Stromal DDR2 Promotes Ovarian Cancer Metastasis through Regulation of Metabolism and Secretion of Extracellular Matrix Proteins.

Ovarian cancer is the leading cause of gynecologic cancer-related deaths. The propensity for metastasis within the peritoneal cavity is a driving factor for the poor outcomes associated with this disease, but there is currently no effective therapy targeting metastasis. In this study, we investigate the contribution of stromal cells to ovarian cancer metastasis and identify normal stromal cell expression of the collagen receptor, discoidin domain receptor 2 (DDR2), that acts to facilitate ovarian cancer metastasis. In vivo, global genetic inactivation of Ddr2 impairs the ability of Ddr2-expressing syngeneic ovarian cancer cells to spread throughout the peritoneal cavity. Specifically, DDR2 expression in mesothelial cells lining the peritoneal cavity facilitates tumor cell attachment and clearance. Subsequently, omentum fibroblast expression of DDR2 promotes tumor cell invasion. Mechanistically, we find DDR2-expressing fibroblasts are more energetically active, such that DDR2 regulates glycolysis through AKT/SNAI1 leading to suppressed fructose-1,6-bisphosphatase and increased hexokinase activity, a key glycolytic enzyme. Upon inhibition of DDR2, we find decreased protein synthesis and secretion. Consequently, when DDR2 is inhibited, there is reduction in secreted extracellular matrix proteins important for metastasis. Specifically, we find that fibroblast DDR2 inhibition leads to decreased secretion of the collagen crosslinker, LOXL2. Adding back LOXL2 to DDR2 deficient fibroblasts rescues the ability of tumor cells to invade. Overall, our results suggest that stromal cell expression of DDR2 is an important mediator of ovarian cancer metastasis. IMPLICATIONS: DDR2 is highly expressed by stromal cells in ovarian cancer that can mediate metastasis and is a potential therapeutic target in ovarian cancer.

Management and prognosis of cervical cancer patients treated with definitive radiation therapy who have partial metabolic response on post-therapy positron emission tomography.

OBJECTIVE: To describe the management and outcomes of cervical cancer patients initially treated with radiation who had partial metabolic response (PMR) on three-month post-radiation 18F-fluorodeoxyglucose positron emissions tomography (FDG-PET). METHODS: Cervical cancer patients treated with radiation between 1997 and 2013 who had PMR on initial post-therapy FDG-PET were identified from a prospectively maintained database. Descriptive statistics were used to summarize patient demographics, tumor characteristics, surveillance methods, and treatment modalities. Kaplan-Meier methods were used to estimate progression-free (PFS) and overall survival (OS) for patients who underwent cervical biopsy prior to additional therapies and for patients who were managed with chemotherapy, radiation, surgery or no intervention. RESULTS: PMR was identified in 81/542 (15%) women on initial post-radiation PET. Thirty women underwent cervical biopsy, of whom 14 (47%) had persistent cancer. Nine underwent treatment, (three surgery, five chemotherapy alone and one chemotherapy and radiation) but all died of disease; PFS and OS were similar whether women had surgery, chemoradiation therapy, or no treatment. A second surveillance FDG-PET had PPV and NPV of 91% and 75% for progression, respectively, and identified the 19% percent of patients with persistent disease outside of the cervix. Cervical biopsy had a higher PPV (100%) and lower NPV (62.5%) for progression. At the end of the study period, 46 (57%) patients were dead of disease, including all 8 patients (100%) with para-aortic or supraclavicular involvement. CONCLUSIONS: If PMR is identified on three-month FDG-PET following completion of radiation for cervical cancer, repeat FDG-PET and/or biopsy are indicated to detect persistence and assist in counseling. PMR predicts poor outcomes, particularly for those with positive cervical biopsies and lymphatic involvement.

Adenomyosis presenting as a molar pregnancy: A case report.

•We present a case of atypical adenomyosis with clinical, laboratory, and imaging findings suggestive of a molar pregnancy.•Adenomyosis causes uterine enlargement and may appear cystic on vaginal ultrasound.•Falsely elevated ß-hCG in the setting of obesity and hypothyroidism may complicate diagnosing abnormal uterine bleeding.

Therapeutic Inhibition of the Receptor Tyrosine Kinase AXL Improves Sensitivity to Platinum and Taxane in Ovarian Cancer.

Ovarian cancer, one of the deadliest malignancies in female cancer patients, is characterized by recurrence and poor response to cytotoxic chemotherapies. Fewer than 30% of patients with resistant disease will respond to additional chemotherapy treatments. This study aims to determine whether and how inhibition of the receptor tyrosine kinase AXL can restore sensitivity to first-line platinum and taxane therapy in ovarian cancer. AXL staining was quantified in a patient tissue microarray and correlated with chemoresponse of patients. We used small hairpin RNAs to knock down AXL expression and the small-molecule inhibitor BGB324 to inhibit AXL and assessed sensitivity of cell lines and primary patient-derived cells to chemotherapy. We quantified platinum accumulation by inductivity-coupled plasma phase mass spectrometry. Finally, we treated chemoresistant patient-derived xenografts with chemotherapy, BGB324, or chemotherapy plus BGB324 and monitored tumor burden. AXL expression was higher in chemoresistant patient tumors and cell lines than in chemosensitive tumors and cell lines. AXL staining significantly predicted chemoresponse. Knockdown and inhibition of AXL dose-dependently improved response to paclitaxel and carboplatin in both cell lines and primary cells. AXL inhibition increased platinum accumulation by 2-fold (*, P < 0.05). In vivo studies indicated that AXL inhibition enhanced the ability of chemotherapy to prevent tumor growth (****, P < 0.0001). AXL contributes to platinum and taxane resistance in ovarian cancer, and inhibition of AXL improves chemoresponse and accumulation of chemotherapy drugs. This study supports continued investigation into AXL as a clinical target.

Factors influencing clinical trial enrollment among ovarian cancer patients.

OBJECTIVE: To characterize patients who did not enroll on a clinical trial and identify barriers that may limit enrollment among patients with advanced epithelial ovarian cancer (EOC) presenting for first-line chemotherapy. METHODS: We conducted a retrospective review of patients diagnosed with stage II-IV EOC from 10/2009-4/2013, a time period during which multiple trials were available to all EOC patients, including optimally debulked, suboptimally debulked, or undergoing neoadjuvant chemotherapy. Enrollment status, demographics, tumor characteristics, and treatment details were recorded. SAS version 9.3 was used for all analyses. RESULTS: 144 patients met study criteria; 67% were enrolled on a trial. Enrolled patients were significantly younger (median 61 vs 68years, p=0.002). Stage (p=0.30), race (p=0.75), and performance status (p=0.38) were similar between enrolled and non-enrolled patients. Distance did not impact enrollment, as nearly half of patients in both groups lived >50miles from the treatment center (39.0% vs 47.8%, p=0.36). Mode of chemotherapy administration significantly differed based on participation (all p<0.05). Despite similar residual disease status (p=1.00) and number of chemotherapy regimens received (p=0.59), patients treated on trial had a higher 3-year survival rate (70.7% vs 51.7%, p=0.031). The difference in median progression-free survival approached significance (20.2 vs 9.2months, p=0.091). CONCLUSION: In an institution where the culture is to offer clinical trials to all eligible patients, 33% of front-line EOC patients did not participate. Increasing age was associated with non-participation. Modifiable barriers must be overcome so that trial enrollment can better reflect true EOC demographics.

Cytotoxicity effects of different surfactant molecules conjugated to carbon nanotubes on human astrocytoma cells.

Phase contrast and epifluorescence microscopy were utilized to monitor morphological changes in human astrocytoma cells during a time-course exposure to single-walled carbon nanotube (SWCNT) conjugates with different surfactants and to investigate sub-cellular distribution of the nanotube conjugates, respectively. Experimental results demonstrate that cytotoxicity of the nanotube/surfactant conjugates is related to the toxicity of surfactant molecules attached on the nanotube surfaces. Both sodium dodecyl sulfate (SDS) and sodium dodecylbenzene sulfonate (SDBS) are toxic to cells. Exposure to CNT/SDS conjugates (0.5 mg/mL) for less than 5 min caused changes in cell morphology resulting in a distinctly spherical shape compared to untreated cells. In contrast, sodium cholate (SC) and CNT/SC did not affect cell morphology, proliferation, or growth. These data indicate that SC is an environmentally friendly surfactant for the purification and dispersion of SWCNTs. Epifluorescence microscopy analysis of CNT/DNA conjugates revealed distribution in the cytoplasm of cells and did not show adverse effects on cell morphology, proliferation, or viability during a 72-h incubation. These observations suggest that the SWCNTs could be used as non-viral vectors for diagnostic and therapeutic molecules across the blood-brain barrier to the brain and the central nervous system.