Tumor intrinsic activity of Chromobox 2 (CBX2) remodels the tumor microenvironment in high grade serous carcinoma.

Chromobox 2 (CBX2), an epigenetic reader and component of Polycomb Repressor Complex 1 (PRC1), is highly expressed in >75% of high-grade serous carcinoma (HGSC). Increased CBX2 expression is associated with poorer survival, while CBX2 knockdown leads to improved chemotherapy sensitivity. In an HGSC immune competent murine model, knockdown of CBX2 decreased tumor progression. We sought to explore the impact of modulation of CBX2 on the tumor immune microenvironment (TIME), understanding that the TIME plays a critical role in disease progression and development of therapy resistance. Exploration of existing datasets demonstrated that elevated CBX2 expression significantly correlated with the specific immune cell types in the TIME. RNA-seq and pathway analysis of differentially expressed genes demonstrated immune signature enrichment. Confocal microscopy and co-culture experiments found modulation of CBX2 leads to increased recruitment and infiltration of macrophages. Flow cytometry of macrophages cultured with CBX2 overexpressing cells showed increased M2-like macrophages and decreased phagocytosis activity. Cbx2 knockdown in the Trp53, Brca2 null ID8 syngeneic murine model (ID8 Trp53-/- Brca2-/-) led to decreased tumor progression compared to control. NanoString Immuno-Oncology Panel analysis suggested knock down in Cbx2 shifts immune cell composition, with an increase in macrophages. Multispectral immunohistochemistry further confirmed an increase in macrophage infiltration. Increased CBX2 expression leads to recruitment and polarization of pro-tumor macrophages and targeting CBX2 may serve to modulate the TIME to enhance the efficacy of immune therapies.

Ovarian cancer think tank: An overview of the current status of ovarian cancer screening and recommendations for future directions.

Early diagnosis and screening of ovarian cancer remain significant challenges to improving patient outcomes. There is an urgent need to implement both established and modern strategies to address the "early detection" conundrum, especially as new research continues to uncover the complexities of the disease. The discussion provided is the result of a unique research conference focused on reviewing early detection modalities and providing insight into future approaches.

Early Ovarian Cancer Detection in the Age of Fallopian Tube Precursors: A Systematic Review.

OBJECTIVE: To determine biomarkers other than CA 125 that could be used in identifying early-stage ovarian cancer. DATA SOURCES: Ovid MEDLINE ALL, EMBASE, Web of Science Core Collection, ScienceDirect, Clinicaltrials.gov , and CAB Direct were searched for English-language studies between January 2008 and April 2023 for the concepts of high-grade serous ovarian cancer, testing, and prevention or early diagnosis. METHODS OF STUDY SELECTION: The 5,523 related articles were uploaded to Covidence. Screening by two independent reviewers of the article abstracts led to the identification of 245 peer-reviewed primary research articles for full-text review. Full-text review by those reviewers led to the identification of 131 peer-reviewed primary research articles used for this review. TABULATION, INTEGRATION, AND RESULTS: Of 131 studies, only 55 reported sensitivity, specificity, or area under the curve (AUC), with 36 of the studies reporting at least one biomarker with a specificity of 80% or greater specificity or 0.9 or greater AUC. CONCLUSION: These findings suggest that although many types of biomarkers are being tested in ovarian cancer, most have similar or worse detection rates compared with CA 125 and have the same limitations of poor detection rates in early-stage disease. However, 27.5% of articles (36/131) reported biomarkers with better sensitivity and an AUC greater than 0.9 compared with CA 125 alone and deserve further exploration.

CASC4/GOLM2 drives high grade serous carcinoma anoikis resistance through the recycling of EGFR.

Ovarian cancer is the deadliest gynecological malignancy, and accounts for over 150,000 deaths per year worldwide. The high grade serous ovarian carcinoma (HGSC) subtype accounts for almost 70% of ovarian cancers and is the deadliest. HGSC originates in the fimbria of the fallopian tube and disseminates through the peritoneal cavity. HGSC survival in peritoneal fluid requires cells to resist anoikis (anchorage-independent apoptosis). Most anoikis resistant mechanisms are dependent on microenvironment interactions with cell surface-associated proteins, such as integrins and receptor tyrosine kinases (RTKs). We previously identified the gene CASC4 as a driver of anoikis resistance. CASC4 is predicted to be a Golgi-associated protein that may regulate protein trafficking to the plasma membrane, but CASC4 is largely uncharacterized in literature; thus, we sought to determine how CASC4 confers anoikis resistance to HGSC cells. Mining of publicly available ovarian cancer datasets (TCGA) showed that CASC4 is associated with worse overall survival and increased resistance to platinum-based chemotherapies. For experiments, we cultured three human HGSC cell lines (PEO1, CaOV3, OVCAR3), and a murine HGSC cell line, (ID8) with shRNA-mediated CASC4 knockdowns (CASC4 KD) in suspension, to recapitulate the peritoneal fluid environment in vitro. CASC4 KD significantly inhibited cell proliferation and colony formation ability, and increased apoptosis. A Reverse Phase Protein Assay (RPPA) showed that CASC4 KD resulted in a broad re-programming of membrane-associated proteins. Specifically, CASC4 KD led to decreased protein levels of the RTK Epidermal Growth Factor Receptor (EGFR), an initiator of several oncogenic signaling pathways, leading us to hypothesize that CASC4 drives HGSC survival through mediating recycling and trafficking of EGFR. Indeed, loss of CASC4 led to a decrease in both EGFR membrane localization, reduced turnover of EGFR, and increased EGFR ubiquitination. Moreover, a syngeneic ID8 murine model of ovarian cancer showed that knocking down CASC4 leads to decreased tumor burden and dissemination.

Incorporation of Palliative Care in Gynecologic Oncology.

PURPOSE OF REVIEW: This review serves to provide clarity on the nature, scope, and benefits of early palliative care integration into the management of patients with gynecologic malignancies. RECENT FINDINGS: There is increased recognition that timely referral to palliative care improves quality of life for patients and their families by providing goal-concordant care that reduces physical and emotional suffering and limits futile and aggressive measures at the end of life. Palliative care services rendered throughout the continuum of illness ultimately increase engagement with hospice services and drive down health expenditures. Despite these myriad benefits, misconceptions remain, and barriers to and disparities in access to these services persist and warrant continued attention. Palliative care should be offered to all patients with advanced gynecologic cancers early in the course of their disease to maximize benefit to patients and their families.

Novel chromobox 2 inhibitory peptide decreases tumor progression.

BACKGROUND: The Polycomb Repressor Complex 1 (PRC1) is an epigenetic regulator of differentiation and development, consisting of multiple subunits including RING1, BMI1, and Chromobox. The composition of PRC1 dictates its function and aberrant expression of specific subunits contributes to several diseases including cancer. Specifically, the reader protein Chromobox2 (CBX2) recognizes the repressive modifications including histone H3 lysine 27 tri-methylation (H3K27me3) and H3 lysine 9 dimethylation (H3K9me2). CBX2 is overexpressed in several cancers compared to the non-transformed cell counterparts, it promotes both cancer progression and chemotherapy resistance. Thus, inhibiting the reader function of CBX2 is an attractive and unique anti-cancer approach. RESEARCH DESIGN & METHODS: Compared with other CBX family members, CBX2 has a unique A/T-hook DNA binding domain that is juxtaposed to the chromodomain (CD). Using a computational approach, we constructed a homology model of CBX2 encompassing the CD and A/T hook domain. We used the model as a basis for peptide design and identified blocking peptides that are predicted to directly bind the CD and A/T-hook regions of CBX2. These peptides were tested in vitro and in vivo models. CONCLUSION: The CBX2 blocking peptide significantly inhibited both 2D and 3D growth of ovarian cancer cells, downregulated a CBX2 target gene, and blunted tumor growth in vivo.

It Does Exist! Diagnosis and Management of Thyroid Carcinomas Originating in Struma Ovarii.

Thyroid carcinoma originating in struma ovarii comprises a small minority of all cases of struma ovarii. Given the rarity of this diagnosis, literature to guide evaluation and management is limited. The most common carcinoma originating from struma ovarii is papillary thyroid carcinoma. Treatment includes surgery, including a fertility sparing approach if disease is confined to the ovary, with consideration of total thyroidectomy and radioactive iodine ablation for high-risk pathologic features or disease spread beyond the ovary. This review discusses the histopathologic findings, molecular pathology, clinical implications and management, and prognosis of thyroid carcinomas originating in struma ovarii.

Small cell carcinoma of the ovary hypercalcemic type (SCCOHT): A review and novel case with dual germline SMARCA4 and BRCA2 mutations.

Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is a rare and aggressive disease. While classically linked to mutations in SMARCA4, we describe a case in a patient with both SMARCA4 and BRCA2 germline mutations. We describe her disease presentation, histopathology and treatment with adjuvant systemic chemotherapy, interval hyperthermic intraperitoneal chemotherapy, high dose chemotherapy with stem cell rescue, and maintenance with a poly-ADP-ribose polymerase inhibitor (PARPi). Additionally, we share spatial transcriptomics completed on original tumor.

Patterns of palliative care referral in platinum resistant ovarian cancer demonstrate reactive rather than proactive approach.

Objective: To evaluate patterns of palliative care (PC) integration in patients with platinum resistant ovarian cancer. Methods: Single institution retrospective study of patients with ovarian, tubal, or peritoneal high-grade carcinoma treated 2011-2020. Platinum resistance was identified by chemotherapy regimen or provider definition. Data was extracted evaluating treatment regimens, time to progression, PC and hospice referrals, and survival. Descriptive statistics and survival analyses were performed. Results: We identified 258 patients with platinum resistant ovarian cancer. Median survival from diagnosis of platinum resistance was 15 months (range 0-161). Most (71 %) patients were referred to PC, with 43 % of referrals within 3 months of death. Fourteen percent of patients were referred directly to hospice without PC involvement. Of 46 patients living with platinum resistant disease, 93 % meet criteria for early PC referral, but less than half have seen PC. Median time from platinum resistance to PC referral was 9 months (range 0-157) and from PC referral to death was 3 months (range 0-110). Median time from platinum resistance to hospice referral was 7 months (range 1-57) and from hospice referral to death was < 1 month (range 0-12). Conclusion: While rates of PC referral in our cohort are high compared with other single institution cohorts, timing of PC referral suggests referral patterns that are reactive to clinical decline rather than proactive as per national recommendations. A significant percentage of patients are directly referred to hospice for end-of-life care, reflecting missed opportunity for concurrent PC and oncology care earlier in the disease course. Diagnosis of platinum resistance should serve as a stimulus for PC involvement.

The Spatial Context of Tumor-Infiltrating Immune Cells Associates with Improved Ovarian Cancer Survival.

Ovarian cancer is the deadliest gynecologic malignancy. Multi-omics techniques have provided a platform for improved predictive modeling of therapy response and patient outcomes. While high-grade serous carcinoma (HGSOC) tumors are immunogenic and numerous studies have defined positive correlation to immune cell infiltration, immunotherapies in clinical trials have exhibited low efficacy rates. There is a significant need to better comprehend the role and composition of immune cells in mediating ovarian cancer therapeutic response and progression. We performed multiplex IHC with an HGSOC tissue microarray (n = 127) to characterize the immune cell composition within tumors. After analyzing the composition and spatial context of T cells (CD4/CD8), macrophages (CD68), and B cells (CD19) within the tumor, we found that increased B-cell and CD4 T-cell presence correlated with overall survival. More importantly, we observed that the proximity between tumor-associated macrophages and B cells or CD4 T cells significantly correlated with overall survival. IMPLICATIONS: The results highlight the antitumor role of B cells and CD4 T cells, and that the spatial interactions between immune cell types are a novel predictor of therapeutic response and patient outcomes.