VDX-111, a novel small molecule, induces necroptosis to inhibit ovarian cancer progression.

Epithelial ovarian cancers that are nonhomologous recombination deficient, as well as those that are recurrent and in a platinum-resistant state, have limited therapeutic options. The objectives of this study were to characterize the mechanism of action and investigate the therapeutic potential of a small molecule, VDX-111, against ovarian cancer. We examined the ability of VDX-111 to inhibit the growth of a panel of ovarian cancer cell lines, focusing on BRCA wild-type lines. We found that VDX-111 causes a dose-dependent loss of cell viability across ovarian cancer cell lines. Reverse phase protein array (RPPA) analysis was used to identify changes in cell signaling in response to VDX-111 treatment. An RPPA analysis performed on cells treated with VDX-111 detected changes in cell signaling related to autophagy and necroptosis. Immunoblots of OVCAR3 and SNU8 cells confirmed a dose-dependent increase in LC3A/B and RIPK1. Incucyte live cell imaging was used to measure cell proliferation and death in response to VDX-111 alone and with inhibitors of apoptosis, necroptosis, and autophagy. Annexin/PI assays suggested predominantly nonapoptotic cell death, while real-time kinetic imaging of cell growth indicated the necroptosis inhibitor, necrostatin-1, attenuates VDX-111-induced loss of cell viability, suggesting a necroptosis-dependent mechanism. Furthermore, VDX-111 inhibited tumor growth in patient-derived xenograft and syngeneic murine models. In conclusion, the cytotoxic effects of VDX-111 seen in vitro and in vivo appear to occur in a necroptosis-dependent manner and may promote an antitumor immune response.

Folate receptor alpha protein expression in ovarian serous cystadenocarcinoma tumors of The Cancer Genome Atlas: exploration beyond single-agent therapy.

Epithelial ovarian cancer (EOC) can be highly lethal, with limited therapeutic options for patients with non-homologous recombination deficient (HRD) disease. Folate receptor alpha (FOLR1/FRα)-targeting agents have shown promise both alone and in combination with available therapies, but the relationship of FRα to other treatment-driving biomarkers is unknown. The Cancer Genome Atlas (TCGA) was queried to assess protein and mRNA expression and mutational burden in patients with differential FRα protein-expressing ovarian tumors, and the results referenced against the standard 324 mutations currently tested through FoundationOne Companion Diagnostics to identify targets of interest. Of 585 samples within TCGA, 121 patients with serous ovarian tumors for whom FRα protein expression was quantified were identified. FRα protein expression significantly correlated with FOLR1 mRNA expression (p=7.19×1014). Progression free survival (PFS) for the FRα-high group (Q1) was 20.7 months, compared to 16.6 months for the FRα-low group (Q4, Logrank, p=0.886). Overall survival (OS) was 54.1 months versus 36.3 months, respectively; however, this result was not significant (Q1 vs. Q4, Logrank, p=0.200). Mutations more commonly encountered in patients with high FRα-expressing tumors included PIK3CA and FGF family proteins. Combinations of FRα-targeting agents with PI3K, mTOR, FGF(R) and VEGF inhibitors warrant investigation to evaluate their therapeutic potential.

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.

Utilizing preoperative arterial embolization to minimize blood loss at time of vulvar sarcoma resection: A case report.

Selective arterial embolization has long been utilized in the field of obstetrics and gynecology as both a prophylactic and therapeutic measure. We present a case of a highly vascularized, poorly differentiated, radiation-related vulvar sarcoma that was resected immediately following selective arterial embolization. Arterial embolization in patients with gynecologic malignancies has been shown to compromise blood supply to the tumor and decrease the risk of hemorrhage and related surgical complications. In this case, the use of embolization prior to surgery appeared to result in a less morbid procedure for the patient with decreased blood loss and improved quality of life thereafter. Based on the presented case, we believe that arterial embolization can be considered a safe preoperative intervention to decrease surgical risk, particularly hemorrhage, at time of resection of highly vascularized vulvar tumors.

Survival and Surgical Approach among Women with Advanced Ovarian Cancer Treated with Neoadjuvant Chemotherapy.

STUDY OBJECTIVE: To evaluate the effect of surgical approach on overall survival (OS) for women with advanced, epithelial ovarian cancer (EOC) after neoadjuvant chemotherapy (NACT) and determine the sociodemographic and clinical factors associated with surgical approach. DESIGN: The primary exposure was surgical approach to interval cytoreduction, minimally invasive versus open, and was evaluated by intention to treat. Primary outcome was OS. Associations were examined using Chi-squared tests, Wilcoxon rank sum tests, and multivariate logistic regression. Survival analysis was performed with Kaplan-Meier methods and Cox proportional hazards. SETTING: The National Cander Database was used to identify eligible patients. PATIENTS: Women diagnosed with stage IIIC/IV EOC from 2010-2016. INTERVENTIONS: Patients were included if they were treated with NACT within 90 days of diagnosis before interval cytoreductive surgery (CRS). MEASUREMENTS AND MAIN RESULTS: A total of 8085 women were identified; 6713 (83%) underwent open interval CRS, and 1372 (17%) underwent minimally invasive interval CRS. The proportion undergoing minimally invasive CRS after NACT increased from 2% in 2010 to 11% in 2016, a nearly 6-fold increase. There was no difference in OS between women who underwent minimally invasive and open interval CRS (median OS 36.5 vs 35.2 months, HR 0.94, 95% CI, 0.86-1.04). After adjusting for demographic and clinical variables, including age, race, ethnicity, income, and Charlson/Deyo score, no difference in OS was observed (HR 0.95, 95% CI, 0.86-1.04). Women of older age (OR 1.35, 95% CI, 1.05-1.74) and Hispanic ethnicity (OR 1.46, 95% CI, 1.14-1.88) had increased odds of receiving minimally invasive CRS after NACT, whereas low income (<$38000/year) women had decreased odds (OR 0.76, 95% CI, 0.60-0.97, p = .03). Length of stay differed for patients undergoing minimally invasive versus open interval CRS (3 vs 5 days, p <.01), but there was no difference in need for postoperative readmission. CONCLUSIONS: Minimally invasive CRS has similar survival outcomes to open CRS among women with EOC who have undergone NACT.

Natural language processing with machine learning to predict outcomes after ovarian cancer surgery.

OBJECTIVE: To determine if natural language processing (NLP) with machine learning of unstructured full text documents (a preoperative CT scan) improves the ability to predict postoperative complication and hospital readmission among women with ovarian cancer undergoing surgery when compared with discrete data predictors alone. METHODS: Medical records from two institutions were queried to identify women with ovarian cancer and available preoperative CT scan reports who underwent debulking surgery. Machine learning methods using both discrete data predictors (age, comorbidities, preoperative laboratory values) and natural language processing of full text reports (preoperative CT scans) were used to predict postoperative complication and hospital readmission within 30 days of surgery. Discrimination was measured using the area under the receiver operating characteristic curve (AUC). RESULTS: We identified 291 women who underwent debulking surgery for ovarian cancer. Mean age was 59, mean preoperative CA125 value was 610 U/ml and albumin was 3.9 g/dl. There were 25 patients (8.6%) who were readmitted and 45 patients (15.5%) who developed postoperative complications within 30 days. Using discrete features alone, we were able to predict postoperative readmission with an AUC of 0.56 (0.54-0.58, 95% CI); this improved to 0.70 (0.68-0.73, 95% CI) (p < 0.001) with the addition of NLP of preoperative CT scans. CONCLUSIONS: Natural language processing with machine learning improved the ability to predict postoperative complication and hospital readmission among women with ovarian cancer undergoing surgery.

Discrepancies between author- and industry-reported disclosures of financial relationships at an annual gynecologic oncology research meeting.

OBJECTIVE: Trillions of dollars pass to physicians from industry-related businesses annually, leading to many opportunities for financial conflicts of interest. The Open Payments Database (OPD) was created to ensure transparency. We describe the industry relationships as reported in the OPD for presenters at the 2019 Society of Gynecologic Oncology (SGO) Annual Meeting and evaluate concordance between author disclosures of their financial interests and information provided by the OPD. METHODS: This is an observational, cross-sectional study. Disclosure data were collected from authors with oral and featured abstract presentations in the 2019 SGO annual conference. These disclosures were compared to data available for each author in the 2018 OPD, which included the amount and nature of industry payments. RESULTS: We examined the disclosures of 301 authors who met inclusion criteria. Of 161 authors who had disclosure statements on their presentations,147 reported "no disclosures," and 14 disclosed industry relationships. The remaining 140 did not list any disclosure information. Sixty percent (184/301) of authors had industry relationships in the 2018 OPD, including 173 of 287 (60.3%) of authors who either reported no disclosures or did not have disclosure data available in their presentations. These transactions totaled over 43 million USD from 122 different companies, with most payments (46%) categorized as "Research or Associated Research." Accurate disclosure reporting was associated with receiving higher payments or research payments, and being a presenting author. CONCLUSIONS: Most authors at the SGO annual conference did not correctly disclose their industry relationships when compared with their entries in the OPD.

Pediatric PK/PD Phase I Trial of Pexidartinib in Relapsed and Refractory Leukemias and Solid Tumors Including Neurofibromatosis Type I-Related Plexiform Neurofibromas.

PURPOSE: Simultaneously targeting the tumor and tumor microenvironment may hold promise in treating children with refractory solid tumors. Pexidartinib, an oral inhibitor of tyrosine kinases including colony stimulating factor 1 receptor (CSF-1R), KIT, and FLT3, is FDA approved in adults with tenosynovial giant cell tumor. A phase I trial was conducted in pediatric and young adult patients with refractory leukemias or solid tumors including neurofibromatosis type 1-related plexiform neurofibromas. PATIENTS AND METHODS: A rolling six design with dose levels (DL) of 400 mg/m2, 600 mg/m2, and 800 mg/m2 once daily for 28-day cycles (C) was used. Response was assessed at regular intervals. Pharmacokinetics and population pharmacokinetics were analyzed during C1. RESULTS: Twelve patients (4 per DL, 9 evaluable) enrolled on the dose-escalation phase and 4 patients enrolled in the expansion cohort: median (lower, upper quartile) age 16 (14, 16.5) years. No dose-limiting toxicities were observed. Pharmacokinetics appeared linear over three DLs. Pharmacokinetic modeling and simulation determined a weight-based recommended phase II dose (RP2D). Two patients had stable disease and 1 patient with peritoneal mesothelioma (C49+) had a sustained partial response (67% RECIST reduction). Pharmacodynamic markers included a rise in plasma macrophage CSF (MCSF) levels and a decrease in absolute monocyte count. CONCLUSIONS: Pexidartinib in pediatric patients was well tolerated at all DL tested, achieved target inhibition, and resulted in a weight-based RPD2 dose.