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High-Grade Serous Ovarian Cancer (HGSOC) is the most fatal of gynecological cancers. The recurrence rate of HGSOC after treatment is more than 80%. The available treatment options for HGSOC are limited; standard of care includes surgery combined with chemotherapy, with radiation therapy in some advanced cases. Both chemotherapy and radiation therapy are known to induce tumor cell aggressiveness. Many cancer studies have demonstrated that cancer stem cells (CSCs) and the epithelial-mesenchymal transition (EMT) promote cancer aggressiveness, invasion, metastasis, and drug resistance. Therefore, to better understand the cause of the poor prognosis in HGSOC, our objective is to scrutinize the role of CSCs and EMT in chemo- and radiation resistance. To lead our inquiry, we utilized the SORE6 reporter to identify Sox2/Oct4 expression, which indicates the stemness, and the Zeb1 3’ UTR reporter to detect EMT. Using flow cytometry, we quantified the reporter activity in 10 ovarian cancer cell types, including chemo-sensitive and chemo-resistant ones, considering both cell lines and patient-derived cells. Chemo-resistant cells are grown under cisplatin treatment. We exposed some of these ovarian cancer cell lines to 0, 1, 2, 4 and 8Gy of 250 MeV proton and 6 MeV photon beams, then analyzed the reporter activity 72 hours post-radiation. Our findings exhibit that chemo-resistant cells express higher stemness and EMT levels than chemo-sensitive cells and have higher resistance to radiation. These reporters can detect radiation-induced stemness and EMT. Furthermore, stemness and EMT levels positively correlate with the radiation dosage increment. We conclude that these reporters are an efficient surrogate for detection of stemness and EMT and can be used to test strategies for prevention of therapy-induced aggressive phenotypes. Citation Format: Yeonkyu Jung, Aaron Keniston, Ashley Antonissen, Ann Morcos, Antonella Bertucci, Marcelo Vazquez, Juli Unternaehrer. High grade serous ovarian cancer: Detecting stemness and EMT levels in response to chemo and radiation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1089.

Simple Summary Ovarian cancer has a dismal prognosis and innovative treatment options are necessary to improve survival. Because the microRNA let-7 is often lost in this and other cancers, and its loss is associated with poor prognosis, we focused on therapeutic strategies to replace it. We report that let-7 overexpression in patient-derived cells resulted in a loss of aggressiveness: inhibition of migration and invasion (associated with metastasis), repression of cancer stem cell attributes (necessary for tumor maintenance and recurrence), and promotion of cell death (required for sensitivity to chemotherapy drugs). Further, cells in which let-7 is overexpressed were more sensitive to PARP inhibitors, even in patients who otherwise could not benefit from these drugs. We show that let-7 reduces the expression of several genes that may contribute to these effects. These actions of let-7 add to the rationale for use of this miRNA as a treatment for selected ovarian cancer patients. Abstract High-grade serous carcinoma of the ovary is a deadly gynecological cancer with poor long-term survival. Dysregulation of microRNAs has been shown to contribute to the formation of cancer stem cells (CSCs), an important part of oncogenesis and tumor progression. The let-7 family of microRNAs has previously been shown to regulate stemness and has tumor suppressive actions in a variety of cancers, including ovarian. Here, we demonstrate tumor suppressor actions of let-7i: repression of cancer cell stemness, inhibition of migration and invasion, and promotion of apoptosis, features important for cancer progression, relapse, and metastasis. Let-7i over-expression results in increased sensitivity to the PARP inhibitor olaparib in samples without BRCA mutations, consistent with induction of BRCAness phenotype. We also show that let-7i inhibits the expression of several factors involved in the homologous recombination repair (HRR) pathway, providing potential mechanisms by which the BRCAness phenotype could be induced. These actions of let-7i add to the rationale for use of this miRNA as a treatment for ovarian cancer patients, including those without mutations in the HRR pathway.

We aimed to determine the mechanism of epithelial-mesenchymal transition (EMT)-induced stemness in cancer cells. Cancer relapse and metastasis are caused by rare stem-like cells within tumors. Studies of stem cell reprogramming have linked let-7 repression and acquisition of stemness with the EMT factor, SNAI1. The mechanisms for the loss of let-7 in cancer cells are incompletely understood. In four carcinoma cell lines from breast cancer, pancreatic cancer and ovarian cancer and in ovarian cancer patient-derived cells, we analyzed stem cell phenotype and tumor growth via mRNA, miRNA, and protein expression, spheroid formation, and growth in patient-derived xenografts. We show that treatment with EMT-promoting growth factors or SNAI1 overexpression increased stemness and reduced let-7 expression, while SNAI1 knockdown reduced stemness and restored let-7 expression. Rescue experiments demonstrate that the pro-stemness effects of SNAI1 are mediated via let-7. In vivo, nanoparticle-delivered siRNA successfully knocked down SNAI1 in orthotopic patient-derived xenografts, accompanied by reduced stemness and increased let-7 expression, and reduced tumor burden. Chromatin immunoprecipitation demonstrated that SNAI1 binds the promoters of various let-7 family members, and luciferase assays revealed that SNAI1 represses let-7 transcription. In conclusion, the SNAI1/let-7 axis is an important component of stemness pathways in cancer cells, and this study provides a rationale for future work examining this axis as a potential target for cancer stem cell-specific therapies.Novelty and ImpactThis study provides new insight into molecular mechanisms by which EMT transcription factor SNAI1 exerts its pro-stemness effects in cancer cells, demonstrating its potential as a stem cell-directed target for therapy. In vitro and in vivo, mesoporous silica nanoparticle-mediated SNAI1 knockdown resulted in restoration of let-7 miRNA, inhibiting stemness and reducing tumor burden. Our studies validate in vivo nanoparticle-delivered RNAi targeting the SNAI1/let-7 axis as a clinically relevant approach.

Tumor recurrence and metastasis contribute to the poor prognosis of ovarian cancer (OC) and glioblastoma multiforme (GBM). The aggressiveness of GBM and OC during recurrence creates a need to identify potential therapeutic targets. The cancer stem cell (CSC)-like phenotype and epithelial mesenchymal transition (EMT) have been shown to contribute to cancer aggressiveness, which makes CSCs and EMT viable targets for therapeutic intervention. EMT is a normal process during development and wound healing, but its reactivation in cancer cells contributes to metastasis. To detect CSC phenotypes in live cells without the use of antibodies, we are analyzing core stem cell transcription factors in which a SOX2/OCT4 response element, designated as SORE6, regulates a GFP reporter system. Also, to detect EMT we are using a GFP based reporter regulated by Zeb1 3’ UTR, a common EMT marker. Our aim is to detect changes in stemness and EMT in response to proton and photon ionizing radiation (IR). We hypothesize that proton and photon IR have similar effects on aggressiveness in OC and GBM. To investigate this, 2 GBM cancer cell lines, 1 breast cancer cell line, 1 OC cell line, and two patient derived samples were exposed to 0, 1, 2, 4 and 8Gy of 250 MeV proton and 6 MeV photon beams. 72 hours post IR exposure, flow cytometry analysis quantified reporter activity. We found an increase in stemness as radiation dosage increased in most cell lines. Results suggest that proton radiation increases stemness more than photon exposure. Citation Format: Aaron Keniston, Alondra Enciso, Yeonkyu Jung, Ashley Antonissen, Ryan Fuller, Ann Morcos, Antonella Bertucci, Marcello Vazquez, Juli Unternaehrer. Detection of stemness and EMT in response to radiation in glioblastoma and ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6396.

We studied ovarian cancer patient‐derived cells to determine their epithelial vs. mesenchymal phenotype, and their stemness, migration, invasion, and tumor growth characteristics. Surprisingly, stemness could be dissociated from invasiveness. We observed that lower let‐7 levels are associated with the epithelial state and stemness, reliably predict self‐renewal and tumor burden in mice, and could contribute to prognosis calculations., Patient‐derived samples present an advantage over current cell line models of high‐grade serous ovarian cancer (HGSOC) that are not always reliable and phenotypically faithful models of in vivo HGSOC. To improve upon cell line models of HGSOC, we set out to characterize a panel of patient‐derived cells and determine their epithelial and mesenchymal characteristics. We analyzed RNA and protein expression levels in patient‐derived xenograft (PDX) models of HGSOC, and functionally characterized these models using flow cytometry, wound healing assays, invasion assays, and spheroid cultures. Besides in vitro work, we also evaluated the growth characteristics of PDX in vivo (orthotopic PDX). We found that all samples had hybrid characteristics, covering a spectrum from an epithelial‐to‐mesenchymal state. Samples with a stronger epithelial phenotype were more active in self‐renewal assays and more tumorigenic in orthotopic xenograft models as compared to samples with a stronger mesenchymal phenotype, which were more migratory and invasive. Additionally, we observed an inverse association between microRNA let‐7 (lethal‐7) expression and stemness, consistent with the loss of let‐7 being an important component of the cancer stem cell phenotype. We observed that lower let‐7 levels were associated with the epithelial state and a lower epithelial mesenchymal transition (EMT) score, more efficient spheroid and tumor formation, and increased sensitivity to platinum‐based chemotherapy. Surprisingly, in these HGSOC cells, stemness could be dissociated from invasiveness: Cells with lower let‐7 levels were more tumorigenic, but less migratory, and with a lower EMT score, than those with higher let‐7 levels. We conclude that let‐7 expression and epithelial/mesenchymal state are valuable predictors of HGSOC proliferation, in vitro self‐renewal, and tumor burden in vivo.

Ovarian cancer ranks fifth among the causes of cancer death in US women. Despite initial positive response to cytoreductive surgery and chemotherapy treatments with platinum-based therapies, over 80% of patients with high-grade serous ovarian cancer (HGSOC), the most common type of ovarian cancer, exhibit relapse. Most recurrent cases of HGSOC are resistant to chemotherapy, and cells are highly invasive. Therefore, further studies are required to understand the mechanisms of invasiveness and chemoresistance in relapse patients. In HGSOC, invasiveness can result when epithelial cancer cells undergo epithelial-mesenchymal transition (EMT). The transcription factor SNAI1 (Snail) initiates the EMT process and increased Snail expression can result in enhancement of metastatic potential, acquisition of stem cell-like characteristics, and resistance to chemotherapeutic drugs. However, the mechanism of activation of invasiveness in ovarian cancer by Snail has not been defined. In OVCAR8, a HGSOC cell line, comparison of shSnail knockdown to control through RNA-sequencing revealed that Snail expression is directly correlated to matrix metalloprotease 1 (MMP1) expression. MMP1 is an extracellular matrix remodeler known to digest interstitial collagens. High MMP1 expression has been linked to increased cancer invasion, metastasis, angiogenesis, and apoptosis. Furthermore, in breast cancer, MMP1 has been reported to be a downstream target of Slug, another major EMT transcription factor. Some evidence for Snail activation of MMPs in liver cancer has been presented, but a direct relationship has not been established. Therefore, we hypothesize that overexpression of Snail in ovarian cancer cells results in MMP1 upregulation, leading to increased invasion. RT-qPCR was performed to analyze relative mRNA expression levels of Snail and MMP1 in eight cell lines. We found that Snail and MMP1 levels were higher in the more mesenchymal-like cell lines, some of which are known to be more invasive. Additionally, Snail overexpression led to a significant corresponding increase in MMP1 mRNA expression and resistance to cisplatin. Chromatin immunoprecipitation (ChIP) experiments demonstrate Snail binding to the MMP1 promoter. Thus, our preliminary findings have shown strong evidence of a Snail-mediated regulation of MMP1 expression in the context of HGSOC invasiveness. Citation Format: Tise Suzuki, Casey Curow, Hanmin Wang, Asis Martinez, Nozomi Hojo, Juli Unternaehrer. Snail-mediated regulation of MMP1 expression in the context of ovarian cancer invasiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2881.

Objective: Patient-derived samples present an advantage over current cell line models of high grade serous ovarian cancer (HGSOC), which are flawed in terms of being reliable and phenotypically faithful models of in vivo HGSOC. To improve upon cell line models of HGSOC, we characterized a panel of patient-derived cells to determine their epithelial and mesenchymal characteristics, invasiveness, proliferation, stemness, and in vivo growth. Experimental procedures: Patient-derived xenograft (PDX) models of HGSOC were analyzed in vitro for phenotypic (RNA, let-7 miRNA, and protein expression, flow cytometry) and functional aspects including growth in spheroids, wound healing assays, invasion assays and in vivo (orthotopic PDX) growth characteristics. Results: Samples fell along the spectrum from epithelial to mesenchymal, and all had hybrid characteristics. Those toward the more epithelial end of the spectrum were most active in self-renewal assays, and grew most robustly in orthotopic xenograft models. Chemoresistance correlated both with the mesenchymal state and with BRCA2 wild type status. Loss of microRNA let-7 (lethal-7) is an important component of the cancer stem cell phenotype, and we observed an inverse association between let-7 expression and the epithelial state. We observed lower levels of let-7, more efficient spheroid and tumor formation, and increased sensitivity to platinum-based chemotherapy in cells with the most epithelial phenotype. Conclusions: Surprisingly, in these HGSOC cells, stemness could be dissociated from invasiveness: epithelial cells (those with least let-7 expression) were less migratory, but more tumorigenic, than the mesenchymal cells with higher let-7 expression. We conclude that epithelial/mesenchymal state and let-7 expression are valuable predictors of HGSOC proliferation, in vitro self-renewal, and tumor burden in vivo. Citation Format: Juli Unternaehrer, Evgeny Chirshev, Nozomi Hojo, Antonella Bertucci, Linda Sanderman, Anthony Nguyen, Hanmin Wang, Tise Suzuki, Emmanuel Brito, Shannalee Martine, Christine Castañón, Saied Mirshahidi, Marcelo Vazquez, Kerby C. Oberg, Yevgeniya J. Ioffe. Epithelial-mesenchymal heterogeneity of high-grade serous ovarian carcinoma samples correlates with let-7 levels and predicts tumor growth and metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1682.

Patients with metastatic castration-resistant prostate cancer (mCRPC) develop resistance to conventional therapies including docetaxel (DTX). Identifying molecular pathways underlying DTX resistance is critical for developing novel combinatorial therapies to prevent or reverse this resistance. To identify transcriptomic signatures associated with acquisition of chemoresistance we profiled gene expression in DTX-sensitive and -resistant mCRPC cells using RNA sequencing (RNA-seq). PC3 and DU145 cells were selected for DTX resistance and this phenotype was validated by immunoblotting using DTX resistance markers (e.g. clusterin, ABCB1/P-gp, and LEDGF/p75). Overlapping genes differentially regulated in the DTX-sensitive and -resistant cells were ranked by Gene Set Enrichment Analysis (GSEA) and validated to correlate transcript with protein expression. GSEA revealed that genes associated with cancer stem cells (CSC) (e.g., NES, TSPAN8, DPPP, DNAJC12, and MYC) were highly ranked and comprised 70% of the top 25 genes differentially upregulated in the DTX-resistant cells. Established markers of epithelial-to-mesenchymal transition (EMT) and CSCs were used to evaluate the stemness of adherent DTX-resistant cells (2D cultures) and tumorspheres (3D cultures). Increased formation and frequency of cells expressing CSC markers were detected in DTX-resistant cells. DU145-DR cells showed a 2-fold increase in tumorsphere formation and increased DTX resistance compared to DU145-DR 2D cultures. These results demonstrate the induction of a transcriptomic program associated with stemness in mCRPC cells selected for DTX resistance, and strengthen the emerging body of evidence implicating CSCs in this process. In addition, they provide additional candidate genes and molecular pathways for potential therapeutic targeting to overcome DTX resistance.

INTRODUCTION: Epithelial ovarian cancer (EOC) is the fifth deadliest malignancy in women in the United States, with a high death-to-incidence ratio and five-year survival of 30%. Aggressiveness and recurrence of EOC has been attributed to cancer stem cells (CSC) within tumors, which contribute to chemoresistance and relapse. Deregulation of miRNAs has been linked to cancer initiation, progression, and the stem cell state. We focus on let-7 miRNA, which is repressed in many cancers and is associated with decreased survival. Let-7 is essential for cell differentiation, and its repression is required for reprogramming. Decreased let-7 level in cancer is associated with stemness. OBJECTIVE: Purpose for our research is to understand let-7 expression and function in EOC cell-lines and patients-derived samples in order to understand mechanisms of its abnormal regulation and develop novel treatments. MATERIALS AND METHODS: Patient-derived samples are used along with EOC cell-lines. Over-expression of Let-7 is achieved by mimic transfection and confirmed via RT-qPCR. Level of miRNA and pluripotency markers mRNA is detected via RT-qPCR, and protein expression confirmed by Western blot. Functional assays to analyze cancer phenotype include wound healing, invasion and spheroid formation assays. Embryoid body (EB) formation is used to mimic murine early embryonic development and guided toward primitive streak via cytokines. Let-7 expression is analyzed via RT-qPCR. RESULTS: We demonstrate that patient-derived EOC samples have decreased Let-7 levels and increased expression of pluripotency markers, therefore, we hypothesize that up-regulation of let-7 in EOC will decrease aggressiveness and increase chemosensitivity. We have demonstrated that up-regulation of let-7 via mimic transfection reduced cancer stem cell properties demonstrated by reduction of pluripotency markers and spheroid formation. Let-7 also decreased in vitro migration and invasion. Our data show that let-7 suppresses stem cell-like phenotype of EOC, indicating that it may be a treatment option in conjunction with conventional chemotherapies. In order to understand deregulation of let-7 in cancer, understanding its normal regulation and function during development is essential. By using mESCs we demonstrate that let-7 is dynamically expressed, contradicting conventional belief that let-7 levels slowly increase upon differentiation. Previously published data demonstrating that Hmga2, a let-7 target, peaks and is required upon exit from pluripotency supports our results. CONCLUSION: In conclusion, let-7 is repressed in EOC, and its over-expression demonstrates tumor suppressive functions via decreasing stemness, migration, invasion, and spheroid formation. During development let-7 is dynamically expressed, demonstrating complex regulation. Citation Format: Evgeny A Chirshev, Anthony Nguyen, Hojo Nozomi, Hill Alyse, Juli Unternaehrer. MICRO-RNA LET-7 REGULATION AND FUNCTION IN OVARIAN CANCER AND EARLY EMBRYONIC DEVELOPMENT [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-065.

PURPOSE: The epithelial-mesenchymal transition (EMT) is a process by which epithelial cells lose their cell polarity and cell-cell adhesion, and become mesenchymal cells with migratory and invasive properties. EMT is essential for numerous developmental processes such as gastrulation, and is involved in the initiation of metastasis for cancer progression. Cancer cells that undergo EMT are enabled to metastasize to form secondary tumors. One characteristic of advanced tumors is a low expression level of let-7, a miRNA known to be vital in both maintenances of cellular differentiation and tumor suppression. There is a gap in the literature concerning the mechanism of let-7 downregulation. Our purpose in this study is to present data that shows Snail, an EMT inducer, directly represses let-7, hence inducing cancer stem cells. EXPERIMENTAL PROCEDURES: Ovarian, pancreatic and breast cancer cell lines treated with TGFβ or EGF, inducers of EMT, were studied in our experiments. Expression of several markers at protein level was visualized with immunofluorescence and quantified with flow cytometry. Gene expression of mesenchymal, epithelial and pluripotency factors and miRNAs was detected by q-RT-PCR. Chromatin immunoprecipitation of Snail was performed in ovarian cancer lines. Let-7i promoter luciferase with and without Snail were co-transfected into OVSAHO and 293T cell lines and followed by luciferase assays for detection of bioluminescence. Snail was knocked down by lentiviral small hairpin RNA. Snail was overexpressed by estrogen receptor fusion protein. Orthotopic xenografts of patient-derived ovarian cancer cells were used to test the effect of Snail knockdown on tumor burden. RESULTS: In selected ovarian cancer lines, levels of Snail expression correlated directly with Nanog, and indirectly with let-7 expression. Snail bound promoters of let-7 in cell lines tested. Luciferase assays demonstrated direct repression of let-7 transcription by Snail. Metastatic burden was significantly reduced in cell line xenografts in which Snail was knocked down. CONCLUSIONS: Let-7 is confirmed to be negatively related to Snail. Our preliminary data also shows Snail directly represses let-7, therefore induces properties of stemness in cancer cells. Cell line and patient-derived data support the relationship between Snail expression, let-7 downregulation, and the induction of cancer stem cells. Snail knockdown appears to disrupt the cancer stem cell state and reduces disease progression. Citation Format: Hanmin Wang, Alyse Huisken-Hill, Evgeny Chirshev, Juli Unternaehrer-Hamm. THE ROLE OF SNAIL IN CELL DIFFERENTIATION STATUS: EPITHELIAL-MESENCHYMAL TRANSITION AND CANCER STEM CELLS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-039.

Introduction: Cell fate choices are made throughout development, and in adult organisms whenever stem cells divide. We study the interrelation of transcription factors (TF) and microRNAs in cell fate decisions. Metastasis of ovarian and other solid tumors involves epithelial-mesenchymal transition (EMT), brought about by TF such as Snail, Twist, Slug, and Zeb1. Cells undergoing reprogramming paradoxically upregulate the EMT TF Snail and downregulate let-7, and Snail binds the promoters of several let-7 family members consistent with direct regulation. Let-7 is a microRNA highly expressed in differentiated cells, and absent in pluripotent cells. Its targets include the oncogenes Myc, Ras, and HMGA2. Many aspects of somatic cell reprogramming are seen as analogous to the acquisition of stem cell phenotypes observed in cancer. Let-7 levels are decreased in many ovarian tumors, and low let-7 correlates with poor prognosis. In breast cancer, let-7 downregulation is associated with metastasis. Results: Let-7 levels are known to be regulated by control of processing by the RNA binding protein and pluripotency factor Lin28, but transcriptional regulators of let-7 have not been described. We show that Snail represses let-7 transcription in cancer-related EMTs. ChIP assays demonstrate binding of Snail to let-7 promoters, and luciferase assays demonstrate direct regulation of Let-7i by Snail. Thus we are exploring two avenues for metastasis inhibition in OC: decreasing Snail and increasing let-7. We have characterized several OC cell lines for their phenotype with regard to EMT and cancer stem cell markers, in order to select agents to advance to testing in our orthotopic patient-derived xenograft model. We have examined the role of Snail in OC metastasis by manipulating expression levels and carrying out invasiveness assays. In epithelial and cancer cell lines, stimulation with TGF-beta or EGF caused morphological and gene expression changes consistent with EMT. The OC line OVSAHO underwent EMT when stimulated with EGF, but not with TGF-b. In breast, pancreatic, and OC cell lines, increases in Snail expression correlate with decreased let-7 expression. Conclusions: We propose that the inverse relationship between Snail and let-7 plays an important role at decision points crucial for cell fate decisions. In cancer metastasis, derepression of let-7 targets (many of them oncofetal genes) leads to dedifferentiation and a more aggressive phenotype. In addition to its role in directly causing EMT and affording cells with the migratory and invasive phenotype necessary for metastasis, our model places Snail at an important control point for initiation of dedifferentiation events normally held in check by let-7. Citation Format: Yevgeniya Ioffe, Alyse Hill, Michael McCarthy, Linda Sanderman, Hugo Campos, Tise Suzuki, Andrew Caster, Juli Unternaehrer-Hamm. The epithelial-mesenchymal transition factor Snail represses the tumor suppressor microRNA let-7 and contributes to invasiveness of ovarian cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B52.