Yue Ma

PARP Inhibitors Display Differential Efficacy in Models of BRCA Mutant High-Grade Serous Ovarian Cancer

Several poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are now in clinical use for tumours with defects in BReast CAncer genes BRCA1 or BRCA2 that result in deficient homologous recombination repair (HRR). Use of olaparib, niraparib or rucaparib for the treatment of high-grade serous ovarian cancer, including in the maintenance setting, has extended both progression free and overall survival for women with this malignancy. While different PARP inhibitors (PARPis) are mechanistically similar, differences are apparent in their chemical structures, toxicity profiles, PARP trapping abilities and polypharmacological landscapes. We have treated ovarian cancer cell line models of known BRCA status, including the paired cell lines PEO1 and PEO4, and UWB1.289 and UWB1.289+BRCA1, with five PARPis (olaparib, niraparib, rucaparib, talazoparib and veliparib) and observed differences between PARPis in both cell viability and cell survival. A cell line model of acquired resistance to veliparib showed increased resistance to the other four PARPis tested, suggesting that acquired resistance to one PARPi may not be able to be rescued by another. Lastly, as a proof of principle, HRR proficient ovarian cancer cells were sensitised to PARPis by depletion of BRCA1. In the future, guidelines will need to emerge to assist clinicians in matching specific PARPis to specific patients and tumours.

CD48 suppresses proliferation and migration as an immune-related prognostic signature in the cervical cancer immune microenvironment

Abstract Cervical cancer (CC) is one of the most common malignant tumors in gynecology. Immunotherapy and targeted therapy are two particularly effective treatments. In this study, weighted gene co-expression network analysis and CIBERSORT algorithm that quantifies the composition of immune cells were used to analyze CC expression data based on the GEO database and identify modules related to T cells. Five candidate hub genes were identified by tumor-infiltrating immune cells estimation and Kaplan–Meier survival analysis according to CC data from The Cancer Genome Atlas (TCGA). Chemotherapeutic response, methylation, and gene mutation analyses were implemented so that the five candidate hub genes identified may be the potential biomarkers and therapeutic targets which were related to T cell infiltration. Moreover, the results of RT-qPCR revealed that CD48 was a tumor suppressor gene, which was negatively correlated with CC stages, lymph node metastasis, and differentiation. Furthermore, the functional study verified that the interference of CD48 was able to boost the proliferation and migration ability in vitro and the growth of transplanted tumors in vivo. Overall, we identified molecular targets related to immune infiltration and prognosis, regarded CD48 as a key molecule involved in the progression of CC, thus providing new insights into the development of molecular therapy and immunotherapeutics against CC.

Should all cervical cancer patients with positive lymph node receive definitive radiotherapy: a population-based comparative study

The optimal initial management strategy for cervical cancer with lymph node metastases (LNM) remains a topic of ongoing debate. This study aimed to explore the correlation between surgery followed by postoperative radiotherapy (PORT) and definitive radiotherapy (RT), as well as their impact on the prognosis of patients with LNM. Patients with positive lymph nodes (PLNs) in 2009 FIGO stage I-III cervical cancer were selected from SEER database. Kaplan-Meier and log-rank analysis were utilized to assess survival outcomes. Cox and Interaction analyses were employed to compare the survival benefits. 2936 patients were included in this study. Multivariate analysis revealed the choice of primary treatment significantly impacted both cancer-specific survival (CSS) and overall survival (OS), serving as an independent prognostic factor for patients with LNM. After adjusting for imbalanced variables, surgery plus PORT exhibited significant improvements in CSS and OS in the stage I-II and PLNs ≤ 5 subgroups. However, no statistically significant difference was observed between the two treatment modalities in stage III and PLNs > 5 subgroups. Through interaction analysis, it was observed that stage I-II and PLNs ≤ 5 subgroups exhibited a significant survival benefit from surgery plus PORT. Surgery plus PORT could lead to improved outcomes for cervical cancer in patients with stage I-II or PLNs ≤ 5. However, this approach did not apply to patients with stage III or PLNs > 5. Therefore, a comprehensive assessment of LNM and local tumor spread should guide rationalized treatment modalities when managing patients presenting LNM.