraparib enhanced cell killing, yet achieved cell viability levels to those of carboplatin alone. In sequential experiments, carboplatin followed by either PARPi or vice versa showed no significant difference in cell viability to carboplatin alone, except in iOvCa195 organoids when treated with a PARPi first.
Conclusions:
Overall, first-line carboplatin treatment remains ideal, yet there may be select utility for PARPi prior to chemotherapy. Using patient-derived tumor models such as spheroids and organoids may provide insights for on-going and future clinical trials to enhance therapeutic outcomes for HGSC patients.
Insights
Poly (ADP-ribose) polymerase inhibitors (PARPis) show promise in treating high-grade serous carcinoma (HGSC) by targeting DNA repair deficiencies. While first-line carboplatin remains optimal, PARPis may offer benefits when used before chemotherapy in select HGSC cases.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- High-grade serous carcinoma (HGSC) exhibits homologous recombination DNA repair deficiencies (HRDs) in 50% of cases.
- PARP inhibitors (PARPis) are emerging targeted therapies exploiting HRDs.
- Current approvals include olaparib for BRCA-mutated HGSC maintenance and niraparib for platinum-sensitive recurrent disease; research explores their front-line and combination potential with carboplatin.
Purpose of the Study:
- To evaluate the sensitivity of immortalized ovarian cancer (iOvCa) cell lines to carboplatin, olaparib, and niraparib.
- To assess the efficacy of PARPis in combination with carboplatin using 3D tumor models.
- To determine optimal sequencing strategies for PARPis and carboplatin in HGSC treatment.
Main Methods:
- Immortalized ovarian cancer (iOvCa) cell lines were treated with carboplatin, olaparib, and niraparib.
- Homologous recombination deficiency (HRD) was assessed via RAD51 immunofluorescence.
- Three-dimensional organoids and spheroids were used to model tumor growth and metastasis for drug combination studies.
Main Results:
- Sensitivity to olaparib and niraparib varied among iOvCa cell lines; the BRCA1-mutant iOvCa195 line showed high sensitivity.
- Combined carboplatin and PARPi enhanced cell killing but did not reduce viability below carboplatin-alone levels.
- Sequential treatment (carboplatin then PARPi, or vice versa) showed no significant difference from carboplatin alone, except for PARPi first in iOvCa195 organoids.
Conclusions:
- First-line carboplatin treatment is generally ideal for HGSC.
- PARPis may have utility prior to chemotherapy in specific HGSC patient subsets.
- Patient-derived tumor models like spheroids and organoids are valuable for informing clinical trial design and improving HGSC therapeutic outcomes.
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