A Genomically Characterized Collection of High-Grade Serous Ovarian Cancer Xenografts for Preclinical Testing.

High-grade serous ovarian cancer (HGSC) is the leading cause of morbidity and mortality from gynecologic malignant tumors. Overall survival remains low because of the nearly ubiquitous emergence of platinum resistance and the paucity of effective next-line treatments. Current cell culture-based models show limited similarity to HGSC and are therefore unreliable predictive models for preclinical evaluation of investigational drugs. This deficiency could help explain the low overall rate of successful drug development and the decades of largely unchanged approaches to HGSC treatment. We used gene expression, copy number variation, and exome sequencing analyses to credential HGSC patient-derived xenografts (PDXs) as effective preclinical models that recapitulate the features of human HGSC. Mice bearing PDXs were also treated with standard-of-care carboplatin therapy. PDXs showed similar sensitivity to carboplatin as the patient's tumor at the time of sampling. PDXs also recapitulated the diversity of genomic alterations (copy number variation and mutation profiles) previously described in large data sets that profiled HGSC. Furthermore, mRNA profiling showed that the PDXs represent all HGSC subtypes with the exception of the immunoreactive group. Credentialing of PDX models of HGSC should aid progress in HGSC research by providing improved preclinical models of HGSC that can be used to test novel targets and more accurately evaluate their likelihood of success.

The optimal time for surgery in women with serous ovarian cancer.

BACKGROUND: Advanced high-grade serous ovarian carcinoma (HGSC) is commonly treated with surgery and chemotherapy. We investigated the survival of patients treated with primary or interval surgery at different times following neoadjuvant chemotherapy. Their survival was compared with that of patients treated with primary cytoreductive surgery and adjuvant chemotherapy. METHODS: Patients with stage III or IV HGSC were included in this retrospective cohort study. Clinical data were obtained from patient records. Patients were divided into 2 groups based on treatment with neoadjuvant chemotherapy and interval cytoreductive surgery (NAC) or with primary cytoreductive surgery and adjuvant chemotherapy (PCS). Study groups were stratified by several clinical variables. RESULTS: We included 334 patients in our study: 156 in the NAC and 178 in the PCS groups. Survival of patients in the NAC group was independent of when they underwent interval cytoreductive surgery following initiation of neoadjuvant chemotherapy (p < 0.001). Optimal surgical cytoreduction had no impact on overall survival in the NAC group (p < 0.001). Optimal cytoreduction (p < 0.001) and platinum sensitivity (p < 0.001) were independent predictors of improved survival in the PCS but not in the NAC group. Patients in the NAC group had significantly worse overall survival than those in the PCS group (31.6 v. 61.3 mo, p < 0.001). CONCLUSION: Women with advanced HGSC who underwent PCS had better survival than those who underwent interval NAC, regardless of the number of cycles of neoadjuvant therapy. Optimal cytoreduction did not provide a survival advantage in the NAC group.

BACKGROUND: La chirurgie et la chimiothérapie sont habituellement le traitement recommandé pour les carcinomes ovariens séreux bien différenciés de haut grade. Nous avons étudié le taux de survie de patientes ayant subi une chirurgie initiale ou d'intervalle à divers moments après une chimiothérapie néoadjuvante et l'avons comparé avec celui de patientes ayant subi une chirurgie de réduction tumorale initiale et une chimiothérapie adjuvante. METHODS: Cette étude de cohorte rétrospective a été menée auprès de patientes présentant un carcinome de stade III ou IV. Les données cliniques ont été tirées de leur dossier médical. Les patientes ont été séparées en 2 groupes : le premier était formé des patientes ayant subi une chimiothérapie néoadjuvante et une chirurgie de réduction tumorale d'intervalle (groupe NAC), et le deuxième de celles ayant subi une chirurgie de réduction tumorale initiale et une chimiothérapie adjuvante (groupe PCS). On a stratifié les 2 groupes à l'aide de plusieurs variables cliniques. RESULTS: L'étude portait sur 334 patientes, soit 156 dans le groupe NAC et 178 dans le groupe PCS. Dans le groupe NAC, aucune corrélation n'a été observée entre le taux de survie des patientes et le temps écoulé entre la chimiothérapie néoadjuvante et la chirurgie de réduction tumorale d'intervalle (p < 0,001). La réduction tumorale optimale n'a eu aucune incidence sur le taux de survie global des patientes du groupe NAC (p < 0,001). La réduction tumorale optimale (p < 0,001) et la sensibilité au platine (p < 0,001) ont été ciblés comme étant 2 prédicateurs indépendants d'un taux de survie accru chez les patientes du groupe PCS, mais pas chez celles du groupe NAC. Le taux de survie des patientes du groupe NAC était beaucoup plus faible que celui des patientes du groupe PCS (31,6 mo contre 61,3 mo, p < 0,001). CONCLUSION: Les femmes atteintes d'un carcinome ovarien séreux bien différencié de haut grade ayant subi une chirurgie de réduction tumorale initiale et une chimiothérapie adjuvante (PCS) ont affiché un taux de survie plus élevé que les patientes ayant subi une chimiothérapie néoadjuvante et une chirurgie de réduction tumorale d'intervalle (NAC), peu importe le nombre de cycles de chimiothérapie néoadjuvante. La réduction tumorale optimale n'a pas été associée à un taux de survie plus élevé chez ces dernières.

Phenotypic heterogeneity and instability of human ovarian tumor-initiating cells.

The cancer stem cell (CSC) model proposes that tumors have a hierarchical organization in which only some cells indefinitely self-renew and thereby sustain tumor growth. In addition, the CSC model requires that tumor-initiating cells (TICs) be prospectively isolatable on the basis of their phenotype. Previous studies have suggested that serous ovarian cancer (SOC) conforms to the CSC model, but these used arguably nonfidelitous immortalized cell lines, cultured primary cells, or passaged xenografts as the source of tumor cells. We developed a robust assay for quantifying TICs from primary SOC. Using this assay, we find that TICs are rare when assayed in either NOD/SCID or NOD/SCID/IL2Rγ(-/-) (NSG) mice. TIC frequency (TICf) varies substantially between patients, although it is similar in primary ovarian masses and omental metastases, suggesting that TICf is an intrinsic property of ovarian tumors. CD133 marks all TICs from several primary SOC cases. However, in other cases, substantial TIC activity is found in both the CD133(+) and CD133(-) fractions, whereas still other cases have exclusively CD133(-) TICs. Furthermore, the TIC phenotype can change in xenografts: primary tumors in which all TICs are CD133(+) can give rise to xenografts that contain substantial numbers of CD133(-) TICs. Our results highlight the need for quantitative rigor in the evaluation of TICs and for caution when using passaged xenografts for such studies. Furthermore, although our data suggest that SOC conforms to the CSC hypothesis, the heterogeneity of the TIC phenotype may complicate its clinical application.

Descriptive regression tree analysis of intersecting predictors of adult self-rated health: Does gender matter? A cross-sectional study of Canadian adults.

BACKGROUND: While self-rated health (SRH) is a well-validated indicator, its alignment with objective health is inconsistent, particularly among women and older adults. This may reflect group-based differences in characteristics considered when rating health. Using a combination of SRH and satisfaction with health (SH) could capture lived realities for all, thus enabling a more accurate search for predictors of subjective health. With the combined measure of SRH and SH as the outcome we explore a range of characteristics that predict high SRH/SH compared with predictors of a low rating for either SRH or SH. METHODS: Data were from the Canadian General Social Survey 2016 which includes participants 15 years of age and older. We performed classification and regression tree (CRT) analyses to identify the best combination of socioeconomic, behavioural, and mental health predictors of good SRH and health satisfaction. RESULTS: Almost 85% of the population rated their health as good; however, 19% of those had low SH. Conversely, about 20% of those reporting poor SRH were, none-the-less, satisfied. CRT identified healthy eating, absence of a psychological disability, no work disability from long-term illness, and high resilience as the main predictors of good SRH/SH. Living with a spouse or children, higher social class and healthy behaviours also aligned with high scores in both self-perceived health measures. Sex was not a predictor. CONCLUSIONS: Combining SRH and SH eliminated sex as a predictor of subjective health, and identified characteristics, particularly resilience, that align with high health and well-being and that are malleable.

The prognostic value of perioperative, pre-systemic therapy CA125 levels in patients with high-grade serous ovarian cancer.

OBJECTIVE: To investigate the ability of preoperative CA125 and post-surgical CA125 changes to predict outcomes among patients with high-grade serous ovarian cancer (HGSC). METHODS: The present retrospective cohort study included patients with HGSC who underwent surgery between January 1, 2003, and December 31, 2011 at Princess Margaret Cancer Center, Toronto, ON, Canada. CA125 was measured at diagnosis and following surgery, and the CA125 ratio was calculated (preoperative CA125/postoperative CA125). Optimal CA125 cutoff levels were identified using the point with the most significant log-rank-test result. Univariate and multivariate analyses with Cox proportional hazard modeling was used to study overall survival. RESULTS: Among 212 patients, an optimal baseline CA125 cutoff value of 174 U/mL and a seven-fold decrease in CA125 after surgery were positive prognostic indicators. A 10-fold increase in baseline CA125 was associated with decreased overall survival (univariate hazard ratio 1.55, 95% confidence interval [CI] 1.17-2.06; P=0.002; multivariate hazard ratio 1.72, 95% CI 1.21-2.44; P=0.002). An increase in the CA125 ratio (log10 [preoperative CA125/postoperative CA125]) was associated with improved overall survival (univariate hazard ratio 0.63, 95% CI 0.43-0.90; P=0.012; multivariate hazard ratio 0.41, 95% CI 0.24-0.70, P<0.001). CONCLUSION: CA125 demonstrated prognostic value for HGSC; baseline CA125 of 174 U/mL or lower and a post-surgical decline of seven-fold or greater were associated with improved overall survival.

Biologically-targeted detection of primary and micro-metastatic ovarian cancer.

Ovarian cancer is the leading cause of morbidity/mortality from gynecologic malignancy. Early detection of disease is difficult due to the propensity for ovarian cancer to disseminate throughout the peritoneum. Currently, there is no single accurate test to detect primary or recurrent ovarian cancer. We report a novel clinical strategy using PPF: a multimodal, PET and optical, folate receptor (FR)-targeted agent for ovarian cancer imaging. The capabilities of PPF were evaluated in primary human ovarian cancer cells, in vivo xenografts derived from primary cells and ex vivo patient omemtum, as the heterogeneity and phenotype displayed by patients is retained. Primary cells uptake PPF in a FR-dependent manner demonstrating approximately a 5- to 25-fold increase in fluorescence. By both PET and fluorescence imaging, PPF specifically delineated FR-positive, ovarian cancer xenografts, with similar tumor-to-background ratios of 8.91±0.91 and 7.94±3.94, and micro-metastatic studding (<1mm), which demonstrated a 3.5-fold increase in PPF uptake over adjacent normal tissue. Ex vivo patient omentum demonstrated selective uptake of PFF by tumor deposits. The ability of PPF to identify metastatic deposits <1mm could facilitate more complete debulking (currently, optimal debulking is <10mm residual tumor), by providing a more sensitive imaging strategy improving treatment planning, response assessment and residual/recurrent disease detection. Therefore, PPF is a novel clinical imaging strategy that could substantially improve the prognosis of patients with ovarian cancer by allowing pre-, post- and intra-operative tumor monitoring, detection and possibly treatment throughout all stages of therapy and tumor progression.

Regulation of CD133 by HDAC6 promotes ß-catenin signaling to suppress cancer cell differentiation.

The pentaspan membrane glycoprotein CD133 marks lineage-specific cancer progenitor cells and is associated with poor prognosis in a number of tumor types. Despite its utility as a cancer progenitor cell marker, CD133 protein regulation and molecular function remain poorly understood. We find that the deacetylase HDAC6 physically associates with CD133 to negatively regulate CD133 trafficking down the endosomal-lysosomal pathway for degradation. We further demonstrate that CD133, HDAC6, and the central molecule of the canonical Wnt signaling pathway, ß-catenin, can physically associate as a ternary complex. This association stabilizes ß-catenin via HDAC6 deacetylase activity, which leads to activation of ß-catenin signaling targets. Downregulation of either CD133 or HDAC6 results in increased ß-catenin acetylation and degradation, which correlates with decreased proliferation in vitro and tumor xenograft growth in vivo. Given that CD133 marks progenitor cells in a wide range of cancers, targeting CD133 may be a means to treat multiple cancer types.