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High grade serous ovarian cancer (HGSOC) is a fatal gynecologic malignancy in the U.S. with limited treatment options. New therapeutic strategies include targeting of the cell cycle checkpoints, e.g., ATR and CHK1. We recently reported a promising clinical activity of the CHK1 inhibitor (CHK1i) prexasertib monotherapy in BRCA wild-type (BRCAwt) HGSOC patients. In this study, biopsies of treated patients and cell line models were used to investigate possible mechanisms of resistance to CHK1i. We report that BRCAwt HGSOC develops resistance to prexasertib monotherapy via a prolonged G2 delay induced by lower CDK1/CyclinB1 activity, thus preventing cells from mitotic catastrophe and cell death. On the other hand, we noted CHK1’s regulation on RAD51-mediated homologous recombination (HR) repair was not altered in CHK1i-resistant cells. Therefore, CHK1i sensitizes CHK1i-resistant cells to DNA damaging agents such as gemcitabine or hydroxyurea by inhibition of HR. In summary, our results demonstrate new mechanistic insights of functionally distinct CHK1 activities and highlight a potential combination treatment approach to overcome CHK1i resistance in BRCAwt HGSOC.

The multi-cohort phase 2 trial NCT02203513 was designed to evaluate the clinical activity of the CHK1 inhibitor (CHK1i) prexasertib in patients with breast or ovarian cancer. Here we report the activity of CHK1i in platinum-resistant high-grade serous ovarian carcinoma (HGSOC) with measurable and biopsiable disease (cohort 5), or without biopsiable disease (cohort 6). The primary endpoint was objective response rate (ORR). Secondary outcomes were safety and progression-free survival (PFS). 49 heavily pretreated patients were enrolled (24 in cohort 5, 25 in cohort 6). Among the 39 RECISTv1.1-evaluable patients, ORR was 33.3% in cohort 5 and 28.6% in cohort 6. Primary endpoint was not evaluable due to early stop of the trial. The median PFS was 4 months in cohort 5 and 6 months in cohort 6. Toxicity was manageable. Translational research was an exploratory endpoint. Potential biomarkers were investigated using pre-treatment fresh biopsies and serial blood samples. Transcriptomic analysis revealed high levels of DNA replication-related genes ( POLA1 , POLE , GINS3 ) associated with lack of clinical benefit [defined post-hoc as PFS < 6 months]. Subsequent preclinical experiments demonstrated significant cytotoxicity of POLA1 silencing in combination with CHK1i in platinum-resistant HGSOC cell line models. Therefore, POLA1 expression may be predictive for CHK1i resistance, and the concurrent POLA1 inhibition may improve the efficacy of CHK1i monotherapy in this hard-to-treat population, deserving further investigation. ATR/CHK1 pathway inhibitors represent a therapeutic option for platinum-resistant high-grade serous ovarian carcinoma (HGSOC). Here the authors report the results of a phase 2 clinical study of the CHK1 inhibitor prexasertib in patients with BRCA wild-type platinum-resistant HGSOC with or without biopsiable disease.

Here we report the efficacy and translational findings of durvalumab, olaparib, and cediranib (D + O + C) and of durvalumab plus cediranib (D + C) from the recurrent ovarian cancer cohort within a single-center, multi-arm, non-randomized, multi-cohort phase I/II trial (NCT02484404). Sixty-eight patients were enrolled (39 in D + O + C, 29 in D + C). The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS) and safety. ORR was 19.4% (95% CI, 9.5-43.5) for D + O + C and 29.6% (95% CI, 13.8-46.9) for D + C; D + C met the primary endpoint while D + O + C did not. Median PFS was 4.5 months in both arms, with four exceptional responders (PFS ≥ 12 months) per arm. Toxicity was manageable. Pre- and on-treatment biopsies and blood samples were collected for prespecified transcriptomic and immunophenotypic profiling; signature analyses and preclinical studies were conducted post hoc and were exploratory. Baseline tumors from exceptional responders and patients with clinical benefit (partial response or stable disease with PFS ≥ 4 months) demonstrated enrichment of immune activation and metabolic pathways, whereas tumors with no clinical benefit (NCB; progressive disease or stable disease with PFS < 4 months) exhibited upregulation of vascular adaptation and cytoskeletal remodeling pathways. These findings support the proof-of-concept clinical activity of D + O + C and D + C and identify molecular signatures with potential predictive value in subsets of recurrent ovarian cancer. Preclinical studies have suggested that PARP inhibitors and anti-angiogenic therapy may favour response to immune checkpoint blockade in ovarian cancer. Here the authors report efficacy and translational data of a phase II trial of anti-PD-L1 durvalumab and cediranib (anti-angiogenic drug) with and without the PARP inhibitor olaparib in patients with recurrent ovarian cancer.

High-grade serous ovarian cancer (HGSOC) is the most common (~80%) and lethal ovarian cancer subtype in the United States, characterized by TP53 mutations and DNA repair defects causing chromosomal instability (CIN). KIF18A is an essential cytoskeletal motor protein for cell division in CIN+ cancer cells, but it is not necessary for cell division in normal cells. Therefore, KIF18A represents a promising target for therapeutic interventions in CIN+ cancers. We investigated the use of a novel KIF18A inhibitor ATX020, for selectively targeting CIN+ HGSOC cells using growth inhibition assays, invasion assays, immunoassays, cell cycle analysis, and immunofluorescence techniques. Using DepMap and flow cytometry, we classified a panel of HGSOC cell lines based on aneuploidy scores (AS) and ploidy levels and identified a correlation between these classifications and sensitivity against ATX020. ATX020 induced cytotoxicity through mitotic arrest and DNA damage, and reduced tumor growth in HGSOC with high aneuploidy scores (AS). Mechanistically, ATX020 blocks KIF18A’s plus-end movement on spindle fibers, increasing spindle length, resulting in chromosomal mis-segregation, aneuploidy, and DNA damage. Our findings suggest that ATX020 inhibits CIN+ HGSOC cells mainly by inducing mitotic arrest and DNA damage, disrupting KIF18A’s function crucial for mitosis.

Foreign body (FB) aspiration is one of the most common emergency scenarios in cardiothoracic surgery and ENT unit consultations. We present the case of a 16-year-old male student who inadvertently ingested board pins while enjoying leftover savory. Despite the initial shock, he promptly sought evaluation at the local primary care facility. Remarkably, he remained largely asymptomatic. A subsequent chest radiograph revealed a radiopaque FB lodged in the right main bronchus. Employing a rigid bronchoscope, we successfully extracted the FB, obviating the need for open surgical intervention. What sets this case apart is the unusual combination of a large FB aspiration with minimal symptoms and the absence of internal injury during retrieval.

Poly (ADP-ribose) polymerase inhibitors (PARPis) show cytotoxicity in homologous recombination deficiency (HRD) seen in BRCA-mutant ovarian cancer (OvCa). Despite initial responses, resistance often develops. The reintroduction of different PARPis, such as niraparib or rucaparib, has shown some clinical activity in BRCA mutation-associated OvCa patients with prior olaparib treatment, yet the underlying mechanisms remain unclear. To investigate the differential sensitivity to different PARPis, we established an olaparib-resistant BRCA1-mutant OvCa cell line (UWB-OlaJR) by exposing UWB1.289 cells to gradually increasing concentrations of olaparib. UWB-OlaJR exhibited restored HR capability without BRCA1 reversion mutation or increased drug efflux. We examined cell viability, DNA damage, and DNA replication fork dynamics in UWB-OlaJR treated with various PARPis. UWB-OlaJR exhibits varying sensitivity to PARPis, showing cross-resistance to veliparib and talazoparib, and sensitivity with increased cytotoxicity to niraparib and rucaparib. Indeed, DNA fiber assay reveals that niraparib and rucaparib cause higher replication stress than the others. Moreover, S1 nuclease fiber assay shows that niraparib and rucaparib induce greater DNA single-strand gaps than other PARPis, leading to increased DNA damage and cell death. Our study provides novel insights into differential PARPi sensitivity in olaparib-resistant BRCA-mutant OvCa, which requires further investigation of inter-agent differences in large prospective studies.

Immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are associated with immunologic tolerance and poor prognosis in ovarian cancer (OvCa). We hypothesized that women with germline BRCA1 and BRCA2 mutation-associated (gBRCAm) OvCa would have fewer circulating immunosuppressive immune cells compared to those with BRCA wild-type (BRCAwt) disease during their early disease course (<5 years post-diagnosis) where gBRCAm is a favorable prognostic factor. We collected and viably froze peripheral blood mononuclear cells (PBMCs) from patients with recurrent OvCa olaparib clinical trials (NCT01445418/NCT01237067). Immune subset analyses were performed using flow cytometry for Tregs, exhausted CD8+ T cells, monocytes and MDSCs. Functional marker expression, including cytotoxic T lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain 3 (TIM-3) and programmed cell death protein 1 (PD-1) was evaluated. Data were analyzed using FlowJo. Pretreatment PBMCs were collected from 41 patients (16 gBRCAm/25 BRCAwt). The percentage of MDSCs among viable CD45+ PBMC was lower in gBRCAm OvCa compared with BRCAwt OvCa (median 0.565 vs. 0.93%, P=0.0086) but this difference was not seen in those women >5 years post-diagnosis. CD8+ T cells among viable CD45+ PBMCs and CTLA-4+/CD8+ T cells were higher in gBRCAm carriers than patients with BRCAwt, in particular for those <5 years post-diagnosis (median 20.4 vs. 9.78%, P=0.031 and median MFI 0.19 vs. 0.22, P=0.0074, respectively). TIM-3 expression on Tregs was associated with poor progression-free survival, independent of gBRCAm status (P<0.001). Our pilot data suggested that patients with gBRCAm OvCa may have fewer circulating MDSCs but higher CD8+ T cells in PBMCs during their early disease course. This may contribute to the observed survival benefit for these women in their first post-diagnosis decade.

High-grade serous ovarian carcinoma is characterised by TP53 mutations, DNA repair defects, and genomic instability. We hypothesised that prexasertib (LY2606368), a cell cycle checkpoint kinase 1 and 2 inhibitor, would be active in BRCA wild-type disease. In an open-label, single-centre, two-stage, proof-of-concept phase 2 study, we enrolled women aged 18 years or older with measurable, recurrent high-grade serous or high-grade endometrioid ovarian carcinoma. All patients had a negative family history of hereditary breast and ovarian cancer or known BRCA wild-type status, measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status score 0–2, and adequate haematological, renal, hepatic, and bone-marrow function. Patients received intravenous prexasertib 105 mg/m2 administered over 1 h every 14 days in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint of investigator-assessed tumour response, based on RECIST version 1.1, was assessed per protocol (assessable patients who had undergone CT imaging at baseline and attended at least one protocol-specified follow-up) and by intention to treat. The final analysis of this cohort of patients with BRCA wild-type high-grade serous ovarian carcinoma is reported here. This ongoing trial is registered with ClinicalTrials.gov, number NCT02203513, and continues to enrol patients for the BRCA-mutated ovarian cancer cohort. Between Jan 20, 2015, and Nov 2, 2016, we enrolled 28 women with a median age of 64 years (IQR 58·0–69·5) who had previously received a median of 5·0 (IQR 2·5–5·0) systemic therapies. Most patients (22 [79%]) had platinum-resistant or platinum-refractory disease. All women received at least one dose of prexasertib, but four (14%) of 28 patients were not assessable for RECIST response. Eight (33%, 95% CI 16–55) of 24 patients assessable per protocol had partial responses. In the intention-to-treat population, eight (29%, 95% CI 13–49) of 28 had a partial responses. The most common (in >10% patients) grade 3 or 4 treatment-emergent adverse events were neutropenia in 26 (93%) of 28 patients, reduced white blood cell count in 23 (82%), thrombocytopenia in seven (25%), and anaemia in three (11%). Grade 4 neutropenia was reported in 22 (79%) patients after the first dose of prexasertib and was transient (median duration 6 days [IQR 4–8]) and recovered without growth-factor support in all cases. The treatment-related serious adverse event of grade 3 febrile neutropenia was reported in two (7%) patients. One patient died during the study due to tumour progression. Prexasertib showed clinical activity and was tolerable in patients with BRCA wild-type high-grade serous ovarian carcinoma. This drug warrants further development in this setting, especially for patients with platinum-resistant or platinum-refractory disease. Intramural Research Program of the National Institutes of Health and National Cancer Institute.

Poly (ADP-ribose) polymerase inhibitors (PARPis) represent a major advance in ovarian cancer, now as a treatment and as a maintenance therapy in the upfront and recurrent settings. However, patients often develop resistance to PARPis, underlining the importance of dissecting resistance mechanisms. Here, we report different dosing/timing schemes of PARPi treatment in BRCA2 -mutant PEO1 cells, resulting in the simultaneous development of distinct resistance mechanisms. PARPi-resistant variants PEO1/OlaJR, established by higher initial doses and short-term PARPi treatment, develops PARPi resistance by rapidly restoring functional BRCA2 and promoting drug efflux activity. In contrast, PEO1/OlaR, developed by lower initial doses with long-term PARPi exposure, shows no regained BRCA2 function but a mesenchymal-like phenotype with greater invasion ability, and exhibits activated ATR/CHK1 and suppressed EZH2/MUS81 signaling cascades to regain HR repair and fork stabilization, respectively. Our study suggests that PARPi resistance mechanisms can be governed by treatment strategies and have a molecular basis on BRCA2 functionality. Further, we define different mechanisms that may serve as useful biomarkers to assess subsequent treatment strategies in PARPi-resistant ovarian cancer.