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Endometrial carcinoma is the most common gynecologic malignancy and the fourth most prevalent cancer in women in the modern world. Despite a relatively high chance of surgical cure, for patients with advanced or recurrent disease there are few therapeutic options. Angiogenesis has been extensively studied ever since vascular endothelial growth factor (VEGF) was discovered in the 1980s. Several clinical trials of anti-angiogenic therapy in endometrial carcinoma have been conducted, with mixed results, and many researchers have tried to determine prognostic and therapeutic biomarkers. Recent trials, which shed new light on possible treatment biomarkers and efficacious combination therapies, are reviewed in this text. While we are still far from effectively tailoring anti-angiogenic treatment to each patient, these data have provided valuable insight and have put us on track for the discovery of novel opportunities for angiogenesis therapy in endometrial carcinoma. • Survival from uterine cancer, specifically endometrial carcinoma (EC), has remained steady for the past 85 years. • Increasing prevalence and treatment failure in advanced or recurrent disease requires better treatment options. • As angiogenesis plays a key role in EC, we reviewed evidence of angiogenesis prognostic and predictive biomarkers in EC. • Recent evidence provides encouraging results for targeted therapy and pathogenesis-based combination treatments. • Research into patient selection, molecular classification and combination therapy will benefit EC patients in the long run. [ABSTRACT FROM AUTHOR]

Objective Bevacizumab, a monoclonal antibody to VEGF, has shown efficacy in ovarian, cervical and endometrial cancer in addition to several other solid tumors. Serious side effects include hypertension, proteinuria, bowel perforation, and thrombosis. We tested the hypothesis that genetic variation in hypertension-associated genes is associated with bevacizumab-induced hypertension (BIH). Methods Patients with solid tumors treated with bevacizumab in combination with other therapy were identified from six clinical trials. Haplotype-tagging (ht) SNPs for 10 candidate genes associated with hypertension were identified through the International Hapmap Project. Germline DNA was genotyped for 103 htSNPs using mass spectrometry. Bevacizumab toxicities were identified from clinical trial reports. Haplotypes were reconstructed from diploid genotyping data and frequencies were compared using standard two-sided statistical tests. Results The study included 114 patients with breast, lung, ovarian, or other cancers, of whom 38 developed BIH. WNK1 , KLKB1 , and GRK4 were found to contain single loci associated with BIH. Haplotype analysis of WNK1 , KLKB1 , and GRK4 identified risk haplotypes in each gene associated with grade 3/4 BIH. A composite risk model was created based on these haplotypes. Patients with the highest risk score were the most likely to develop grade 3/4 BIH (OR = 6.45; P = 0.005; 95%CI, 1.86–22.39). Conclusions We concluded that genetic variation in WNK1 , KLKB1 , and GRK4 may be associated with BIH. These genes are biologically plausible mediators due to their role in blood pressure control, regulating sodium homeostasis and vascular tone. This preliminary risk model performed better than population-based risk models and when further validated may help risk-stratify patients for BIH prior to initiating therapy. [ABSTRACT FROM AUTHOR]

Objective High-grade serous carcinoma (HGSC) generally presents at an advanced stage with poor long-term (LT) survival. Here we describe clinical features found in women surviving HGSC for ten or more years. Methods A multi-center research consortium was established between five participating academic centers. Patient selection criteria included high-grade serous ovarian, fallopian tube, or peritoneal carcinoma with at least ten years of follow up. Non-serous, borderline tumors and low-grade serous subtypes were excluded. Results The 203 identified LT ten-year survivors with HGSC were diagnosed at a median age of 57 years (range 37–84 years). The majority of patients had stage IIIC (72.4%) disease at presentation. Of those who underwent primary cytoreductive surgery, optimal cytoreduction was achieved in 143 (85.6%) patients. After a median follow up of 144 months, 88 (46.8%) patients did not develop recurrent disease after initial treatment. Unexpected findings from this survey of LT survivors includes 14% of patients having had suboptimal cytoreduction, 11% of patients having an initial platinum free interval of < 12 months, and nearly 53% of patients having recurrent disease, yet still surviving more than ten years after diagnosis. Conclusions LT survivors of HGSC of the ovary generally have favorable clinical features including optimal surgical cytoreduction and primary platinum sensitive disease. The majority of patients will develop recurrent disease, however many remained disease free for more than 10 years. Future work will compare the clinical features of this unusual cohort of LT survivors with the characteristics of HGSC patients having less favorable outcomes. [ABSTRACT FROM AUTHOR]

Abstract: Objective: GOG study 172 demonstrated improved progression-free (PFS) and overall (OS) survival for patients with stage III optimally debulked ovarian and peritoneal carcinoma treated with IV/IP paclitaxel and IP cisplatin compared to standard IV therapy. The inpatient administration, toxicity profile, and limited completion rate have been blamed for the lack of acceptance and widespread use of this regimen. We sought to evaluate the PFS, OS, toxicity, and completion rate of a modified outpatient IP regimen. Methods: Using a prospectively maintained database, we evaluated the outcomes of patients who underwent primary optimal cytoreduction for stage III ovarian, tubal, or peritoneal carcinoma followed by IV/IP chemotherapy from 1/05-3/09. Our modified regimen was as follows: IV paclitaxel (135mg/m2) over 3h on day 1, IP cisplatin (75mg/m2) on day 2, and IP paclitaxel (60mg/m2) on day 8, given every 21days for 6cycles. Results: We identified 102 patients who initiated the modified IV/IP regimen and completed chemotherapy. The median follow-up was 43months. The median age at diagnosis was 57years (range, 23–76). Primary disease site was: ovary, 77 (75%); fallopian tube, 13 (13%); peritoneum, 12 (12%). FIGO stage was: IIIA, 8 (8%); IIIB, 4 (4%); IIIC, 90 (88%). Residual disease after cytoreduction was: none, 58 (57%); ≤1cm, 44 (43%). The most frequent grade 3/4 toxicities were: neutropenia, 12 (12%); gastrointestinal, 8 (8%); neurologic, 6 (6%). Eighty-two (80%) of 102 patients completed 4 or more cycles of IV/IP therapy; 56 (55%) completed all 6cycles. The median PFS and OS were 29 and 67months, respectively. Conclusions: By modifying the GOG 172 treatment regimen, convenience, toxicity, and tolerability appear improved, with survival outcomes similar to those of GOG 172. This modified IV/IP regimen warrants further study. [Copyright &y& Elsevier]

Treatment options and associated biomarkers for advanced and recurrent disease are limited. Endometrial cancers (ECs) with CTNNB1 exon 3 mutations appear to have preferential response to bevacizumab, an anti-angiogenesis treatment, though the mechanism of action is unknown. We aim to identify mediators of bevacizumab-responsive endometrial cancers. We analyzed RNA expression from TCGA and protein expression from CPTAC to identify likely targets for β-catenin overactivity. We then transiently and stably overexpressed β-catenin in EC cells to confirm the results suggested by our in silico analysis. We performed corroborative experiments by silencing CTNNB1 in mutated cell lines to demonstrate functional specificity. We implanted transduced cells into xenograft models to study microvessel density. CTNNB1- mutated ECs were associated with increased β-catenin and MMP7 protein abundance (P < 0.001), but not VEGF-A protein abundance. Overexpressing β-catenin in EC cells did not increase VEGF-A abundance but did increase expression and secretion of MMP7 (P < 0.03). Silencing CTNNB1 in CTNNB1- mutated cells decreased MMP7 gene expression in EC (P < 0.0001). Microvessel density was not increased. These data provide a mechanistic understanding for bevacizumab-response in CTNNB1 -mutated ECs demonstrated in GOG-86P. We hypothesize that overexpressed and secreted MMP7 potentially digests VEGFR-1, releasing VEGF-A, and increasing its availability. These activities may drive the formation of permeable vessels, which contributes to tumor progression, metastasis, and immune suppression. This mechanism is unique to EC and advocates for further clinical trials evaluating this treatment-related biomarker. • CTNNB1 mutated tumors treated with bevacizumab are associated with improved outcomes without identified mechanism. • CTNNB1 mutations appear to increase expression of MMP7 without directly increasing VEGF-A abundance. • CTNNB1 mutations may increase available VEGF-A in endometrial cancers via an MMP7-related mechanism. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The recent EORTC-NCIC randomized trial comparing primary debulking surgery (PDS) to neoadjuvant chemotherapy (NACT) in advanced epithelial ovarian carcinoma (EOC) reported a median progression-free survival (PFS) of 12months and overall survival (OS) of 30months for both arms. Due to the equivalent survival and decreased morbidity with NACT, many now consider it the preferred approach. We analyzed the outcomes of patients treated with PDS at our institution during the same time period in which the EORTC-NCIC trial was conducted, using identical inclusion criteria. Methods: We identified all patients undergoing primary treatment for advanced EOC at our institution from 9/98-12/06. Study inclusion and exclusion criteria were identical to those of the EORTC-NCIC trial. Standard statistical tests were used. Results: Of 316 eligible patients, 285 (90%) underwent PDS and 31 (10%) received NACT due to extra-abdominal disease, medical comorbidities, and/or advanced age (>85years). Of the 285 patients who underwent PDS, most had carcinoma of ovarian origin (248, 87%); stage IIIC disease (249, 87%); grade 3 tumors (237, 83%); and serous histology (249, 87%). Optimal cytoreduction (≤1cm residual) was achieved in 203 patients (71%). Postoperative platinum-based chemotherapy was given to 281 of 285 patients (99%). The median PFS and OS were 17 and 50months, respectively. Conclusion: PDS should continue to be the preferred initial management for patients with bulky stages IIIC–IV ovarian carcinoma. NACT should be reserved for those who cannot tolerate PDS and/or for whom optimal cytoreduction is not feasible. [Copyright &y& Elsevier]

Objective Paclitaxel and carboplatin (PC) is a standard initial therapy for advanced endometrial cancer. We evaluated the efficacy and tolerability of incorporating three novel agents into initial therapy. Methods In this randomized phase II trial, patients with chemotherapy-naïve stage III/IVA (with measurable disease) and stage IVB or recurrent (with or without measurable disease) endometrial cancer were randomly assigned to treatment with PC plus bevacizumab (Arm 1), PC plus temsirolimus (Arm 2) or ixabepilone and carboplatin (IC) plus bevacizumab (Arm 3). The primary endpoint was progression-free survival (PFS). Comparable patients on the PC Arm of trial GOG209 were used as historical controls. Secondary endpoints were response rate, overall survival (OS), and safety. Results Overall, 349 patients were randomized. PFS duration was not significantly increased in any experimental arm compared with historical controls (p > 0.039). Treatment HRs (92% CI) for Arms 1, 2, and 3 relative to controls were 0.81 (0.63–1.02), 1.22 (0.96–1.55) and 0.87 (0.68–1.11), respectively. Response rates were similar across arms (60%, 55% and 53%, respectively). Relative to controls, OS duration (with censoring at 36 months), was significantly increased in Arm 1 (p < 0.039) but not in Arms 2 and 3; the HRs (92% CIs) were 0.71 (0.55–0.91), 0.99 (0.78–1.26), and 0.97 (0.77–1.23), respectively. No new safety signals were identified. Common mutations and rates of mismatch repair protein loss are described by histotype. Potential predictive biomarkers for temsirolimus and bevacizumab were identified. Conclusion PFS was not significantly increased in any experimental arm compared to historical controls. NRG Oncology/Gynecologic Oncology Group Study GOG-86P. [ABSTRACT FROM AUTHOR]

Objective Mucinous ovarian cancer (MOC) is a rare type of epithelial ovarian cancer resistant to standard chemotherapy regimens. We sought to characterize the repertoire of somatic mutations in MOCs and to define the contribution of massively parallel sequencing to the classification of tumors diagnosed as primary MOCs. Methods Following gynecologic pathology and chart review, DNA samples obtained from primary MOCs and matched normal tissues/blood were subjected to whole-exome ( n  = 9) or massively parallel sequencing targeting 341 cancer genes ( n  = 15). Immunohistochemical analysis of estrogen receptor, progesterone receptor, PTEN, ARID1A/BAF250a, and the DNA mismatch (MMR) proteins MSH6 and PMS2 was performed for all cases. Mutational frequencies of MOCs were compared to those of high-grade serous ovarian cancers (HGSOCs) and mucinous tumors from other sites. Results MOCs were heterogeneous at the genetic level, frequently harboring TP53 (75%) mutations, KRAS (71%) mutations and/or CDKN2A / B homozygous deletions/mutations (33%). Although established criteria for diagnosis were employed, four cases harbored mutational and immunohistochemical profiles similar to those of endometrioid carcinomas, and one case for colorectal or endometrioid carcinoma. Significant differences in the frequencies of KRAS , TP53 , CDKN2A , FBXW7 , PIK3CA and/or APC mutations between the confirmed primary MOCs ( n  = 19) and HGSOCs, mucinous gastric and/or mucinous colorectal carcinomas were found, whereas no differences in the 341 genes studied between MOCs and mucinous pancreatic carcinomas were identified. Conclusions Our findings suggest that the assessment of mutations affecting TP53 , KRAS , PIK3CA , ARID1A and POLE , and DNA MMR protein expression may be used to further aid the diagnosis and treatment decision-making of primary MOC. [ABSTRACT FROM AUTHOR]

The article focuses on a study regarding the engineering of prototype optical sensor composed of an antibody-functionalized carbon nanotube complex for the detection of high-grade serous ovarian carcinoma (HGSC) biomarker. Topics discussed include U.S. Food and Drug Administration (FDA) has approved cancer antigen 125 and human epididymis protein 4 (HE4) as biomarker for HGSC, response of HE4 via modulation of the nanotube optical bandgap and progress in electronic implants.

Abstract: Objectives: High-grade serous ovarian cancer (HGSOC) mostly presents at an advanced stage and has a low overall survival rate. However, a subgroup of patients are seemingly cured after standard initial therapy. We hypothesize that the molecular profiles of these patients vary from long-term survivors who recur. Methods: Patients with advanced HGSOC who underwent primary cytoreductive surgery and platinum-based chemotherapy were identified from The Cancer Genome Atlas (TCGA) and institutional (MSKCC) samples. A curative-intent group was defined by recurrence-free survival of >5years. A long-term recurrent group was composed of patients who recurred but survived >5years. RNA was hybridized to Affymetrix U133A transcription microarrays. The NanoString nCounter gene expression system was used for validation in an independent patient population. Results: In 30 curative and 84 recurrent patients, class comparison identified twice as many differentially expressed probes between the groups than expected by chance alone. TCGA and MSKCC data sets had 19 overlapping genes. Pathway analyses identified over-represented networks that included nuclear factor kappa B (NFkB) transcription and extracellular signal-regulated kinase (ERK) signaling. External validation was performed in an independent population of 28 curative and 38 recurrent patients. Three genes (CYP4B1, CEPT1, CHMP4A) in common between our original data sets remained differentially expressed in the external validation data. Conclusions: There are distinct transcriptional elements in HGSOC from patients likely to be cured by standard primary therapy. Three genes have withstood rigorous validation and are plausible targets for further study, which may provide insight into molecular features associated with long-term survival and chemotherapy resistance mechanisms. [Copyright &y& Elsevier]

BACKGROUND: Low-grade serous (LGS) ovarian cancer is a chemoresistant disease that accounts for 10% of serous ovarian cancers. Prior studies have reported that 28% to 35% of serous borderline (SB)/LGS ovarian tumors harbor a BRAF mutation, suggesting that BRAF inhibitors may be a rational therapeutic approach for this disease. In the current study, the authors sought to determine whether BRAF or KRAS mutation status was associated with disease stage and/or histology in patients with SB and LGS ovarian cancer. METHODS: Genetic profiles were constructed for 75 SB and LGS ovarian tumors to determine BRAF and KRAS mutation status. The incidence and identity of BRAF and KRAS mutations were defined, and the results were correlated with disease stage, response to treatment, and overall survival. RESULTS: Of 75 samples examined, 56 tumors (75%) had SB histology, and 19 tumors (25%) had LGS histology. Fifty-seven percent of tumors harbored either a KRAS mutation (n = 17) or a BRAF mutation (a valine-to-glutamate substitution at residue 600 [V600E]; n = 26). The BRAF V600E mutation was associated significantly with early disease stage (stage I/II; P < .001) and SB histology ( P = .002). KRAS mutations were not associated significantly with disease stage or histology. Of the 22 patients (29%) who required chemotherapy, 20 had tumors with wild-type KRAS/BRAF, 2 had KRAS mutant tumors, and none had tumors that harbored a BRAF mutation. All patients with BRAF tumors remained alive at a median follow-up of 3.6 years (range, 1.9-129.3 months). CONCLUSIONS: V600E BRAF mutations were present in 35% of patients who had SB/LGS ovarian cancers. The presence of the BRAF V600E mutation in SB/LGS ovarian cancer was associated with early stage disease and improved prognosis. The authors concluded that patients with SB/LGS ovarian cancer who require systemic therapy are unlikely to have BRAF mutant tumors. Cancer 2013. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Little prospective data exist on quality of life (QOL) after pelvic exenteration (PE). This ongoing study prospectively examines the QOL changes following this radical procedure using a comprehensive battery of psychological instruments. Methods: Since 2005, enrolled patients were interviewed (EORTC QLQ-C30, EORTC QLQ-CR38, EORTC QLQ-BLM30, BFI, BPI-SF, IADL, CES-D, IES-R) preoperatively and at 3, 6, and 12months after PE for physical/psychological symptoms. Data were examined using repeated measure ANOVA. Results: Sixteen women (3 anterior, 1 posterior, and 12 total PEs), with more than 1 year of follow-up, completed all scheduled interviews. Median age was 58years (range, 28–76years). Overall QOL (F =6.3, p <0.02), ability to perform instrumental daily activities (F =6.8, p <0.02), body image (F =11.9, p <0.00), and sexual function (F =8.0, p <0.01) all declined at 3months but were near baseline by 12months after PE. Although, overall, physical function followed a similar trend (F =14.8, p <0.00), it did not return to baseline. At the 12-month interview, patients reported increased gastrointestinal symptoms (F =8.9, p <0.01) but significantly less stress-related ideation (F =6.1, p <0.03) compared to baseline. Pain levels did not change significantly during the study period (F =0.4, p <0.74). Conclusions: Although patients report lingering gastrointestinal symptoms and some persistent decline in physical function after PE, most adjust well, returning to almost baseline functioning within a year. Providers can counsel patients that many, though not all, symptoms in the first 3months following exenteration are likely to improve as they adapt to their changed health status. These preliminary results await confirmation of a larger analysis. [Copyright &y& Elsevier]

Abstract: Objective: Adjuvant intraperitoneal (IP) platinum-based chemotherapy has been shown to improve outcome for patients with advanced ovarian cancer. We hypothesize that patients who have received adjuvant IP chemotherapy more commonly recur first at extraperitoneal sites than patients who have received adjuvant intravenous (IV) chemotherapy. Methods: Patients with newly diagnosed stage IIIC optimally debulked serous ovarian cancer were identified from institutional databases. Patterns of recurrence were compared between patients who received IV and IP chemotherapy using standard two-sided statistical tests. Results: Of the 104 patients who met inclusion criteria, 60 received IV chemotherapy and 44 received IP chemotherapy. Patients in the IV group had a first recurrence more commonly in the lower abdomen or pelvis than the IP group. Patients in the IP group more commonly recurred in the upper abdomen and extra-abdominal lymph nodes. More patients in the IP group than the IV group recurred at extra-abdominal sites (45.5% versus 23.3%, P =0.018). Conclusions: Patients receiving adjuvant IP chemotherapy are less likely to first recur in the lower abdomen or pelvis and more likely to recur outside of the abdominal cavity. The data suggest that IP chemotherapy is highly effective in the anatomic areas of peritoneal distribution. [Copyright &y& Elsevier]

Abstract: Objectives: MicroRNAs (miRNAs) are a class of small non-coding RNAs that negatively regulate gene expression primarily through post-transcriptional modification. We tested the hypothesis that miRNA expression is associated with overall survival in advanced ovarian cancer. Methods: Cases included newly diagnosed patients with stage III or IV serous ovarian cancer. RNA from a training set of 62 cases was hybridized to an miRNA microarray containing 470 mature human transcripts. Cox Regression was performed to identify miRNAs associated with overall survival. External validation was performed using quantitative RT-PCR miRNA assays in an independent test set of 123 samples. MiRNA targets and associated biologic pathways were predicted in silico. Results: Of all patients, 80% had high-grade, stage IIIC tumors and 64% underwent optimal cytoreduction. The median survival for the entire cohort was 49±4months. The training set identified 3 miRNAs associated with survival — miR-337, miR-410, and miR-645. An miRNA signature containing miR-410 and miR-645 was most strongly associated with overall survival in the training set (HR=2.96, 95% CI: 1.51–5.78). This miRNA survival signature (MiSS) was validated in the test set (HR=1.71, 95% CI: 1.05–2.78). The MiSS was independent of FIGO stage and surgical debulking. Conclusions: The data suggest that an MiSS that contains miR-410 and miR-645 is negatively associated with overall survival in advanced serous ovarian cancer. This signature, when further validated, may be useful in individualizing care for the ovarian cancer patient. Pathway analyses identify biologically plausible mechanisms. [Copyright &y& Elsevier]

Abstract: Objective: To describe the accuracy of SLN mapping in patients with a preoperative diagnosis of grade 1 endometrial cancer. Methods: A prospective, non-randomized study of women with a preoperative diagnosis of endometrial cancer and clinical stage I disease was conducted. A subset analysis of patients with a preoperative diagnosis of grade 1 endometrial endometrioid cancer was performed. All patients had preoperative lymphoscintigraphy with Tc99m on the day of or day before surgery followed by an intraoperative injection of 2 cm3 of isosulfan or methylene blue dye deep into the cervix or both cervix and fundus. All patients underwent hysterectomy, bilateral salpingo-oophorectomy, and regional nodal dissection. Hot and/or blue nodes were labeled as SLNs and sent for histopathological analysis. Results: Forty-two patients with a preoperative diagnosis of grade 1 endometrial carcinoma treated from 3/06 to 8/08 were identified. Twenty-five (60%) had laparoscopic surgery; 17 (40%) were treated by laparotomy. Preoperative lymphoscintigraphy visualized SLNs in 30 patients (71%); intraoperative localization of the SLN was possible in 36 patients (86%). A median of 3 SLNs (range, 1–14) and 14.5 non-SLNs (range, 4–55) were examined. In all, 4/36 (11%) had positive SLNs—3 seen on H&E and 1 as cytokeratin-positive cells on IHC. All node-positive cases were picked up by the SLN; there were no false-negative cases. The sensitivity of the SLN procedure in the 36 patients who had an SLN identified was 100%. Conclusion: Sentinel lymph node mapping using a cervical injection with combined Tc and blue dye is feasible and accurate in patients with grade 1 endometrial cancer and may be a reasonable option for this select group of patients. Regional lymphadenectomy remains the gold standard in many practices, particularly for the approximately 15% of cases with failed SLN mapping. [Copyright &y& Elsevier]

Overcoming chemoresistance will improve outcomes for all women with tubo-ovarian carcinomas. Mechanisms of chemoresistance are multifactorial and heterogeneous. ABCB1 (MDR1) represents one common resistance mechanism in tubo-ovarian carcinomas and is under the regulation of CD44. In the present study we examined the effects of a novel CD44 modulator, SPL-108, in a panel of ovarian cancer cell lines. We assessed chemosensitivity and migration effects of SPL-108 in a panel of ovarian cancer cell lines with (OVCAR5, OVCAR8, OVCAR3) and without (OVCAR4, CAOV3) MDR1 expression. In vitro experiments (cell viability assay, Western blot analysis, Calcein AM fluorescence assay, and migration assay) were carried out to determine the functional effects of SPL-108. Higher expression of CD44 was seen in OVCAR5 and OVCAR8 on Western Blot analysis. In transwell migration assay, treatment with SPL-108 decreased the number of migrating cells compared to control in OVCAR8 (mean ± SEM, 149.1 ± 22.8 vs 89.0 ± 16.5 cells, p=0.04), OVCAR5 (177.7 ± 15.4 vs 134.5 ± 14.7 cells, p=0.04) and OVCAR3 (111.2 ± 12.4 vs 50.5 ± 9.4 cells, p<0.01) cell lines. Migratory response was independent of CD44 expression. SPL-108 led to the accumulation of MDR1 substrate, as measured by the Calcein AM assay, in OVCAR5 (1.9 fold, p<0.01), OVCAR8 (1.6 fold, p<0.001) and OVCAR3 (1.2 fold, p=0.01) cells lines compared to controls. Retention of the MDR1 substrate after SPL-108 treatment positively correlated with MDR1 protein expression and no Calcein retention was seen in cells that lacked MDR1 expression. Co-treatment of OVCAR5 cells with paclitaxel and SPL-108 decreased the percentage of viable cells from 94% when treated with paclitaxel alone to 63% with combination therapy. No toxicity was observed with SPL-108 monotherapy. SPL-108 treatment has anti-metastatic properties and suppresses chemoresistance in preclinical models of ovarian cancer. Ongoing studies in animal models will help to guide the further clinical development of SPL-108. [Display omitted] [ABSTRACT FROM AUTHOR]

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, highly aggressive form of ovarian cancer primarily diagnosed in young women. We identified inactivating biallelic SMARCA4 mutations in 100% of the 12 SCCOHT tumors examined. Protein studies confirmed loss of SMARCA4 expression, suggesting a key role for the SWI/SNF chromatin-remodeling complex in SCCOHT. [ABSTRACT FROM AUTHOR]