Nucleolar Localization of the RNA Helicase DDX21 Predicts Survival Outcomes in Gynecologic Cancers.

Cancer cells with DNA repair defects (e.g., BRCA1/2 mutant cells) are vulnerable to PARP inhibitors (PARPi) due to induction of synthetic lethality. However, recent clinical evidence has shown that PARPi can prevent the growth of some cancers irrespective of their BRCA1/2 status, suggesting alternative mechanisms of action. We previously discovered one such mechanism in breast cancer involving DDX21, an RNA helicase that localizes to the nucleoli of cells and is a target of PARP1. We have now extended this observation in endometrial and ovarian cancers and provided links to patient outcomes. When PARP1-mediated ADPRylation of DDX21 is inhibited by niraparib, DDX21 is mislocalized to the nucleoplasm resulting in decreased rDNA transcription, which leads to a reduction in ribosome biogenesis, protein translation, and ultimately endometrial and ovarian cancer cell growth. High PARP1 expression was associated with high nucleolar localization of DDX21 in both cancers. High nucleolar DDX21 negatively correlated with calculated IC50s for niraparib. By studying endometrial cancer patient samples, we were able to show that high DDX21 nucleolar localization was significantly associated with decreased survival. Our study suggests that the use of PARPi as a cancer therapeutic can be expanded to further types of cancers and that DDX21 localization can potentially be used as a prognostic factor and as a biomarker for response to PARPi. SIGNIFICANCE: Currently, there are no reliable biomarkers for response to PARPi outside of homologous recombination deficiency. Herein we present a unique potential biomarker, with clear functional understanding of the molecular mechanism by which DDX21 nucleolar localization can predict response to PARPi.

Vulvar cancer management and wrangling recurrent disease: A report from the society of gynecologic oncology journal club.

The Society of Gynecologic Oncology (SGO) Journal Club webinar series is an open forum that invites national experts to discuss the literature pertaining to important topics in the management of gynecologic cancers. On August 14th, 2023, SGO hosted a journal club focused on the management of upfront and recurrent vulvar cancer. Our discussants included Dr. Brian M Slomovitz from Mount Sinai Medical Center in Miami Beach, Dr. Emi Yoshida from the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, and Dr. Lilian Gien from the University of Toronto Sunnybrook Odette Cancer Center. During the discussion,we reviewed the progression of vulvar cancer surgery from en bloc resection of the vulva and groins, to partial radical vulvectomy and sentinel lymph nodes. We also reviewed the management of node positive vulvar cancer including published and accruing Groningen International Study on Sentinel Nodes in Vulvar Cancer (GROINSS) trials and other sentinel trials from the Gynecologic Oncology Group (GOG). Here we will also review the literature on the management of recurrent vulvar cancer, highlighting current treatment options and ongoing clinical trials. The following is a report of the journal club presentation.

Current practice patterns in nodal evaluation and adjuvant treatment of advanced stage endometrioid endometrial cancer: An SGO survey.

The use of sentinel lymph node (SLN) mapping over full lymphadenectomy for endometrioid endometrial cancer (EC) has had varying uptake. Adjuvant therapy for advanced stage EC is also a debated topic globally. Two recent randomized controlled trials have attempted to clarify which treatment approach should be recommended. Our aims were to identify common practice patterns in the intraoperative lymph node evaluation as well as the practice patterns in the treatment of advanced stage (stage III-IV) endometrioid EC among gynecologic oncologists. A 16-question survey was distributed via email to all Society of Gynecologic Oncology members. Study data were collected anonymously and managed using REDCap electronic data tools. Respondents were asked questions regarding demographics, assessing nodal status, and choice of adjuvant treatment for each stage. Descriptive statistics, student's t-tests, and chi-squared analyses were performed. A total of 1531 surveys were distributed and 187 (12%) members responded. The majority (70%) of respondents identified nodal metastases by performing SLN mapping prior to nodal evaluation in grade 1-2 disease, however only half perform SLN mapping in grade 3 EC. Adjuvant chemotherapy was recommended by 90% of practitioners for advanced EC. However, external beam radiation or brachytherapy was combined with chemotherapy in 74% of stage III EC and 35% of stage IV EC. While 90% of practitioners recommend chemotherapy-based adjuvant treatment for women with stage IIIA-IVA endometrioid EC, decreasing local recurrence appears to be a factor in treatment planning as radiation combined with chemotherapy is used in 63% of cases.