Association of reviewer experience with discriminating human-written versus ChatGPT-written abstracts.

OBJECTIVE: To determine if reviewer experience impacts the ability to discriminate between human-written and ChatGPT-written abstracts. METHODS: Thirty reviewers (10 seniors, 10 juniors, and 10 residents) were asked to differentiate between 10 ChatGPT-written and 10 human-written (fabricated) abstracts. For the study, 10 gynecologic oncology abstracts were fabricated by the authors. For each human-written abstract we generated a ChatGPT matching abstract by using the same title and the fabricated results of each of the human generated abstracts. A web-based questionnaire was used to gather demographic data and to record the reviewers' evaluation of the 20 abstracts. Comparative statistics and multivariable regression were used to identify factors associated with a higher correct identification rate. RESULTS: The 30 reviewers discriminated 20 abstracts, giving a total of 600 abstract evaluations. The reviewers were able to correctly identify 300/600 (50%) of the abstracts: 139/300 (46.3%) of the ChatGPT-generated abstracts and 161/300 (53.7%) of the human-written abstracts (p=0.07). Human-written abstracts had a higher rate of correct identification (median (IQR) 56.7% (49.2-64.1%) vs 45.0% (43.2-48.3%), p=0.023). Senior reviewers had a higher correct identification rate (60%) than junior reviewers and residents (45% each; p=0.043 and p=0.002, respectively). In a linear regression model including the experience level of the reviewers, familiarity with artificial intelligence (AI) and the country in which the majority of medical training was achieved (English speaking vs non-English speaking), the experience of the reviewer (ß=10.2 (95% CI 1.8 to 18.7)) and familiarity with AI (ß=7.78 (95% CI 0.6 to 15.0)) were independently associated with the correct identification rate (p=0.019 and p=0.035, respectively). In a correlation analysis the number of publications by the reviewer was positively correlated with the correct identification rate (r28)=0.61, p<0.001. CONCLUSION: A total of 46.3% of abstracts written by ChatGPT were detected by reviewers. The correct identification rate increased with reviewer and publication experience.

Robotic surgery in gynecologic oncology - a bibliometric study.

STUDY OBJECTIVE: To characterize robotic surgery publications in gynecologic oncology, and to identify factors associated with high citation metrics. DESIGN: A cross-sectional study SETTING: Original articles on robotic surgery in gynecologic oncology. PATIENTS: No patients involved. INTERVENTIONS: Robotic surgeries in gynecologic oncology. MEASUREMENTS AND MAIN RESULTS: We performed PubMed MeSH search for original articles on robotic surgery in gynecologic oncology. We analyzed citation scores and income level of country of publication, as well as factors associated with high citation metrics. Overall, 566 studies during 2005 - 2023 were included. Of those 292, 51.6% were from North America and 182 32.2% from Europe. The leading tumor site studied was endometrial cancer (57.4%). The majority (87.6%) of studies were retrospective and 13 (2.3%) were randomized controlled trials. Most studies (94.2%) originated in high-income countries. Articles from middle-income countries had lower citations per year as compared to high-income countries (median 1.6 vs. 2.5, p=.002) and were published in lower impact factor journals (median 2.6 vs. 4.3, p<.001) when compared with high-income countries. Cervical cancer studies had higher representation in middle-income countries than in high income countries (48.5% vs. 18.4%, p<.001). In a multivariable regression analysis, journal's impact factor [aOR 95% CI 1.26 (1.12-1.40)], cervical cancer topic [aOR 95% CI 3.0 (1.58-5.91)] and North American publications [aOR 95% CI 2.07 (1.08-3.97)] were independently associated with higher number of citations per year. CONCLUSION: The majority of robotic surgery research in gynecologic oncology is retrospective and from high-income countries. Middle-income countries are not as frequently cited and are predominantly in lower impact factor journals.

Correlation of surgeon radiology assessment with laparoscopic disease site scoring in patients with advanced ovarian cancer.

BACKGROUND: Radiographic triage measures in patients with new advanced ovarian cancer have yielded inconsistent results. OBJECTIVE: To determine the correlation between surgeon radiology assessment and laparoscopic scoring by disease sites in patients with newly diagnosed advanced stage ovarian cancer. METHODS: Fourteen gynecologic oncology surgeons from a single institution performed a blinded review of pre-operative contrast-enhanced CT imaging from patients with advanced stage ovarian cancer. Each of the patients had also undergone laparoscopic scoring assessment, between April 2013 and December 2017, to determine primary resectability using the validated Fagotti scoring method, and assigned a predictive index value score. Surgeons were asked to provide expected predictive index value scores based on their blinded review of the antecedent CT imaging. Linear mixed models were conducted to calculate the correlation between radiologic and laparoscopic score for surgeons individually, and as a group. Once the model was fit, the inter-class correlation and 95% CI were calculated. RESULTS: Radiology review was performed on 20 patients with advanced stage ovarian cancer who underwent laparoscopic scoring assessment. Surgeon faculty rank included assistant professor (n=5), associate professor (p=4), and professor (n=5). The kappa inter-rater agreement was -0.017 (95% CI -0.023 to -0.005), indicating low inter-rater agreement between radiology review and actual laparoscopic score. The inter-class correlation in this model was 0.06 (0.02-0.21), indicating that surgeons do not score the same across all the images. When using a clinical cut-off point for the predictive index value of 8, the probability of agreement between radiology and actual laparoscopic score was 0.56 (95% CI 0.49 to 0.73). Examination of disease site sub-scales showed that the probability of agreement was as follows: peritoneum 0.57 (95% CI 0.51 to 0.62), diaphragm 0.54 (95% CI 0.48 to 0.60), mesentery 0.51 (95% CI 0.45 to 0.57), omentum 0.61 (95% CI 0.55 to 0.67), bowel 0.54 (95% CI 0.44 to 0.64), stomach 0.71 (95% CI 0.65 to 0.76), and liver 0.36 (95% CI 0.31 to 0.42). The number of laparoscopic scoring cases, tumor reductive surgery cases, or faculty rank was not significantly associated with overall or sub-scale agreement. CONCLUSIONS: Surgeon radiology review did not correlate highly with actual laparoscopic scoring assessment findings in patients with advanced stage ovarian cancer. Our study highlights the limited accuracy of surgeon radiographic assessment to determine resectability.

Platelets increase the proliferation of ovarian cancer cells.

Platelets promote metastasis and angiogenesis, but their effect on tumor cell growth is uncertain. Here we report a direct proliferative effect of platelets on cancer cells both in vitro and in vivo. Incubation of platelets with ovarian cancer cells from murine (ID8 and 2C6) or human (SKOV3 and OVCAR5) origin increased cell proliferation. The proliferative effect of platelets was not dependent on direct contact with cancer cells, and preincubation of platelets with blocking antibodies against platelet adhesion molecules did not alter their effect on cancer cells. The proliferative effect of platelets was reduced by fixing platelets with paraformaldehyde, preincubating platelets with a TGF-ß1-blocking antibody, or reducing expression of TGF-ßR1 receptor on cancer cells with siRNA. Infusing platelets into mice with orthotopic ovarian tumors significantly increased the proliferation indices in these tumors. Ovarian cancer patients with thrombocytosis had higher tumor proliferation indices compared with patients with normal platelet counts.

Epigenetic analysis of the Notch superfamily in high-grade serous ovarian cancer.

OBJECTIVES: Gene methylation and other epigenetic modifications of gene regulation have been implicated in the growth of ovarian cancer, but the clinical significance of such modifications in the Notch pathway in high-grade serous ovarian cancer (HGS-OvCa) is not well understood. We used The Cancer Genome Atlas (TCGA) data to study the clinical relevance of epigenetic modifications of Notch superfamily genes. METHODS: We analyzed the interaction of DNA methylation and miRNAs with gene expression data for Notch superfamily members with the Spearman rank correlation test and explored potential relationships with overall survival (OS) with the log-rank test. We downloaded clinical data, level 3 gene expression data, and level 3 DNA methylation data for 480 patients with stage II-IV HGS-OvCa from the TCGA data portal. Patients were randomly divided into training and validation cohorts for survival analyses. In each set, patients were grouped into percentiles according to methylation and microRNA (miRNA) or messenger RNA (mRNA) levels. We used several algorithms to predict miRNA-mRNA interaction. RESULTS: There were significant inverse relationships between methylation status and mRNA expression for PPARG, CCND1, and RUNX1. For each of these genes, patients with a lower methylation level and higher expression level had significantly poorer OS than did patients with a higher methylation level and lower expression level. We also found a significant inverse relationship between miRNAs and mRNA expression for CCND1, PPARG, and RUNX1. By further analyzing the effect of miRNAs on gene expression and OS, we found that patients with higher levels of CCND1, PPARG, and RUNX1 expression and lower expression levels of their respective miRNAs (502-5p, 128, and 215/625) had significantly poorer OS. CONCLUSIONS: Epigenetic alterations of multiple Notch target genes and pathway interacting genes (PPARG, CCND1, and RUNX1) may relate to activation of this pathway and poor survival of patients with HGS-OvCa.

Risk factors for prolonged hospitalization after gynecologic laparoscopic surgery.

OBJECTIVE: To determine perioperative risk factors for prolonged hospitalization after gynecologic laparoscopic surgery. METHODS: Data on patients who underwent gynecologic laparoscopic surgery at a single academic institution from January 2000 to January 2009 were evaluated. Patient demographics, clinical history, intraoperative data, and postoperative adverse events were analyzed. Logistic regression analysis identified significant predictors of prolonged hospitalization (hospital stay>48 h after surgery). A risk score was created from the analysis to predict prolonged hospitalization. RESULTS: Eight hundred seven patients were included. The median body mass index was 26.5 kg/m(2) (range, 14.2-72.3 kg/m(2)), and the median age was 49 years (range, 12-88 years). Four hundred fifty-nine patients (56.9%) underwent surgery for benign conditions, and 348 (43.1%) underwent surgery for malignant disease. A total of 78 patients (9.7%) had a prolonged hospitalization. Independent predictors of prolonged hospitalization were age>54 years (P<0.0001), operative blood loss>120 mL (P<0.0001), intraoperative or postoperative blood transfusion (P=0.0237), and early postoperative complication (P<0.0001). Having a prior laparoscopy was associated with a shorter hospital stay (P=0.0276). The risk score showed how changes in perioperative factors change the risk of prolonged hospitalization. CONCLUSION: Factors such as age, blood loss, perioperative blood transfusion, and postoperative complications are associated with prolonged length of stay after laparoscopic surgery, while having a prior laparoscopy is associated with a shorter hospital stay. A clinical scoring system can be used to estimate probability of prolonged hospitalization after gynecologic laparoscopic surgery.

Rate of para-aortic lymph node micrometastasis in patients with locally advanced cervical cancer.

OBJECTIVE: Patients with micrometastasis to para-aortic lymph nodes may benefit from extended field chemoradiation. To determine the rate of para-aortic node micrometastasis in patients with locally advanced cervical cancer undergoing laparoscopic extraperitoneal para-aortic lymphadenectomy. METHODS: We prospectively identified consecutive patients diagnosed with stage IB2-IVA biopsy-proven cervical cancer. Eligible patients included those who were candidates for treatment with radiotherapy and concurrent chemotherapy and had no evidence of para-aortic lymphadenopathy (all lymph nodes< 2 cm in diameter) by preoperative computed tomography or magnetic resonance imaging. All patients underwent preoperative positron emission tomography/computed tomography and laparoscopic extraperitoneal para-aortic lymphadenectomy. All lymph nodes were assessed for metastasis by routine hematoxylin-eosin (H&E) staining. Ultrastaging (serial sectioning) and immunohistochemical analysis were performed in H&E-negative specimens. RESULTS: Thirteen (22%) of 60 consecutive patients had para-aortic lymph node metastases detected on routine H&E staining. Of the remaining 47 patients, one (2.1%) had evidence of micrometastasis, which was detected by ultrastaging. This patient completed whole pelvic radiotherapy and chemotherapy but had a recurrence 27 months after completion of therapy. CONCLUSIONS: The rate of para-aortic node micrometastasis in patients with locally advanced cervical cancer is low. The role of routine ultrastaging and immunohistochemical analysis in such patients remains uncertain. Future studies are needed to determine the clinical impact of para-aortic node micrometastasis in patients with locally advanced cervical cancer.

Blockade of the Short Form of Prolactin Receptor Induces FOXO3a/EIF-4EBP1-Mediated Cell Death in Uterine Cancer.

Abnormal activity of human prolactin (PRL) and its membrane-associated receptor (PRLR) contributes to the progression of uterine carcinoma. However, the underlying mechanisms are not well understood, and current means of targeting the PRL/PRLR axis in uterine cancer are limited. Our integrated analyses using The Cancer Genome Atlas and Genotype-Tissue Expression (GTEx) databases demonstrated that a short form of PRLR (PRLR_SF) is the isoform predominantly expressed in human uterine cancers; expression of this PRLR_SF was elevated in uterine cancers in comparison with cancer-free uterine tissues. We hypothesized that the overexpression of PRLR_SF in uterine cancer cells contributes, in part, to the oncogenic activity of the PRL/PRLR axis. Next, we employed G129R, an antagonist of human PRL, to block the PRL/PRLR axis in both PTEN wt and PTEN mut orthotopic mouse models of uterine cancer. In comparison with control groups, treatment with G129R as monotherapy or in combination with paclitaxel resulted in a significant reduction of growth and progression of orthotopic uterine tumors. Results from protein profiling of uterine cancer cells and in vivo tumors revealed a set of new downstream targets for G129R. Our results showed that G129R induced sub-G0 population arrest, decreased nascent protein synthesis, and initiated FOXO3a/EIF-4EBP1-mediated cell death in both PTEN wt and PTEN mut uterine cancer cells. Collectively, our results show a unique pattern of PRLR_SF expression predominantly in uterine cancer. Moreover, FOXO3a and EIF-4EBP1 are important mediators of cell death following G129R treatment in uterine cancer models.

Author Correction: Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction.

Mounting clinical and preclinical evidence supports a key role for sustained adrenergic signaling in the tumor microenvironment as a driver of tumor growth and progression. However, the mechanisms by which adrenergic neurotransmitters are delivered to the tumor microenvironment are not well understood. Here we present evidence for a feed-forward loop whereby adrenergic signaling leads to increased tumoral innervation. In response to catecholamines, tumor cells produced brain-derived neurotrophic factor (BDNF) in an ADRB3/cAMP/Epac/JNK-dependent manner. Elevated BDNF levels in the tumor microenvironment increased innervation by signaling through host neurotrophic receptor tyrosine kinase 2 receptors. In patients with cancer, high tumor nerve counts were significantly associated with increased BDNF and norepinephrine levels and decreased overall survival. Collectively, these data describe a novel pathway for tumor innervation, with resultant biological and clinical implications.Significance: Sustained adrenergic signaling promotes tumor growth and metastasis through BDNF-mediated tumoral innervation. Cancer Res; 78(12); 3233-42. ©2018 AACR.

SSRI use and clinical outcomes in epithelial ovarian cancer.

Selective serotonin reuptake inhibitor (SSRI) use is common among ovarian cancer patients. We examined the effect of SSRIs on survival and progression in ovarian cancer patients and effects of 5-HT on ovarian cancer cell (OCC) proliferation. Ovarian cancer patients from a 6-site study between 1994 and 2010 were included. Cox proportional hazards models were used for multivariate analysis. SSRI use was associated with decreased time to disease recurrence (HR 1.3, CI 1.0-1.6, p=0.03), but not overall survival (HR 1.1, CI 0.9-1.3, p=0.56). Compared to normal ovarian cells, most OCCs had elevated 5-HT2A receptor mRNA expression (up to 1600 fold greater expression). Clonogenic survival increased in cells treated with 10 uM (1.6 fold, p<0.001) and 20uM (1.9 fold, p=0.018) 5-HT. Mice receiving 5-HT injections had increases in tumor weight (p=0.07) and nodules (p=0.08) with increased Ki67 expression. Injections with sertraline doubled mean tumor weight in mice (p=0.16). 5-HT and sertraline both increased Ki67 expression in mouse tumors (p < 0.001).Patients using SSRIs had significantly decreased time to disease progression. It is possible that SSRIs alter serotonin levels in the tumor microenvironment, resulting in activation of proliferation pathways. Further characterization of serotonergic pathways in ovarian cancer is recommended to demonstrate safety of these medications.

FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal.

Recent studies in patients with ovarian cancer suggest that tumor growth may be accelerated following cessation of antiangiogenesis therapy; however, the underlying mechanisms are not well understood. In this study, we aimed to compare the effects of therapy withdrawal to those of continuous treatment with various antiangiogenic agents. Cessation of therapy with pazopanib, bevacizumab, and the human and murine anti-VEGF antibody B20 was associated with substantial tumor growth in mouse models of ovarian cancer. Increased tumor growth was accompanied by tumor hypoxia, increased tumor angiogenesis, and vascular leakage. Moreover, we found hypoxia-induced ADP production and platelet infiltration into tumors after withdrawal of antiangiogenic therapy, and lowering platelet counts markedly inhibited tumor rebound after withdrawal of antiangiogenic therapy. Focal adhesion kinase (FAK) in platelets regulated their migration into the tumor microenvironment, and FAK-deficient platelets completely prevented the rebound tumor growth. Additionally, combined therapy with a FAK inhibitor and the antiangiogenic agents pazopanib and bevacizumab reduced tumor growth and inhibited negative effects following withdrawal of antiangiogenic therapy. In summary, these results suggest that FAK may be a unique target in situations in which antiangiogenic agents are withdrawn, and dual targeting of FAK and VEGF could have therapeutic implications for ovarian cancer management.

Role of Increased n-acetylaspartate Levels in Cancer.

BACKGROUND: The clinical and biological effects of metabolic alterations in cancer are not fully understood. METHODS: In high-grade serous ovarian cancer (HGSOC) samples (n = 101), over 170 metabolites were profiled and compared with normal ovarian tissues (n = 15). To determine NAT8L gene expression across different cancer types, we analyzed the RNA expression of cancer types using RNASeqV2 data available from the open access The Cancer Genome Atlas (TCGA) website (http://www.cbioportal.org/public-portal/). Using NAT8L siRNA, molecular techniques and histological analysis, we determined cancer cell viability, proliferation, apoptosis, and tumor growth in in vitro and in vivo (n = 6-10 mice/group) settings. Data were analyzed with the Student's t test and Kaplan-Meier analysis. Statistical tests were two-sided. RESULTS: Patients with high levels of tumoral NAA and its biosynthetic enzyme, aspartate N-acetyltransferase (NAT8L), had worse overall survival than patients with low levels of NAA and NAT8L. The overall survival duration of patients with higher-than-median NAA levels (3.6 years) was lower than that of patients with lower-than-median NAA levels (5.1 years, P = .03). High NAT8L gene expression in other cancers (melanoma, renal cell, breast, colon, and uterine cancers) was associated with worse overall survival. NAT8L silencing reduced cancer cell viability (HEYA8: control siRNA 90.61% ± 2.53, NAT8L siRNA 39.43% ± 3.00, P < .001; A2780: control siRNA 90.59% ± 2.53, NAT8L siRNA 7.44% ± 1.71, P < .001) and proliferation (HEYA8: control siRNA 74.83% ± 0.92, NAT8L siRNA 55.70% ± 1.54, P < .001; A2780: control siRNA 50.17% ± 4.13, NAT8L siRNA 26.52% ± 3.70, P < .001), which was rescued by addition of NAA. In orthotopic mouse models (ovarian cancer and melanoma), NAT8L silencing reduced tumor growth statistically significantly (A2780: control siRNA 0.52 g ± 0.15, NAT8L siRNA 0.08 g ± 0.17, P < .001; HEYA8: control siRNA 0.79 g ± 0.42, NAT8L siRNA 0.24 g ± 0.18, P = .008, A375-SM: control siRNA 0.55 g ± 0.22, NAT8L siRNA 0.21 g ± 0.17 g, P = .001). NAT8L silencing downregulated the anti-apoptotic pathway, which was mediated through FOXM1. CONCLUSION: These findings indicate that the NAA pathway has a prominent role in promoting tumor growth and represents a valuable target for anticancer therapy.Altered energy metabolism is a hallmark of cancer (1). Proliferating cancer cells have much greater metabolic requirements than nonproliferating differentiated cells (2,3). Moreover, altered cancer metabolism elevates unique metabolic intermediates, which can promote cancer survival and progression (4,5). Furthermore, emerging evidence suggests that proliferating cancer cells exploit alternative metabolic pathways to meet their high demand for energy and to accumulate biomass (6-8).

Differential platelet levels affect response to taxane-based therapy in ovarian cancer.

PURPOSE: We hypothesized that platelet levels during therapy could serve as a biomarker for response to therapy and that manipulation of platelet levels could impact responsiveness to chemotherapy. EXPERIMENTAL DESIGN: The medical records of patients with recurrent or progressive ovarian cancer were retrospectively queried for changes in platelet and CA-125 levels during primary therapy. In vitro coculture experiments and in vivo orthotopic models of human ovarian cancer in mice were used to test the effect of modulating platelet levels on tumor growth and responsiveness to docetaxel. RESULTS: Thrombocytosis at the diagnosis of ovarian cancer was correlated with decreased interval to progression (P = 0.05) and median overall survival (P = 0.007). Mean platelet levels corrected during primary therapy and rose at recurrence. Contrary to treatment-responsive patients, in a cohort of patients refractory to primary therapy, platelet levels did not normalize during therapy. In A2780, HeyA8, and SKOV3-ip1 ovarian cancer cell lines, platelet coculture protected against apoptosis (P < 0.05). In orthotopic models of human ovarian cancer, platelet depletion resulted in 70% reduced mean tumor weight (P < 0.05). Compared with mice treated with docetaxel, mice treated with both docetaxel and platelet-depleting antibody had a 62% decrease in mean tumor weight (P = 0.04). Platelet transfusion increased mean aggregate tumor weight 2.4-fold (P < 0.05), blocked the effect of docetaxel on tumor growth (P = 0.55) and decreased tumor cell apoptosis. Pretransfusion aspirinization of the platelets blocked the growth-promoting effects of transfusion. CONCLUSIONS: Platelet-driven effects of chemotherapy response may explain clinical observations.

Immunotherapy targeting folate receptor induces cell death associated with autophagy in ovarian cancer.

PURPOSE: Cancer cells are highly dependent on folate metabolism, making them susceptible to drugs that inhibit folate receptor activities. Targeting overexpressed folate receptor alpha (FRα) in cancer cells offers a therapeutic opportunity. We investigated the functional mechanisms of MORAB-003 (farletuzumab), a humanized mAb against FRα, in ovarian cancer models. EXPERIMENTAL DESIGN: We first examined FRα expression in an array of human ovarian cancer cell lines and then assessed the in vivo effect of MORAB-003 on tumor growth and progression in several orthotopic mouse models of ovarian cancer derived from these cell lines. Molecular mechanisms of tumor cell death induced by MORAB-003 were investigated by cDNA and protein expression profiling analysis. Mechanistic studies were performed to determine the role of autophagy in MORAB-003-induced cell death. RESULTS: MORAB-003 significantly decreased tumor growth in the high-FRα IGROV1 and SKOV3ip1 models but not in the low-FRα A2780 model. MORAB-003 reduced proliferation, but had no significant effect on apoptosis. Protein expression and cDNA microarray analyses showed that MORAB-003 regulated an array of autophagy-related genes. It also significantly increased expression of LC3 isoform II and enriched autophagic vacuolization. Blocking autophagy with hydroxychloroquine or bafilomycin A1 reversed the growth inhibition induced by MORAB-003. In addition, alteration of FOLR1 gene copy number significantly correlated with shorter disease-free survival in patients with ovarian serous cancer. CONCLUSIONS: MORAB-003 displays prominent antitumor activity in ovarian cancer models expressing FRα at high levels. Blockade of folate receptor by MORAB-003 induced sustained autophagy and suppressed cell proliferation.

XPO1/CRM1 Inhibition Causes Antitumor Effects by Mitochondrial Accumulation of eIF5A.

PURPOSE: XPO1 inhibitors have shown promise for cancer treatment, and yet the underlying mechanisms for the antitumor effects are not well understood. In this study, we explored the usefulness of selective inhibitors of nuclear export (SINE) compounds that are specific inhibitors of XPO1. EXPERIMENTAL DESIGN: We used proteomic analysis in XPO1 inhibitor-treated ovarian cancer cell lines and examined antitumor effects in ovarian and breast cancer mouse models. We also studied the effects of XPO1 inhibitor in combination with chemotherapeutic agents. RESULTS: XPO1 inhibitor treatment substantially increased the percentage of apoptotic cells (60%) after 72 hours of incubation. XPO1 inhibitor promoted the accumulation of eIF5A in mitochondria, leading to cancer cell death. Topotecan showed the greatest synergistic effect with XPO1 inhibitor. XPO1 inhibitors prevented the translocation of IGF2BP1 from the nucleus to the cytoplasm, thereby permitting the localization of eIF5A in the mitochondria. This process was p53, RB, and FOXO independent. Significant antitumor effects were observed with XPO1 inhibitor monotherapy in orthotopic ovarian (P < 0.001) and breast (P < 0.001) cancer mouse models, with a further decrease in tumor burden observed in combination with topotecan or paclitaxel (P < 0.05). This mitochondrial accumulation of eIF5A was highly dependent on the cytoplasmic IGF2BP1 levels. CONCLUSIONS: We have unveiled a new understanding of the role of eIF5A and IGF2BP1 in XPO1 inhibitor-mediated cell death and support their clinical development for the treatment of ovarian and other cancers. Our data also ascertain the combinations of XPO1 inhibitors with specific chemotherapy drugs for therapeutic trials.

Erythropoietin Stimulates Tumor Growth via EphB4.

While recombinant human erythropoietin (rhEpo) has been widely used to treat anemia in cancer patients, concerns about its adverse effects on patient survival have emerged. A lack of correlation between expression of the canonical EpoR and rhEpo's effects on cancer cells prompted us to consider the existence of an alternative Epo receptor. Here, we identified EphB4 as an Epo receptor that triggers downstream signaling via STAT3 and promotes rhEpo-induced tumor growth and progression. In human ovarian and breast cancer samples, expression of EphB4 rather than the canonical EpoR correlated with decreased disease-specific survival in rhEpo-treated patients. These results identify EphB4 as a critical mediator of erythropoietin-induced tumor progression and further provide clinically significant dimension to the biology of erythropoietin.

Biologic effects of platelet-derived growth factor receptor α blockade in uterine cancer.

PURPOSE: Platelet-derived growth factor receptor α (PDGFRα) expression is frequently observed in many kinds of cancer and is a candidate for therapeutic targeting. This preclinical study evaluated the biologic significance of PDGFRα and PDGFRα blockade (using a fully humanized monoclonal antibody, 3G3) in uterine cancer. EXPERIMENTAL DESIGN: Expression of PDGFRα was examined in uterine cancer clinical samples and cell lines, and biologic effects of PDGFRα inhibition were evaluated using in vitro (cell viability, apoptosis, and invasion) and in vivo (orthotopic) models of uterine cancer. RESULTS: PDGFRα was highly expressed and activated in uterine cancer samples and cell lines. Treatment with 3G3 resulted in substantial inhibition of PDGFRα phosphorylation and of downstream signaling molecules AKT and mitogen-activated protein kinase (MAPK). Cell viability and invasive potential of uterine cancer cells were also inhibited by 3G3 treatment. In orthotopic mouse models of uterine cancer, 3G3 monotherapy had significant antitumor effects in the PDGFRα-positive models (Hec-1A, Ishikawa, Spec-2) but not in the PDGFRα-negative model (OVCA432). Greater therapeutic effects were observed for 3G3 in combination with chemotherapy than for either drug alone in the PDGFRα-positive models. The antitumor effects of therapy were related to increased apoptosis and decreased proliferation and angiogenesis. CONCLUSIONS: These findings identify PDGFRα as an attractive target for therapeutic development in uterine cancer.