Research Symposium Research Articles

Abstract DP-013: DEVELOPMENT AND VALIDATION OF CIRCULATING CA125 PREDICTION MODEL IN POSTMENOPAUSAL WOMEN WITHOUT OVARIAN CANCER

Abstract BACKGROUND: Cancer antigen 125 (CA125) is a membrane bound glycosylated mucin which has been reported to be the most promising biomarker for ovarian cancer screening. However, results from two large randomized trials comparing screening with CA125 and transvaginal ultrasound to usual care have shown no clinically significant difference in ovarian cancer mortality. A major limitation of CA125 as an ovarian cancer screening biomarker has been low specificity and variation between individuals by personal characteristics. Identifying personal characteristics that influence CA125 levels could be used to create personalized thresholds for CA125 thereby improving its performance as an ovarian cancer screening biomarker. We developed and conducted internal and external validation of two prediction models (linear and dichotomous) of circulating CA125 among postmenopausal women using 28,842 controls without ovarian cancer in four large population-based studies. METHODS: We identified controls from three prospective cohort studies, including Prostate, Lung, Colorectal, and Ovarian (PLCO, n=26,981), European Prospective Investigation into Cancer and Nutrition (EPIC, n=861), and the Nurses' Health Studies (NHS, n=164) as well as one population-based case-control study, the New England Case Control Study (NEC, n=1,000). CA125 was measured using the CA125II assay in PLCO, NHS, and NEC. Meso Scale Discovery (MSD) platform was used to measure CA125 in EPIC. The MSD assay values were recalibrated to the CA125II scale based on 534 NEC controls with both measurements. CA125 levels were log-transformed to achieve normal distribution or dichotomized by the upper limit of normal (35 U/ml). The prediction models were developed and internally validated using postmenopausal controls in PLCO, and then were externally validated using postmenopausal controls in EPIC, NHS and NEC. The prediction models were developed using stepwise linear or logistic regression with <0.15 as significance level for entry and retention considering factors which have been previously reported to be associated CA125 in postmenopausal women as candidate predictors (age, race, body-mass index (BMI), smoking status and duration, age at menarche, oral contraceptive use, party, age at menopause, time since menopause, hormone replacement therapy (HRT) use and duration, family history of ovarian or breast cancer, previous history of cancer, previous history of benign ovarian cyst, history of endometriosis). We then evaluated the performance of the model in the independent validation datasets. RESULTS: The linear CA125 prediction model included age, race, BMI, smoking status and duration, hysterectomy, parity, age at menopause, and duration of HRT use as predictors, explaining 5% of the variability of log-transformed CA125 levels. The correlation coefficient of the measured and predicted log-transformed CA125 was 0.18 in the PLCO testing dataset, and showed comparable correlations across the independent validation datasets (0.14-0.16). The dichotomous CA125 prediction model included age, race, BMI, duration of HRT use, and hysterectomy as predictors with an AUC of 0.63 in the PLCO testing dataset and 0.71 in NEC. CONCLUSION: We developed linear and dichotomous circulating CA125 prediction models in postmenopausal women that can form the foundation for creating personalized thresholds of CA125. However, other factors should be considered to increase the predictive capacity of the model. Citation Format: Naoko Sasamoto, Ana Babic, Bernard A. Rosner, Renée T. Fortner, Allison F. Vitonis, Hidemi Yamamoto, Raina N. Fichorova, Daniel W. Cramer, Rudolf Kaaks, Shelley S. Tworoger, Kathryn L. Terry. DEVELOPMENT AND VALIDATION OF CIRCULATING CA125 PREDICTION MODEL IN POSTMENOPAUSAL WOMEN WITHOUT OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr DP-013.

Abstract NT-112: APTAMER CONJUGATED NANOPARTICLES FOR TARGETED DRUG DELIVERY

Abstract Targeted Delivery of therapeutic drugs and imaging agents, using nanoparticles, shows great promise in diverse fields, including the diagnostics and treatment of cancer. Monoclonal antibodies (mAbs) that have been traditionally used for detecting specific proteins can also be used as targeting moieties. However, due to their intrinsic characteristics such as immunogenicity, batch-to-batch variation and instability, antibodies have several limitations for in vivo applications. Nucleic acid based aptamers are emerging as attractive alternatives for mAbs. We have developed single-stranded DNA aptamers, which can specifically recognize and bind to ovarian cancer endothelial cells. Using mass-spectroscopy based proteomics, we have identified Annexin A2 as the protein target for the selected aptamers. These aptamers can act as homing devices to deliver therapeutic drugs and/or imaging agents specifically to ovarian cancer cells. Using a highly stable, three-way junction (3WJ) motif from the phi29 packaging RNA as a scaffold, we made a multi-functional RNA nanoparticle that can harbor therapeutic drugs, imaging agent, siRNA and the targeting ligand. The aptamer-containing multi-functional RNA nanoparticle is used to deliver Doxorubicin to Annexin A2 positive ovarian cancer cells, while the control nanoparticles failed to deliver. After systemic injection in mice, the DNA/RNA hybrid nanoparticles remained intact and strongly bound to tumors with little accumulation in healthy organs 6 hour post-injection. The aptamer-3WJ-Sph1/Dox intercalates selectively enhanced toxicity to Annexin A2 positive ovarian cancer cells in vitro, demonstrating the potential of the constructed DNA/RNA hybrid nanoparticles to enhance the therapeutic efficiency of Doxorubicin at low doses for ovarian cancer treatment. The use of the aptamer-3WJ RNA nanoparticle will benefit ovarian cancer patients by reducing the side effects of cancer chemo-therapeutics and increasing its local concentration in the tumor microenvironment after systemic administration. Our ultimate goal is the development of patient-optimized aptamer-nanoparticle delivery systems for chemotherapy and molecular diagnostics imaging. Citation Format: Varatharasa Thiviyanathan, Fengmei Pi, Hui Zhang, Hui Li , Hongyu Wang, Peixuan Guo, Anil Sood. APTAMER CONJUGATED NANOPARTICLES FOR TARGETED DRUG DELIVERY [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-112.

Abstract NT-093: THE N6-METHYLATION OF ADENOSINE (M6A) IN FZD10 MRNA CONTRIBUTES TO RESISTANCE TO PARP INHIBITOR

Abstract Chemical modifications of RNAs have emerged as a new layer of epigenetic gene regulation. N6-methyladenosine (m6A) is the most abundant chemical modification of messenger RNA. The m6A modification affects RNA fate and functions such as RNA stability. Despite the high initial clinical response rates to PARP inhibitors in BRCA1/2-mutated epithelial ovarian cancers, PARP inhibitor (PARPi) resistance remains a major challenge. The role of m6A modification in PARPi resistance has not previously been explored. Here we show that m6A modification of FZD10 mRNA contributes to PARPi resistance by upregulating the Wnt/β-catenin pathway in BRCA-mutated EOC cells. Global m6A profile reveals a significant increase in m6A modification in FZD10 mRNA. This correlates with an increase in FZD10 mRNA stability and an upregulation of the Wnt/β-catenin pathway in PARPi resistant cells. FZD10 knockdown or inhibition of the Wnt/β-catenin sensitizes the resistant cells to PAPRi. Mechanistically, downregulation of m6A demethylases FTO and ALKBH5 is sufficient to increase FZD10 mRNA m6A modification and reduce PARPi sensitivity. Moreover, PAPRi and Wnt/β-catenin inhibitor showed synergistic suppression of growth of PAPRi resistant cancer both in vitro and in vivo in a xenograft ovarian cancer mouse model. Our results show that m6A contributes to PAPRi resistance in BRCA-deficient EOC cells by upregulating the Wnt/β-catenin pathway through stabilizing FZD10. They also suggest that inhibition of Wnt/β-catenin pathway represents a potential strategy to overcome PARPi resistance. Citation Format: Takeshi Fukumoto, Hengrui Zhu, Sergey Karakashev, Timothy Nacarelli, Nail Fatkhutdinov, Shuai Wu, Andrew V. Kossenkov, Louise Showe, Stephanie Jean, Lin Zhang, Rugang Zhang. THE N6-METHYLATION OF ADENOSINE (M6A) IN FZD10 MRNA CONTRIBUTES TO RESISTANCE TO PARP INHIBITOR [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-093.

Abstract GMM-046: CCNE1 AND BRD4 EXPRESSION AND PLATINUM RESISTANCE IN HIGH-GRADE SEROUS OVARIAN CANCERS

Abstract BACKGROUND: Epithelial ovarian cancer (EOC) is the deadliest gynecologic cancer and the fifth leading cause of cancer deaths among women in the United States. An even poorer prognostic type of EOC is BRCA wild-type CCNE1 (cyclin E) amplified/gain tumors. This subtype of EOC is characterized by unchecked replication, high levels of genomic instability, and replicative stress. CCNE1 amplified EOC is mutually exclusive to BRCA mutated EOC in part because CCNE1 amplified cells require functional BRCA for survival. Bromodomain and extraterminal 4 (BRD4) amplified ovarian cancer is a recently discovered subtype of BRCA wild-type EOC, and is also associated with poor outcomes. OBJECTIVE: To determine if mRNA and immunohistochemical (IHC) profiles of CCNE1 and BRD4 are associated with platinum sensitivity in serous ovarian cancers. METHODS: Copy number analysis data was extracted from The Cancer Genome Atlas (TCGA) for high-grade serous ovarian tumors with BRD4 and CCNE1 (cyclin E) amplification. (www.cbioportal.org). Immunostaining for cyclin E and BRD4 was performed in 130 serous ovarian tumors on a tissue microarray (TMA) IHC in 130 clinically annotated formalin-fixed paraffin-embedded serous tumors from Vanderbilt University Medical Center (VUMC). Staining intensity (1: weak; 2: moderate; 3: strong) and percent of positive nuclei (0-100) were multiplied to yield an H score for NR4A1 expression. Pearson correlation coefficients were determined for mRNA expression of cyclin E and BRD4 in 307 TCGA tumors (RSEM V2 data extracted from the Broad Firehose database) and protein expression of cyclin E and BRD4 in 130 serous ovarian tumors. CCNE1 and BRD4 expression in relation to platinum sensitivity were evaluated using the Mann-Whitney t test. RESULTS: The Cancer Genome Atlas (TCGA) demonstrated about 20% of high-grade serous EOC harbor amplifications in CCNE1 and BRD4. BRD4 amplification overlaps with CCNE1 amplification in 26/57 (46%) of high-grade serous EOC of the TCGA. Immunostaining for cyclin E and BRD4 in 130 serous ovarian tumors on a tissue microarray yielded intermediate-to-high staining of CCNE1 in 52.1% of tumors and intermediate-to-high staining of BRD4 in 71.6% of tumors. Protein expression by IHC between CCNE1 and BRD4 was positively correlated, r= 0.25, (p =0.005). High expression of CCNE1 was associated with platinum resistance (p = 0.023). High BRD4 expression was not associated with platinum resistance (p=0.95). CONCLUSION: TCGA mRNA and TMA IHC expression analysis suggest that a subset of serous ovarian tumors have high levels of CCNE1 and BRD4 expression. High CCNE1 expression is associated with poor prognosis and platinum resistance. High BRD4 expression is not associated with platinum resistance in this cohort. Future studies are warranted to evaluate the subset of tumors with elevated expression of both CCNE1 and BRD4 in relation to platinum resistance and clinical outcomes. Citation Format: Shariska Petersen, Andrew J. Wilson, Dineo Khabele. CCNE1 AND BRD4 EXPRESSION AND PLATINUM RESISTANCE IN HIGH-GRADE SEROUS OVARIAN CANCERS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-046.

Abstract GMM-018: CD73: A NEW DRIVER AND A THERAPEUTIC TARGET IN OVARIAN CANCER STEM CELLS

Abstract Many biological and clinical features of ovarian cancer (OC) support the notion that the disease is driven by a subpopulation of self-renewing cancer stem cells (CSC) that are able to generate the entire progeny of short-lived, differentiated and heterogeneous cells that compose the tumor bulk. Ovarian cancer stem cells (OCSC), in particular, have been proposed to drive and sustain tumor dissemination, recurrence and chemoresistance, most likely due to their slow cycling rate and their detoxifying molecular machineries. This provides the rationale for investigating OCSC as suitable targets for OC eradication. Our study aims at assessing the functional contribution of OCSC to OC etiology and progression and at defining their molecular and functional traits. Specifically, we are pursuing these objectives through the accomplishment of the following milestones: 1) collection of normal and pathological samples; 2) identification of OCSC based on functional properties; 3) molecular profiling of OCSC and their normal counterpart; 4) characterization of novel genes/pathways involved in OCSC function (clonogenicity, tumorigenicity, quiescence, chemoresistance, etc.). We have established a repository of patient-derived primary cells isolated either from OC or from its tissues of origin, ovarian surface or fallopian tube epithelium. The OCSC subpopulation and their normal counterpart were then derived from primary cultures and used to profile their specific transcriptome, inferring a OCSC signature. Among the genes differentially expressed in OCSC, we focused on CD73, which encodes a membrane-associated 5'-ectonucleotidase that accounts for the generation of extracellular adenosine. Genetic ablation experiments revealed that CD73 acts as a driver of OC cell stemness and tumor initiation. Furthermore, the pharmacological inhibition of CD73 reduced OCSC self-renewal and tumorigenesis, highlighting the druggability of CD73 in the context of OCSC-directed therapies. The biological function of CD73 in OCSC required its enzymatic activity and involved adenosine signaling. Mechanistically, CD73 promotes the expression of stemness and epithelial-mesenchymal transition-associated genes, implying a regulation of OCSC function at the transcriptional level. In summary, CD73 is involved in OCSC biology and may represent a therapeutic target for innovative treatments aimed at OC eradication. In this context, CD73 is involved in tumor immune escape and actively investigated as a target to restore antitumor response. Thus, CD73-targeted therapies may combine the benefit of OCSC neutralization with overcoming CD73-driven immune escape, resulting in a synergistic effect towards OC eradication. Furthermore, CD73 neutralization might help preventing OCSC-dependent chemoresistance, thus enhancing the therapeutic efficacy of conventional chemotherapy. The therapeutic potential of CD73-based treatments and the molecular function of CD73 in OCSC are currently under investigation. Citation Format: Michela Lupia, Kris F. Sachsenmeier, Nicoletta Colombo, Fabrizio Bianchi, and Ugo Cavallaro. CD73: A NEW DRIVER AND A THERAPEUTIC TARGET IN OVARIAN CANCER STEM CELLS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-018.

Abstract GMM-022: IDH1 IS A PRO-SENESCENT THERAPY IN HIGH-GRADE SEROUS OVARIAN CANCER

Abstract Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. High-grade serous carcinoma (HGSC) is the most frequently diagnosed and fatal histosubtype of EOC. We found that HGSC cell lines exhibit increased TCA cycle metabolites compared to fallopian tube cells, the proposed site of HGSC origin. Therefore, we propose that inhibition of TCA cycle metabolism may be a novel therapeutic strategy for HGSC. To determine which TCA cycle metabolism enzymes are dysregulated in ovarian cancer, we performed an unbiased qPCR screen of all 27 enzymes in the pathway. Our results indicate that isocitrate dehydrogenase I (IDH1) expression is significantly altered in EOC cell lines compared to fallopian tube cells. IDH1 catalyzes the conversion of isocitrate to alpha ketoglutarate (αKG) in a reversible reaction. It is well-known that IDH1 mutations play a role in cancer; however, recent publications suggest wildtype IDH1 overexpression promotes primary glioblastoma progression in the absence of mutation. Wildtype IDH1 and its role in metabolism and epigenetics has never been investigated in HGSC. To determine whether IDH1 plays a functional role in HGSC, we used both genetic and pharmacological approaches to suppress IDH1 in multiple HGSC cell lines. Knockdown or inhibition of IDH1 using the small molecule inhibitor GSK864 significantly decreased HGSC cell proliferation. Mechanistically, this was due to induction of senescence, a stable cell cycle arrest. We next aimed to determine the molecular mechanism underlying senescence induction due to inhibition of IDH1. Increased histone methylation of proliferation promoting genes (i.e., CCNA2 and PCNA) is a characteristic of senescence. αKG acts as a cofactor for the Jumonji C (JmjC) histone demethylase family, suggesting that suppression of αKG may affect the methylation status of histones. αKG levels were significantly decreased in IDH1 knockdown cells. Therefore, we hypothesized that decreasing αKG levels in HGSC may modulate the epigenome to induce senescence. Chromatin immunoprecipitation (ChIP) experiments showed an increase in repressive H3K9me2 histone methylation at proliferation-promoting gene loci (CCNA2 and PCNA) when IDH1 was knocked down. This correlated with a decrease in mRNA of both genes. These data suggest that knockdown of IDH1 induces senescence of HGSC cells by increased histone methylation of proliferation promoting genes. Finally, we aimed to determine the JmjC demethylase family member that is inhibited by IDH1 knockdown. The JmjC KDM4 family modulates histone demethylation of histone H3 lysine 9. KDM4A is upregulated in EOC and correlates with worse overall survival. Interestingly, knockdown studies of KDM4A phenocopied those of IDH1 knockdown. Future studies are aimed to dissect the role of KDM4A in senescence induction. Altogether, these data suggest that targeting the metabolic enzyme IDH1 in HGSC induces senescence through epigenetic reprogramming and may be a novel metabolic therapy for HGSC patients. Citation Format: Erika S Dahl, Nathaniel W Snyder, Katherine M Aird. IDH1 IS A PRO-SENESCENT THERAPY IN HIGH-GRADE SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-022.

Abstract AP24: ALTERNATIVELY ACTIVATED MACROPHAGE SECRETOME MODULATES METASTATIC POTENTIAL OF OVARIAN CANCER CELLS

Abstract High-grade serous ovarian cancer (HGSOC) metastasizes when tumor spheroids detach from the primary tumor and re-attach throughout the peritoneal cavity. Once spheroids have attached in a new site, the top layer of mesothelial cells is lost and the cancer cells expand across the underlying extracellular matrix (ECM). The factors that influence this process are unclear, but may provide therapeutic targets to slow disease spread. As HGSOC progresses an increase in alternatively activated macrophages (AAMs) in the surrounding ascites fluid has been observed and AAMs enhance tumor invasion and growth in a wide range of cancers. Thus we hypothesized that soluble factors from the AAMs in the peritoneal microenvironment promote the disaggregation of HGSOC spheroids across the underlying ECM. In order to model interactions between primary human AAMs and HGSOC spheroids (OVCAR3, OVCA433, OV90), an in vitro micro-culture device was used that allows for the examination of paracrine signaling in a controlled environment. After two days of co-culture on an 8 mg/mL collagen I hydrogel the area covered by the HGSOC cells was measured and normalized to the initial area of the spheroid. We determined that co-culture with AAMs significantly increased HGSOC spheroid spreading across the collagen matrix for all the HGSOC cell lines examined. To identify the AAM-derived soluble factors responsible for this increased spreading, media was collected from the device and screened for 35 cytokines using a Bioplex assay. The correlation between spheroid spreading and AAM-derived soluble factors was examined using PLSR; a one component PLSR model captured the co-variation between soluble factors and spheroid spreading (R2Y = 0.9) and was able to predict spheroid spreading given the cytokine profile (Q2Y = 0.66). Analysis of the PLSR model identified five ligands (Flt-3L, HB-EGF, IL-6, IL-8, and leptin) that strongly correlated with increased spheroid spreading. These findings were experimentally validated by adding recombinant versions of these proteins in the absence of AAMs as well as inhibiting the receptors for these factors in the presence of AAMs. From these experiments we discovered that each of the HGSOC cell lines was responding to a different AAM-secreted factor; Flt-3L induced spreading in the OVCAR3 cell line, leptin induced spreading in the OVCA433 cell line, and HB-EGF induced spreading in the OV90 cell line. The downstream pathway of these ligands was then interrogated by adding growth factors that induced spreading in combination with cucurbitacin-I, a selective JAK2/STAT3 inhibitor, ab142180, a selective MMP9 inhibitor, or verteporfin, a YAP inhibitor. The effect of these stimulants was inhibited by both cucurbitacin-I and ab142180 yet not by verteporfin, indicating that the AAM-derived factors utilize a common signaling pathway to mediate their effect on spheroid spreading: JAK2/STAT3 activation followed by MMP-9 mediated spreading. These data suggest that inhibiting singular soluble factors will not inhibit AAM-induced effects across a broad group of patients and that downstream pathways should instead be examined as potential therapeutic targets to slow metastasis in HGSOC. Citation Format: Kaitlin Fogg, Will Olson, Jamison Miller, and Pamela Kreeger. ALTERNATIVELY ACTIVATED MACROPHAGE SECRETOME MODULATES METASTATIC POTENTIAL OF OVARIAN CANCER CELLS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP24.

Abstract GMM-032: UNRAVELLING THE STEROID METABOLOME IN EPITHELIAL OVARIAN CANCER

Abstract INTRODUCTION: Ovarian tissue possesses the capacity for steroidogenesis from as early as seven weeks gestation. Perturbations in the steroidogenic pathways have been implicated in the development and progression of epithelial ovarian carcinoma in adulthood but the evidence has been limited. Analysis of RNA-seq data from ovarian tissue now allows the genes involved in these pathways to be studied comprehensively helping direct future investigations and highlighting possible mechanisms of the disease. METHODS: RNA-seq data from 293 serous epithelial ovarian carcinomas from The Cancer Genome Atlas were extracted and the genes involved in steroidogenesis were systematically interrogated for high and low expression. Pathway analysis was employed to confirm significant findings. Comparison was made with novel RNA-seq data from first trimester fetal ovary and healthy adult ovary. RESULTS: Genes involved in the synthesis of androgens (HSD17B1, SRD5A1, AKR1C3, AR and STS) were all significantly upregulated in the high grade serous ovarian carcinoma group when compared to normal healthy ovary (p<0.05). Expression of several steroidogenic genes in malignancy appeared to mimic increased fetal expression with relative quiescence noted in the healthy ovary group. CONCLUSIONS: Transcriptome analysis shows upregulated gene expression of the androgen synthesis pathway is associated with epithelial ovarian cancer. This is supported by immunohistochemistry findings in recent studies. Investigation of the androgen pathway does remain a valid opportunity for mechanistic insight into this disease and potentially diagnostic and therapeutic exploitation. Ovarian steroidogenic gene expression in the first trimester appears to correlate with neoplastic growth in serous ovarian cancer but the significance of this is uncertain. Citation Format: David N. Jeevan, Wiebke Arlt, Paul A. Foster and Sudha Sundar. UNRAVELLING THE STEROID METABOLOME IN EPITHELIAL OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-032.

Abstract TMIM-083: A TWO-STEP TARGETING STRATEGY UTILIZING GLYCOENGINEERED MESENCHYMAL STEM CELLS FOR OVARIAN CANCER

Abstract Current tumor targeted drug delivery systems suffer from a lack of selectivity for tumor cells. We propose a two-step tumor targeting strategy to improve the delivery of therapeutic agents to metastatic ovarian cancer. The two-step targeting approach relies on the introduction of non-natural targets (azide functional groups) in the tumor tissue, followed by the delivery of drug-loaded polymeric nanoparticles that are surface modified (with dibenzyl cyclooctyne; DBCO) and have high affinity for these synthetic targets. The objective of the present study was to determine the in vivo efficacy of two-step targeting in a clinically-realistic, patient-derived xenograft (PDX) model of ovarian cancer. The DBCO functionalized, paclitaxel (PTX)-loaded nanoparticles (16.2% w/w PTX; diameter 320 ± 10 nm; and zeta potential -11.5 ± 1.3 mV) were formulated using the FDA approved, biodegradable and biocompatible polymer, poly (DL-lactide-co-glycolide) (PLGA), by emulsion-solvent evaporation method. Glycoengineered mesenchymal stem cells (MSC-Az) were generated by culturing MSCs in N-azidoacetylmannosamine-tetraacylated supplemented media without affecting their viability or tumor homing properties. Anticancer efficacy of MSC-Az mediated two-step targeting strategy was evaluated in female athymic nude mice bearing PDX tumors. Mice with generation 2 tumors were randomly divided into four groups receiving intravenous injection of saline, PTX solution, DBCO-PTX nanoparticles, and intravenous injection of MSC-Az followed by intravenous injection of DBCO-PTX nanoparticles (MSC-Az + DBCO-PTX). We observed significantly reduced tumor growth (p <0.05) and improved survival in the group receiving MSC-Az + DBCO-PTX compared to all other groups. Furthermore, immunohistochemical analysis of the tumor tissues demonstrated that the animals treated with MSC-Az + DBCO-PTX had extensive necrosis compared to other groups, suggesting the potential of MSCs for improved tumor targeting and inhibition. In summary, our results demonstrate the potential of two-step tumor targeting strategy to enhance tumor specific delivery of conventional chemotherapeutic drugs resulting in significantly improved anti–cancer efficacy. Citation Format: Buddhadev Layek, Mihir Shetty, Tim Starr, Swayam Prabha. A TWO-STEP TARGETING STRATEGY UTILIZING GLYCOENGINEERED MESENCHYMAL STEM CELLS FOR OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-083.

Abstract GMM-057: A FUNCTIONAL HOMOLOGOUS RECOMBINATION ASSAY PREDICTS PRIMARY CHEMOTHERAPY RESPONSE AND LONG-TERM SURVIVAL IN OVARIAN CANCER PATIENTS

Abstract PURPOSE: Homologous recombination deficiency (HRD) correlates with platinum sensitivity in ovarian cancer patients, which clinically is the most useful predictor of sensitivity to PARPi. For this reason, there is clearly a critical need to identify homologous recombination deficiency (HRD) as early as possible. Currently, HRD is mostly diagnosed by genetic testing, which however fails to identify a large proportion of HR-deficient tumors and predict a patient's response to chemotherapy, thus we aimed to develop an ex vivo functional HRD detection test that could predict both platinum-sensitivity and patient eligibility to targeted drug treatments. METHODS: We obtained a functional HR score by quantifying homologous recombination (HR) repair after ionizing radiation-induced DNA damage in primary ovarian cancer samples (n=32). Samples clustered in 3 categories: HR-deficient, HR-low and HR-proficient. We analysed the HR score association with platinum sensitivity and treatment response, platinum-free interval (PFI) and overall survival (OS), and compared it with other clinical parameters. In parallel, we performed whole-genome sequencing and targeted DNA-sequencing of HR genes to assess if functional HRD can be predicted by currently offered genetic screening. RESULTS: Low HR scores predicted primary platinum sensitivity with high statistical significance (p=0.0103), associated with longer PFI (HR-deficient vs HR-proficient: 531 vs 53 days), and significantly correlated with improved OS (HR score <35 vs ≥35, hazard ratio=0.08, p=0.0116). At the genomic level, we identified a few unclear mutations in HR genes and the mutational signature associated with HRD, but, overall, genetic screening failed to predict functional HRD. CONCLUSIONS: We developed an ex vivo assay that detects tumor functional HRD and an HR score able to predict platinum sensitivity, which holds the clinically relevant potential to become the routine companion diagnostic in the management of ovarian cancer patients. Citation Format: Manuela Tumiati, Sakari Hietanen, Johanna Hynninen, Elina Pietilä, Anniina Färkkilä, Amjad Alkodsi, Yilin Li, Rainer Lehtonen, Erdogan Pekcan Erkan, Minna M. Tuominen, Kaisa Lehti, Sampsa K. Hautaniemi, Anna Vähärautio, Seija Grénman, Olli Carpén, and Liisa Kauppi. A FUNCTIONAL HOMOLOGOUS RECOMBINATION ASSAY PREDICTS PRIMARY CHEMOTHERAPY RESPONSE AND LONG-TERM SURVIVAL IN OVARIAN CANCER PATIENTS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-057.

Abstract NT-095: ERADICATION OF CHEMORESISTANT METASTATIC OVARIAN CANCER WITH IMMUNOTARGETED EPIGENOMIC NANOSURGERY (IEN)

Abstract INTRODUCTION: Resistance to conventional chemotherapy such as cisplatin, and radiotherapy in ovarian cancer may be caused by deregulated oncogenic miRNA-221/222 inhibiting induction of apoptosis. METHODS: Chemoradioresistant cells overexpressing EphA2 were obtained for developing an ovarian metastatic cancer model, which was treated with anti-EphA2 MAbs immunotargeted pegylated nanosomes with encapsulated paired guide-RNAs targeting 3' and 5' of the precursor microRNA 221/222. RESULTS: Post-treatment, the paired guide-RNAs caused deletions in the targeted pre-microRNA 221/222 genomic-sequences removing the stem-loop hairpins after blockade of RNase-III Drosha and DGCR8 (microprocessor-complex), subsequent transport by exportin-5/RanGTP and cleavage by Dicer inhibiting miRNA221/222 biogenesis, and miRNP circumventing their incorporation in RISC, and subsequent mRNA cleavage of coding genes regulating according to NGS the PTEN, GJA1, SEMA3B, TIMP3, PTPRM, CDKN1C, MGMT, CDKN1B, PUMA, connexin-43 (CX-43), c-Jun, MMP, NF-kB, PI3K, p27/Kip1, PTPμ, NIAP, ICAM-1, STAT1, STAT2, STAT3/Akt, CDK4, CDKN1C/p57, p53, and p57 inhibiting metastatic ovarian cancer cell proliferation, chemo/radioresistance, migration, angiogenesis, invasion, metastasis and maintenance of MET expressing ovarian metastatic cancer stem cells, while inducing cytotoxic immune responses (CTLs), and D2 irreversible stage of apoptosis or programmed cell death type-I leading to a bystander killing effect (BKE) due to phagocytosis of adjacent tumor cells according to transmission electron micrographs. CONCLUSION: Immunotargeted epigenomic nanosurgery may eradicate metastatic ovarian cancer after inhibition of oncogenic miRNA 221/222 expression, and downstream signaling pathways involving interactions with coding RNA genes leading to apoptosis or PCD type I and BKE after the circumvention of chemo/radioresistant mechanisms. Citation Format: John N. Giannios. ERADICATION OF CHEMORESISTANT METASTATIC OVARIAN CANCER WITH IMMUNOTARGETED EPIGENOMIC NANOSURGERY (IEN) [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-095.

Abstract DP-012: STUDYING THE SIGNALING PATHWAYS OF DISTINCT SUBPOPULATIONS OF CELLS GENERATED UPON PTEN DELETION FROM FTE AND IDENTIFICATION OF MARKERS OF EARLY TUMORIGENESIS

Abstract SIGNIFICANCE: High Grade Serous Cancer (HGSOC) Requires Novel Biomarkers for early detection. Survival rates for HGSOC patients have not substantially improved, over the past decades, mainly because the disease is only detected at the metastatic stage. The findings of early pre-malignant lesions in the fallopian tube, but not in the ovary, suggested that HGSOCs may originate from the fallopian tube epithelium (FTE) and metastasize to the ovary. Studying the mechanisms of HGSOC genesis from the correct cell of origin is critical to the early detection of the disease. Our main goal is to determine how genetic and molecular alterations contribute to the early events of HGSOC genesis from FTE. Recent transgenic animal models of FTE-derived HGSOC have pointed out the critical role of loss of PTEN (phosphatase and tensin homolog) from FTE in generating HGSOC when in combination with p53 mutation and alteration of BRCA1/2, but not by itself. Our lab was the first to show that deletion of PTEN alone in FTE is sufficient to lead to tumor formation and peritoneal dissemination suggesting that the importance of PTEN in the early events of the tumorigenic cascade may have been underestimated. Loss of PTEN from FTE is sufficient to drive ovarian cancer, however, the key signaling driving tumorigenesis when PTEN expression is low remain poorly defined and yet pivotal to new treatment options given its common occurrence. Studying the progression of HGSOC genesis from FTE is essential to refining the strategy for targeted therapies and to discovering novel biomarkers for early detection of the disease. PURPOSE: to identify signaling pathways and drug response of different subpopulations of tumorigenic cells generated upon PTEN deletion. RESULTS: Loss of PTEN in the FTE upregulates markers of cancer stem cells (CSC) such as WNT4, LGR5, ALDH1, c-Kit, CD44, and Dll4. We also discovered that the CSC markers are confined in a specific subpopulation of cells with increased diameter that we call CSCHigh as compared to a smaller population that we call CSCLow. In fact, when these two populations are separated by flow cytometry based sorting, the CSCHigh retains all the CSC markers. In addition, using a limiting dilution assay, we found that the CSCHigh subpopulation forms tumor at a faster rate in vivo. In addition, CSCHigh forms bigger spheroids and are more resistant to chemotherapeutic agents, suggesting that more targeted therapy may be developed for these stem-like, tumorigenic subpopulations. We also show that loss of PAX2 is mediating the CSCHigh phenotype suggesting that therapies to re-express PAX2 may prevent development of HGSOC. CONCLUSIONS: Together, these findings provide a novel model to study the mechanism of fallopian tube tumor initiation and invasion to the ovary mediated by loss of PTEN, which may help to define early events of human ovarian carcinogenesis. Citation Format: Angela Russo, Austin A. Czarnecki, Matthew Dean, Dan Lantvit, Jian-Jun Wei Joanna E. Burdette. STUDYING THE SIGNALING PATHWAYS OF DISTINCT SUBPOPULATIONS OF CELLS GENERATED UPON PTEN DELETION FROM FTE AND IDENTIFICATION OF MARKERS OF EARLY TUMORIGENESIS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr DP-012.

Abstract NT-114: CATALYTIC SUBUNITS SWITCH DRIVES RESISTANCE TO EZH2 INHIBITORS IN ARID1A-MUTATED CELLS

Abstract The SWI/SNF chromatin remodeling complex is altered in ~20% of human cancers. ARID1A, a component of the SWI/SNF chromatin-remodeling complex, is the most frequently mutated epigenetic regulator in human cancers. Inactivation of the SWI/SNF complex is synthetically lethal with inhibition of EZH2 activity. EZH2 inhibitors are entering clinical trials for specific tumor types with SWI/SNF mutations. However, mechanisms of de novo or acquired resistance to EZH2 inhibitors in cancers with inactivating SWI/SNF mutations are unknown. Here we show that the switch of the SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 drives resistance to EZH2 inhibitors in ARID1A-mutated ovarian cancer cells. SMARCA4 decease dominates over SMARCA2 increase in the switch. SMARCA4 loss leads to suppression of apoptotic pathways through upregulating anti-apoptotic genes such as BCL2 in the EZH2 inhibitor resistant cells. EZH2 inhibitor resistant ARID1A-mutated cells are hypersensitive to BCL2 inhibitors such as ABT263. ABT263 is sufficient to overcome resistance to EZH2 inhibitor and synergistic with EZH2 inhibitor in vivo in ARID1A-inactivted ovarian tumour mouse models. Together, these data establish that the switch of the SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 underlies the acquired resistance to EZH2 inhibitors and BCL2 inhibition alone or in combination with EZH2 inhibition represents a novel strategy to overcome and/or prevent EZH2 inhibitor resistance in ARID1A-mutated cancers. Given that the SWI/SNF subunits are among the most frequently mutated genes in human cancers and EZH2 inhibitors are in the clinical trials for tumor with mutations in the SWI/SNF complex, we expect our findings to have far-reaching implications for developing cancer epigenetic therapeutics. Citation Format: Shuai Wu, Nail Fatkhutdinov, Takeshi Fukumoto, Benjamin G. Bitler, Pyoung Hwa Park, Andrew V. Kossenkov, Marco Trizzino, Alessandro Gardini, David W. Speicher, Rugang Zhang,. CATALYTIC SUBUNITS SWITCH DRIVES RESISTANCE TO EZH2 INHIBITORS IN ARID1A-MUTATED CELLS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-114.

Abstract NT-099: NOVEL ANTIBODY DRUG CONJUGATE (ADC) AND COMPANION DIAGNOSTICS AGAINST CD248+ CANCER

Abstract Antibodies recognizing specific tumor targets can be used to deliver therapeutic payloads with high degree of specificity. The simultaneous use of antibody against same target for imaging and for therapy, an approach named “theranostics”, offers unique opportunities for precision medicine and rapidly assessing therapeutic response at molecular level. The first example of such antibody-based theranotics is Herceptin in HER2-positive breast cancer: Herceptin is used as companion diagnostic imaging tool as well as the targeted therapy. To develop effective anti-tumor therapeutics, one needs a robust biomarker, AND a good antibody that can specifically bind to the target. We and others have found one for EOC: CD248/TEM1. It is present at high level in tumor and its microenvironment in EOC and almost absent in normal organs. Importantly, CD248 is expressed by >90% EOC patients on the tumor or tumor vasculature, and its high expression correlates with poor survival. This means that if we can target it, we may destroy tumor but leave normal tissues intact. We also have developed robust antibody against CD248 (78Fc panel, US Patent 61/639,325). We showed that our patented antibodies can find the biomarker and upon binding deliver a payload, for PET imaging, near-infrared optical imaging or therapeutic, to CD248-expressing cells. Different toxin payload, such as auristatin and MD117, were conjugated to the antibody, and such ADCs were tested in vitro and in vivo in mice models. Surprisingly, we found such immunotherapies only directly kill, but also induce significant lymphocyte infiltration into tumors. In addition, tumor rejection was observed upon re-challenging in preclinical models. Such immune activation we observed could in turn sensitizing previously “cold tumor” EOC, to checkpoint inhibitors such as PD-1/CDLA4. The long term goal is to develop companion diagnostics and antibody-immunotherapy: screening methods (such as antibody-based immunoPET and serum ELISA) to identify patients with EOC that can be treated with anti-CD248 drugs; and develop drugs that are linked to the antibody (such as antibody-drug conjugate) so it can be delivered to the tumor directly to kill. In addition, combined with PD-1 blockade, ADC therapies may exert antitumor immune response to sensitize “cold” tumors that previously resistant to PD-1 therapy. Citation Format: Yi Guo, Yujue Wang, Xiaohui Peng, George Coukos, Chunsheng Li. NOVEL ANTIBODY DRUG CONJUGATE (ADC) AND COMPANION DIAGNOSTICS AGAINST CD248+ CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-099.

Abstract GMM-024: TARGETING THE FORMIN-ASSEMBLED ACTIN CYTOSKELETON AS AN ANTI-INVASION STRATEGY IN OVARIAN CANCER SPHEROIDS

Abstract Due to high rates of recurrent metastasis during EOC progression, there is a critical unmet need to limit advancement of metastatic lesions present at diagnosis and upon initial recurrence. In non-hematogenous dissemination, cancer cells metastasize within the peritoneum and attach to visceral organs. Single cells, multi-cell clusters, or highly invasive multi-cellular spheroids are shed into peritoneal fluid from primary tumors, or are released by mechanical disruption of peritoneal metastases during cytoreductive surgery. Peritoneal EOC metastasis is not halted upon surgical removal of primary or metastatic tumors; it is a dynamic, longitudinal process of recurring tumors in the peritoneal cavity/pleural space. Recurrent peritoneal metastasis likely occurs via tumor cells suspended in the accumulating ascites fluid attaching to and invading the peritoneal mesothelium. Thus, EOC spheroids promote recurrent peritoneal metastasis and must be targeted for therapeutic intervention. We wished to assess the therapeutic utility of small molecules called intramimics (IMM) and Diaphanous-autoregulatory domain (DAD) in EOC spheroid peritoneal metastasis models. Both IMMs and DADs stimulate mDia2 formin function, and are thus classified as agonists. Formins are intracellular cytoskeletal nanomachines that assemble G-actin monomers into F-actin filaments. Formin-mediated F-actin assembly regulates stress fiber formation and generates forces to deform membranes into protrusive structures (i.e., lamellae, filopodia) to enable cell migration. While this process is necessary for normal cell migration (i.e., wound healing, development), it is abnormally invoked in metastasis. mDia proteins also support tumor cell-cell interactions by promoting the assembly of the F-actin architecture underlying cell-cell adherens junctions (AJs) that link cells of epithelial sheets together. IMMs and DADs specifically agonize mDia2 formins, keeping the nanomachine “on”, and in so doing, promote constitutive F-actin assembly within cells. Therefore, we hypothesize that mDia2 formin agonism would effectively block EOC spheroid invasion in 3D matrices by halting single cell invasive egress from spheroids. Using SKOV-3 and OVCA429 adenocarcinoma EOC cells, we demonstrated that mDia2 protein associates with proteins underlying AJ complexes. Specifically, mDia2 protein associates with alpha and beta catenins, yet not E- or N-cadherins. We further show that siRNA-mediated depletion of mDia2 alters the subcellular localization of AJ-associated proteins, impacting F-actin accumulation at the AJ and enhancing spheroid invasive dissemination. In contrast, mDia agonism using IMM and mDia DAD small molecules effectively inhibits EOC spheroid invasion, disallowing single cell egress from spheroids. Collectively, these results indicate a role for mDia formins in regulating invasive egress from EOC spheroids. Thus, there may be therapeutic utility to targeting mDia formin cytoskeleton effectors in halting EOC spheroid invasive egress. Citation Format: Krista M. Pettee, Yuqi Zhang, Kathryn M. Eisenmann. TARGETING THE FORMIN-ASSEMBLED ACTIN CYTOSKELETON AS AN ANTI-INVASION STRATEGY IN OVARIAN CANCER SPHEROIDS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-024.

Abstract DP-011: PRE-DIAGNOSIS USE OF MENOPAUSAL HORMONE THERAPY ASSOCIATED WITH BETTER OVARIAN CANCER SURVIVAL

Abstract BACKGROUND: Several lifestyle factors have consistently been associated with survival of ovarian cancer, including body mass index, analgesic medications, physical activity, and smoking. Menopausal hormone therapy (HT), which can comprise of estrogen only (ET) or a combination of estrogen and progestin (EPT), has also been studied for its impact on ovarian survival. Randomized trials as well as a recent meta-analysis have shown better survival for women who took HT after their diagnosis in comparison to women who did not (HR=0.67, 95% CI 0.47-0.97). However, the relationship between use of HT prior to ovarian cancer diagnosis and survival is less clear. METHODS: Approximately 4,700 ovarian cancer patients across nine population-based studies participating in the Ovarian Cancer Association Consortium (OCAC) were included in our analysis. Information on HT use prior to diagnosis and potential confounders was obtained via phone or in-person interviews. To estimate the effect of pre-diagnostic HT use on ovarian cancer survival, hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models with left and right truncation to account for different observation times. Effects by type and duration of HT use as well as disease histotype were also evaluated. RESULTS: Women who used HT before diagnosis had an 11% decreased risk of death in comparison to those who did not use HT (95% CI 0.82-0.97). Similar effects were observed for both types of HT (HR=0.86, 95% CI 0.75-0.98 for ET and HR=0.89, 95% CI 0.80-0.99 for EPT). In addition, there appeared to be a duration effect with longer HT use conferring better survival (p-trend=0.07 for ET, p-trend=0.003 for EPT). When histotype was considered, the overall decreased risk was driven by serous and mucinous ovarian cancers (HR=0.85, 95% CI 0.77-0.93 and HR=0.54, 95% CI 0.28-1.07, respectively). CONCLUSIONS: Use of HT after diagnosis also affords a survival advantage based on published observational and clinical trials data. We now report that pre-diagnosis HT use may confer a survival advantage among women with ovarian cancer. Interestingly, use of ET prior to diagnosis is associated with increased risk of ovarian cancer, but better survival among women diagnosed with the disease. These observations taken together demonstrate the complex nature of ovarian cancer. Citation Format: Alice W. Lee, Siri Peterson, Ashley Wiensch, Malcolm C. Pike, Celeste L. Pearce on behalf of the Ovarian Cancer Association Consortium. PRE-DIAGNOSIS USE OF MENOPAUSAL HORMONE THERAPY ASSOCIATED WITH BETTER OVARIAN CANCER SURVIVAL [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr DP-011.

NEW FINDINGS ON WORK AND FAMILY USING IPUMS DATA

The IPUMS Data in Aging Research symposium will showcase aging research that is possible using freely available population-level data accessible via IPUMS. This session will feature papers that use IPUMS data in novel ways to examine aging-related topics including living arrangements, widowhood and divorce, paths toward retirement, intergenerational effects of interventions on later life outcomes, and time use of caregivers. In addition to the common threads of work and family, these papers all represent innovative contributions to aging research based on census and nationally-representative survey data. The potential value of these types of data for studying aging may not be immediately apparent to all researchers. By combining papers on an array of topics from a variety of data sources, this symposium highlights exemplar papers that demonstrate the types of novel research possible using public use census and survey data.

Methodological gaps and opportunities for studying multisectoral collaboration for health in low- and middle-income countries.

The current body of research into multisectoral collaborations (MSCs) for health raises more questions than it answers, both in terms of how to implement MSCs and how to study them. This article reflects on current methodological gaps and opportunities for advancing MSC research, based on a targeted review of existing literature and qualitative input from researchers and practitioners at the 2018 Health Systems Research (HSR) Symposium in Liverpool. Through framework analysis of 205 MSC research papers referenced in a separately published MSC 'overview of reviews' paper, this article identifies six broad MSC question domains ('meta questions') and applies content analysis to estimate the relative frequency with which these meta questions and the research method(s) used to answer them are present in the literature. Results highlight a preponderance of research exploring MSC implementation using case study methods, which, in aggregate, does not seem to adequately meet policymakers' and practitioners' needs for generalizable or transferable insights. The content analysis is complemented by qualitative insights from HSR Symposium participants and the authors' own experience to identify six key methodological gaps in research on MSC for health. For each of these gaps, we propose areas in which we believe there are opportunities for methodological development and innovation to help advance this field of study, including: better understanding the role of power dynamics in shaping MSCs; development of a classification framework (or frameworks) of governance arrangements; exploring divergence of perspective and experience among MSC partners; identifying or generating theoretical frameworks for MSC that work across sectors and disciplines; developing intermediate indicators of collaboration; and increasing transferability of insights to other contexts. Collaboration with researchers outside of the health sector will enhance efforts in each of these areas, as will the establishment and strengthening of pluralistic MSC evidence networks also involving policymakers and practitioners.

Author Index

Asia-Pacific Journal of Clinical OncologyVolume 15, Issue S7 p. 41-42 AUTHOR INDEX Author Index First published: 03 November 2019 https://doi.org/10.1111/ajco.13273AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume15, IssueS7Special Issue: 2019 Hunter Cancer Research Symposium, 8 November 2019, Newcastle City Hall, Newcastle, NSW, AustraliaNovember 2019Pages 41-42 RelatedInformation

2019 Hunter Cancer Research Symposium Program.

Asia-Pacific Journal of Clinical OncologyVolume 15, Issue S7 p. 4-7 2019 HUNTER CANCER RESEARCH SYMPOSIUM PROGRAM 2019 Hunter Cancer Research Symposium Program First published: 03 November 2019 https://doi.org/10.1111/ajco.13251Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume15, IssueS7Special Issue: 2019 Hunter Cancer Research Symposium, 8 November 2019, Newcastle City Hall, Newcastle, NSW, AustraliaNovember 2019Pages 4-7 RelatedInformation