Epithelial Ovarian Adenocarcinoma Research Articles

Abstract B111: Mechanism-informed photochemical strategies to overcome fluid shear stress-induced platinum resistance in ovarian cancer

Abstract Background: Over 75% of patients with disseminated ovarian cancer develop resistance to platinum-based chemotherapies (carboplatin or cisplatin). Patients with a high volume of malignant ascites or excessive fluid buildup in the peritoneum are more likely to present with primary platinum-resistant disease. It is hypothesized that the physical forces generated by ascites may contribute to the dissemination and progression of ovarian cancer. Our research group has shown that fluid shear stress (FSS) induces carboplatin resistance and a motile and aggressive phenotype in monolayer cultures and 3D models for adherent ovarian cancer. In this study, the effects of FSS on treatment response to cisplatin and doxorubicin were examined. The latter is used to manage recurrent platinum-resistant disease. Changes in mitochondrial function under FSS as they relate to platinum resistance were also characterized. Finally, the use of photodynamic therapy (PDT), which utilizes 690 nm light and a clinical photosensitizer benzoporphyrin derivative (BPD) to locally generate cytotoxic reactive molecular species as a means of overcoming FSS-induced platinum resistance, was explored. Methods: Human epithelial ovarian adenocarcinoma cells OVCAR-3 and Caov-3 (ATCC) were cultured in tissue culture plates (static culture) or chamber slides (ibidi) connected to a perfusion pump for 48 h (flow rate: 0.11 mL/min, shear stress: 0.41 dyn/cm2). Cells in static and flow cultures were exposed to cisplatin, doxorubicin, BPD-PDT or combinations thereof and survival fractions were measured 72 h post-treatment. Mitochondrial membrane potential was measured using JC-1 fluorescence assay, and mitochondrial DNA (mtDNA) copy number was quantified using qPCR. ATP content per cell was measured with a CellTiterGlo luminescence assay. Results: OVCAR-3 and Caov-3 cells grown under FSS developed significant resistance to cisplatin. Specifically, 3.13 µM cisplatin induced a 50% decrease in the survival fraction in OVCAR-3 static cultures but failed to decrease the survival fraction under flow. In contrast to these findings with platins, no resistance to doxorubicin was observed under flow. Evaluation of the mitochondrial function revealed increased ATP content and mtDNA copy number in flow cultures, suggesting that increased mitochondrial activity may contribute to platinum resistance. Finally, low-dose BPD-PDT (IC10, 0.15 J/cm2) enhanced the efficacy of cisplatin in OVCAR-3 cells under flow, indicating that PDT is a viable strategy to sensitize tumors exposed to FSS to platinum-based chemotherapy. Conclusions: Our data suggest that ovarian cancer cells that acquired resistance to platinum due to FSS remain sensitive to doxorubicin. Changes in mitochondrial function, including increased ATP content per cell and mtDNA copy number, have been identified as potential contributing factors to platinum resistance under FSS. Finally, low-dose BPD-PDT can be used to re-sensitize cells to cisplatin and overcome platinum resistance. Citation Format: Marta Overchuk, Brittany P. Rickard, Justin Tulino, Frances S. Ligler, Imran Rizvi. Mechanism-informed photochemical strategies to overcome fluid shear stress-induced platinum resistance in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B111.

A Tertiary Cancer Center Experience of 52 Cases of Primary Ovarian Mucinous Adenocarcinomas.

Background Primary mucinous epithelial ovarian adenocarcinoma (mEOC) constitutes a small percentage (2–5%) of ovarian cancer. Our aim is to understand the clinicopathological characteristics and survival results of patients with mEOC after a long-term follow-up. Materials and Methods This is a retrospective study of primary mEOC cases treated at a tertiary cancer center in India, from January 1, 2005, to December 31, 2012. Results Out of 958 malignant ovarian tumors, 52 (5.43%) were mucinous adenocarcinoma. Nearly 71.2% of cases were of early-stage disease, and the remaining were of advanced-stage disease. After a follow-up period of 63 months (range: 1–138 months), the 5-year actuarial overall survival for stages I, II, III, and IV was 92.5, 70, 38.5, and 0%, respectively. Among advanced-stage tumors, half of them progressed without undergoing cytoreductive surgery and died. Conclusion Most of the mEOC cases present in early stages and have good clinical outcome. Patients with advanced-stage disease do not respond well to standard chemotherapy regimens in use and have poor survival figures. The use of primary cytoreduction should be considered in the place of interval cytoreduction for advanced mEOC.

Characterization of ascites-derived aldehyde dehydrogenase–positive ovarian cancer stem cells isolated from Leghorn chickens

Leghorn chickens are used as a preclinical model of ovarian cancer as they develop epithelial ovarian adenocarcinoma spontaneously at a very high frequency. Ovarian cancer is the most lethal disease among all gynecological malignancies in women. A small proportion of ovarian cancer stem cells are responsible for drug resistance and relapse of ovarian cancer. The objectives of this study are to isolate ovarian cancer stem cells from ascites of Leghorn chickens that spontaneously developed ovarian cancer and to determine their invasiveness, spheroid formation in three-dimensional culture devoid of extracellular matrix over several months. Ovarian cancer cells obtained from ascites were subjected to ALDEFLOUR assay that measures aldehyde dehydrogenase (ALDH) activity to separate ALDH1+ and ALDH1- cells by fluorescence-activated cell sorting. The cells were cultured using serum-free media for up to 6 mo in ultra-low attachment plates. Invasiveness of ALDH1+ and ALDH1- cells was determined by Matrigel invasion assay. Cellular uptake of acetylated low-density lipoprotein was evaluated. A small proportion (<4.75%) of ovarian cancer cells isolated from ascites were found to be ALDH1+ cells. ALDH1+ cells formed a greater number of spheroids and were also highly invasive in extracellular matrix compared to ALDH1- cells. Several spheroids developed 0.1- to 1-mm-long capillary-like tubules connecting other spheroids, thus forming a complex network that underwent remodeling over several months. Cells in the spheroids incorporated acetylated low-density lipoprotein suggestive of scavenger receptor activity. In summary, ALDH1+ ovarian cancer stem cells isolated from ascites of chickens appear to be invasive and form spheroids with complex networks of tubules reminiscent of vascular mimicry. Understanding the structure and function of spheroids and tubular network would provide valuable insight into the biology of ovarian cancer and improve poultry health.

The Relationship of FOXR2 Gene Expression Profile with Epithelial-Mesenchymal Transition Related Markers in Epithelial Ovarian Cancer.

Several factors have been evaluated for their competency as applied bio-markers regarding dia-gnosis and therapy of ovarian cancer as one of the most cause of death due to the gynecologic malignancies. However, some Fox-factors have been shown to modulate cancer progression primarily by their impacts on the proliferation of the cells, the expression and potential function of FOXR2 (Forkhead Box R2), newly identified as a probable oncogene in a few human cancers, remains undecided in ovarian cancer. The aim of this study was to evaluate the FOXR2 and some epithelial-mesenchymal transition (EMT) -related gene expression profiles in epithelial ovarian cancer (EOC) tissues and their healthy samples as well as an ovarian cancer cell line (SKOV-3). In this observational study, 20 epithelial ovarian adenocarcinoma and their marginal samples, obtained from 20 women with EOC, as well as SKOV-3, were investigated for the relative gene expression levels of FOXR2, CDH1 (encoding E-cadherin) and FN1 (encoding fibronectin-1) in 2 groups using qualitative real-time polymerase chain reaction technique (qRT-PCR). The findings demonstrated a significant up-regulation of FOXR2 and FN1 despite the CDH1 down-regulation in case samples compared to controls (P &lt; 0.05). There was a significant correlation between FOXR2 gene expression profile and EMT-related markers in high-grade tumors. Furthermore, the bio-marker index of 0.772 was obtained for FOXR2 gene expression levels. The findings indicated that the expression levels of FOXR2 have a significant association with ovarian cancer as far as it can be used as a dia-gnostic and therapeutic molecular bio-marker in ovarian cancer.

Artemisinin induced reversal of EMT affects the molecular biological activity of ovarian cancer SKOV3 cell lines.

Accumulating evidence suggests that celecoxib and artemisinin could mediate ovarian cancer development and metastasis. The present study investigated the effects of celecoxib and artemisinin on the epithelial-mesenchymal transition (EMT) characteristics of the human ovarian epithelial adenocarcinoma cell line, SKOV3. SKOV3 cells were incubated with celecoxib (10 µM) for different periods of time to establish an EMT cell model. Subsequently, artemisinin (20, 40 and 80 µM) was used to establish a cell model of the reverse process, mesenchymal-epithelial transition (MET). Cell proliferation, metastasis, invasiveness and the expression of vimentin and E-cadherin were measured using Cell Counting Kit-8, wound healing assay, western blotting, flow cytometry and immunofluorescence. The EMT cell model exhibited enhanced proliferative capacity, increased migration, increased vimentin expression and decreased E-cadherin expression. By contrast, artemisinin decreased proliferative capacity, decreased migration, decreased vimentin expression and increased E-cadherin expression of EMT model cells, indicating that MET was induced. These results demonstrated that artemisinin may reverse celecoxib-induced epithelial-mesenchymal transition in SKOV3 cells.

Abstract CT160: A Phase I, open-label, safety, pharmacokinetic, and preliminary efficacy study of STRO-002, an anti-folate receptor alpha (FolRα) antibody drug conjugate (ADC), in patients with advanced epithelial ovarian cancer (including fallopian tube or primary peritoneal cancers) and endometrial cancers

Abstract Background: Folate receptor alpha (FolRα) is overexpressed in 80% of epithelial ovarian cancer (EOC) and endometrial adenocarcinoma (EC), with minimal expression on normal tissues and is thus a relevant target for cancer therapy using antibody drug conjugates (ADCs). STRO-002 is a novel, site-specific FolRα-targeting ADC that was generated using Sutro’s XpressCF+™ cell free protein synthesis platform. STRO-002 has highly specific cytotoxic activity on cells expressing FolRα. STRO-002 demonstrated reproducible and significant therapeutic efficacy in multiple preclinical models in vivo. STRO-002 activity was evaluated in EC patient-derived xenograft (PDX) models with a range of FolRα expression. Statistically significant efficacy was observed in 60% of the FolRα-positive PDX models tested, with response appearing to positively correlate with FolRα expression levels. Toxicology studies in cynomolgus monkeys demonstrate dose-dependent and reversible neutropenia when STRO-002 is administered at up to 9 mg/kg, with no evidence of ocular toxicity (Solis et al. AACR 2019). Methods: This study is a first-in-human Phase 1, open-label, multicenter, dose escalation (Part 1) study with dose expansion (Part 2) to identify the maximum tolerated dose (MTD), recommended phase 2 doses (RP2D) and to evaluate the safety, tolerability, and preliminary anti-tumor activity of STRO-002 in adults with ovarian cancer and endometrial cancer who are refractory to, or intolerant of, therapies known to provide clinical benefit. STRO-002 is given to all patients on study via intravenous infusion on Day 1of each 21-day cycle until disease progression. Dose limiting toxicities will be assessed in the first cycle (Days 1-21) of dose escalation. Part 1 will enroll about 30 ovarian cancer patients to determine the MTD and RP2D for expansion while Part 2 will enroll 2 cohorts based on disease subtypes (ovarian or endometrial). Efficacy will be evaluated per RECIST 1.1 criteria. Key inclusion criteria include relapsed and or progressive disease, adequate bone marrow and renal function, and ability to comply with treatment, testing and pharmacokinetic (PK) schedules. Key exclusion criteria include clear cell, mucinous or sarcomatous ovarian carcinoma, prior treatment with a FolRα-targeting ADC, need for ongoing immunotherapy including systemic corticosteroids and a history of CNS involvement. Samples will be collected to assess FolRα expression levels, PK and immunogenicity. No formal statistical hypothesis testing will be conducted in this study. This study is currently open for enrollment in the US with the ClinicalTrials.gov Identifier: NCT03748186.: Citation Format: Robert Wendel Naumann, Denise S. Uyar, Russell J. Schilder, Michael A. Palumbo, Venita DeAlmeida, Shannon L. Matheny, Arturo Molina. A Phase I, open-label, safety, pharmacokinetic, and preliminary efficacy study of STRO-002, an anti-folate receptor alpha (FolRα) antibody drug conjugate (ADC), in patients with advanced epithelial ovarian cancer (including fallopian tube or primary peritoneal cancers) and endometrial cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT160.

Detection of Human Papillomavirus Prevalence in Ovarian Cancer by Different Test Systems

Background/Aims: High-risk human papillomavirus (HPV) infection is associated with different malignancies, but its role in the pathogenesis of ovarian cancer remains inconclusive. Published studies demonstrated a wide variation (0–50%) in HPV prevalence in ovarian cancer. To evaluate the contribution of detection tests to controversial results in different populations, we determined the presence of HPV DNA in Russian ovarian cancer patients using 10 different PCR-based tests. Methods: Epithelial ovarian adenocarcinomas were tested with 5 general primer sets commonly used for HPV screening of cervical and ovarian cancer and 5 HPV type-specific primers. Results: The use of a single PCR primer set resulted in a wide variation (0–29%) and an underestimation of the incidence of HPV-positive cancers. The combination of MY09/MY11 and GP5+/6+ primers in nested PCR revealed HPV DNA in 53% (18/34) of adenocarcinomas. HPV16 was found in 94% of the HPV-positive cases. In 6/6 positive cases, the active status of HPV16 was demonstrated by RT-PCR detection of E6 and E7 oncogene mRNAs. Conclusion: These findings indicate the need to employ multiple PCR-based tests to detect all HPV-positive patients. The identification of viral DNA and oncogene transcripts in cancerous tissues indicate the possible role of HPV in ovarian carcinogenesis in Russia.

The Antithrombotic Potential of Tinzaparin and Enoxaparin Upon Thrombin Generation Triggered In Vitro by Human Ovarian Cancer Cells IGROV1.

A documented relationship between ovarian cancer and thrombosis does exist. Low-molecular-weight heparins (LMWHs) are cornerstone drugs in the primary prevention and treatment of venous thromboembolic events in patients with cancer. However, cancer cells may alter the efficiency of these antithrombotic agents. We aimed to characterize the procoagulant phenotype of human epithelial ovarian adenocarcinoma cells, IGROV1, and to compare the capacity of tinzaparin and enoxaparin to inhibit thrombin generation triggered by these cells. Thrombin generation induced by different concentrations of IGROV1 cells on platelet poor plasma (PPP) was assessed by the calibrated automated thrombogram assay. Tissue factor (TF) expression was studied using Western blot analysis. Then, the experimental model of thrombin generation was used to compare the inhibitory effect of clinically relevant concentrations of both tinzaparin and enoxaparin. The inhibitory concentration 50 (IC50) of the mean rate index and the endogenous thrombin potential and the 2-fold increase in lag time were analyzed on the basis of the anti-Xa and anti-IIa activities of the LMWHs. IGROV1 cells suspended into PPP resulted in a significant increase in thrombin generation in the absence of any exogenous source of TF and phospholipids. Tissue factor was expressed by IGROV1 cells. Tinzaparin was a more potent inhibitor of thrombin generation than enoxaparin. The inhibition of thrombin generation induced by IGROV1 cancer cells depended mainly on the anti-Xa activity of the LMWHs. This experimental study in ovarian cancer cells demonstrates that the antithrombotic activity of LMWHs is not completely predicted by the anti-Xa or anti-IIa activities measured in PPP.

Ovarian Cancer Revealed by Perineal Tumor: A Case Report and a Literature Review

Background: Cutaneous metastasis of ovarian epithelial adenocarcinoma is rare, and most cases present as cutaneous nodules, generally as periumbilical Sister Joseph’s nodules. An uncommon presentation of cutaneous metastases from ovarian carcinoma is perineal tumor. Case: A 56-year-old patient has a serous adenocarcinoma reveled with a perineal tumor. After surgery, the patient started chemotherapy with bad evolution, and the patient died after 3 months. Conclusions: The prognosis of the cutaneous metastasis of the ovarian adenocarcinoma is poor, but palliative treatment is usually indicated that further studies evaluating the role of specific therapies are needed to guide treatment.

Reactive Oxygen Species and Serous Epithelial Ovarian Adenocarcinoma.

Serous ovarian cancer (SOC) is usually diagnosed at late stage and stage-adjusted five year survival rate is low. Mortality is relatively heavy on African-Americans/Black (AA) affected with SOC compared to their Caucasian counterparts, though the cause for the disparity remains unclear. DNA damage induced by oxidative stress has been linked to ovarian cancer, but the role of oxidative stress in distinguishing differences in aggressive SOC tumors among patients is yet to be determined. This study aims to determine the levels of reactive oxygen species (ROS), malondialdehyde (MDA), reactive carbonyl groups and antioxidants in primary SOC normal, precancerous (cystadenoma, borderline) and invasive (III/IV) tissue samples obtained from AA and Caucasian subgroups. Additionally, the study seeks to investigate significant changes in the level of ROS between AA and Caucasian SOC samples. A fluorogenic probe, dichlorodihydrofluorescein (DCFH-DiOxyQ), was used to scavenge reactive oxygen species in SOC normal, precancerous and malignant stages III/IV tissue samples. Malondialdehyde (MDA), a lipid peroxidation marker, and reactive carbonyl groups were measured as indicators of oxidative injury. Moreover, antioxidant status was assessed by estimating glutathione peroxidase 3 (GPX3) enzyme levels. Results indicate ROS concentration was approximately 96% higher in the malignant tissues in comparative to the normal non-diseased controls. In addition, ROS concentration among AA women was approximately 9% higher than Caucasian women. MDA levels increased exponentially from non-disease control and precancerous tissues relative to malignant tissues. Furthermore, malignant serous ovarian samples showed significantly higher reactive carbonyl content compared to the non-disease controls (p=0.009), while GPX3 levels decreased considerably in serous cystadenoma and malignant tissue samples, and non-diseased control compared to borderline disease. The results suggest accumulation of ROS and MDA levels may be a causative factor for SOC. Elevated levels of MDA and reactive carbonyl proteins could override the GPX3 enzyme capacity therefore, initiating serous ovarian neoplasm.

Abstract C170: Preclinical evaluation of mirvetuximab soravtansine (IMGN853) combination therapy in ovarian cancer xenograft models

Abstract Background: IMGN853 is a folate receptor α (FRα)-binding antibody-drug conjugate (ADC) that utilizes the potent tubulin-targeting maytansinoid, DM4, as its cytotoxic agent. FRα is highly expressed in many solid tumors, particularly epithelial ovarian cancer (EOC), endometrial cancer and non-small cell lung adenocarcinoma. IMGN853 is currently being evaluated as monotherapy in FRα-positive solid tumors in a Phase 1 trial (NCT01609556), with encouraging results recently reported in 17 evaluable patients treated at 6.0 mg/kg adjusted ideal body weight (AIBW) with platinum-resistant EOC (Moore K et al, 2015). Methods: EOC cell line xenograft models plus EOC patient derived xenograft (PDX) models that had FRα expression representative of patients enrolled in the Phase 1 trial were used to assess IMGN853 single agent and combination therapy activity. Anti-cancer therapies used in EOC were assessed. Results from studies with bevacizumab (Bev), carboplatin and pegylated liposomal doxorubicin (PLD) are reported herein. Results: IMGN853 plus Bev was assessed in multiple models including OV90 and IGROV-1 EOC cell line xenografts and a platinum-resistant EOC PDX model, and was consistently more active than either agent alone. In most studies, monotherapy IMGN853 or Bev was active with few partial or complete regressions. In contrast, combination IMGN853 + Bev was highly active, with a majority of the animals having partial or complete tumor regression. The combination activity was substantially more than additive and studies to understand the mechanism(s) responsible for the enhanced activity are ongoing. Combination carboplatin + IMGN853 was more active than carboplatin + paclitaxel in OV90 EOC xenografts. The addition of Bev to carboplatin + paclitaxel enhanced activity compared to carboplatin + paclitaxel. Carboplatin + IMGN853 was more efficacious than the triple combination of carboplatin + paclitaxel + Bev. Carboplatin + IMGN853 + Bev was the most active combination with all mice having tumors that completely regressed. Finally, the combination of PLD and IMGN853 was highly active in a platinum-resistant EOC PDX model, and much more active than PLD or IMGN853 alone. All combinations with IMGN853 described above were well tolerated. Conclusion: Combination therapy efficacy of IMGN853 with Bev was substantially more than additive in multiple models of platinum resistant EOC. Combination IMGN853 + PLD is more efficacious than either monotherapy and combination IMGN853 + carboplatin is more efficacious than carboplatin + paclitaxel in the models studied. Addition of Bev to the carboplatin + IMGN853 combination further enhanced activity. Studies to understand the mechanism(s) responsible for the enhanced combination activity are under way. The efficacy observed in these models suggests that IMGN853 in combination with PLD, or Bev and/or carboplatin may be promising regimens to evaluate in clinical trials of EOC both in the relapsed and upfront settings. A phase1b clinical study assessing doublet combinations of IMGN853 with PLD, Bev and carboplatin in relapsed EOC is planned for 2015. Citation Format: Jose F. Ponte, Jennifer Coccia, Leanne Lanieri, Rabih Gabriel, Jan Pinkas, Rodrigo Ruiz-Soto. Preclinical evaluation of mirvetuximab soravtansine (IMGN853) combination therapy in ovarian cancer xenograft models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C170.

Abstract C47: Association of folate receptor alpha (FRα) expression level and clinical activity of IMGN853 (mirvetuximab soravtansine), a FRα-targeting antibody-drug conjugate (ADC), in FRα -expressing platinum-resistant epithelial ovarian cancer (EOC) patients (pts)

Abstract Background: IMGN853 is a FRα-targeting ADC comprising a FRα-binding antibody conjugated with the potent maytansinoid, DM4, a tubulin-targeting agent. FRα is a membrane protein that is highly expressed in many solid tumors, particularly epithelial ovarian cancer (EOC), endometrial cancer and lung adenocarcinoma. An immunohistochemistry (IHC) assay was developed to support the FRα-expression based patient selection strategy for the clinical development of IMGN853. The assay was optimized to detect a broad dynamic range of FRα expression, allowing discrimination among weak (1+), moderate (2+) and strong (3+), levels of expression (AACR 2015 Zhao J et al). In the EOC expansion cohort of the ongoing phase 1 trial (ASCO 2015 Moore K, et al), 80% of the patients with platinum-resistant EOC screened were found to meet the FRα expression inclusion criteria of ≥ 25% of cells with at least moderate expression. Methods: Here we report the preliminary analysis evaluating the association of FRα expression with overall response rate [partial response (PR) or complete response (CR)] for the first seventeen evaluable patients with platinum-resistant EOC who received IMGN853 at 6.0 mg/kg (adjusted ideal body weight) IV q3wk. Patients were grouped based on their FRα expression into low (25-49% of cells with ≥ moderate expression), medium (50-74% of cells with ≥ moderate expression) and high (≥ 75% of cells with ≥ moderate expression) groups. Analysis to assess the association between expression level and clinical response was performed. Results: Of the 17 patients in the analysis, 2/17 (12%) had low, 5/17 (29%) had moderate and 10/17 (59%) had high FRα expression. In the overall cohort, clinical response was observed in 9/17 patients (1 CR and 8 PRs), for an objective response rate (ORR) of 53%. When the cohort of 17 patients was grouped based on FRα expression, clinical response was observed in 0/2 low, 1/5 moderate and 8/10 high expression patients. The majority of adverse events were CTCAE grade 1 or 2, with diarrhea, blurry vision, cough, fatigue, decreased appetite, neuropathy and nausea reported in &amp;gt; 20% of patients. Conclusion: In these heavily pretreated platinum-resistant ovarian cancer patients, IMGN853 demonstrates promising preliminary clinical activity, with an ORR of 53% in the overall cohort and 80% in the high FRα expression subset. Preliminary analysis suggests that FRα-expression correlates well with IMGN853 activity. The association of FRα expression with IMGN853 activity will continue to be assessed as the phase I trial continues to enroll patients in the expansion cohort. Citation Format: Lainie P. Martin, Kathleen Moore, David M. O'Malley, Shelley Seward, Todd M. Bauer, Ramon Perez, Woondong Jeong, Yinghui Zhou, Joseph Ponte, Maurice Kirby, Mohammed Al-Adhami, Rodrigo Ruiz-Soto, Michael Birrer. Association of folate receptor alpha (FRα) expression level and clinical activity of IMGN853 (mirvetuximab soravtansine), a FRα-targeting antibody-drug conjugate (ADC), in FRα -expressing platinum-resistant epithelial ovarian cancer (EOC) patients (pts). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C47.

Abstract 3400A: Development and application of an immunohistochemistry-based clinical assay for evaluating Folate Receptor Alpha (FRα) expression in a phase I clinical trial of IMGN853

Abstract A biomarker-based patient selection strategy, coupled with the co-development of a companion diagnostic, is key to the successful development of molecularly targeted cancer therapeutics. IMGN853 is a Folate Receptor Alpha (FRα)-targeting antibody-drug conjugate (ADC) consisting of an anti-FRα antibody linked to DM4, a highly cytotoxic maytansinoid, via a cleavable disulfide linker. FRα is a glycosyl-phosphatidylinositol-linked membrane protein commonly over-expressed in several solid tumor types including epithelial ovarian cancer (EOC), endometrial cancer and lung adenocarcinoma, with limited expression in normal tissues. Previously reported preclinical data demonstrated regression or significant inhibition of tumor growth by the conjugate in tumor models with clinically relevant levels of FRα expression. IMGN853 is currently in a phase I clinical trial for safety and tolerability in patients with FRα-positive solid tumors. Preliminary evidence of clinical activity has been observed in patients receiving IMGN853 treatment. Immunohistochemistry (IHC) is one of the most widely adopted techniques in clinical labs for semi-quantitative determination of protein expression in different cellular compartments. We have developed an IHC assay to support the FRα-expression based patient selection strategy in the clinical development of IMGN853. To this end, a novel murine monoclonal antibody with high specificity for human FRα was generated. This antibody, 353-2.1, is compatible with formalin fixed and paraffin embedded (FFPE) tissue samples and can recognize the same pool of FRα molecules as IMGN853, making it an ideal candidate for a companion diagnostic for IMGN853. The antibody was used to develop and optimize an assay that covers a broad dynamic range of FRα expression, allowing discrimination among high, moderate and low levels of expression. Data from tissue microarrays that cover a broad range of normal and tumor tissue types, as well as additional prevalence data in selected tumor types, were used to validate this assay. They also demonstrate that the FRα-expression data generated using this assay are consistent with previous findings. This clinical FRα IHC assay has been successfully used to measure FRα expression in more than 100 patient tumor samples submitted for testing in the ongoing IMGN853 phase I trial. A summary of FRα staining pattern and expression level data from these patients will be presented, as well as the prevalence in each tumor type. Citation Format: Jianhua Zhao, Alyssa LaBelle, Olga Ab, Krista Acosta, Al Yates, Yinghui Zhou, Angela Romanelli. Development and application of an immunohistochemistry-based clinical assay for evaluating Folate Receptor Alpha (FRα) expression in a phase I clinical trial of IMGN853. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3400A. doi:10.1158/1538-7445.AM2015-3400A

Radical surgical approach for synchronous ovarian and uterine cervix tumor with uterine cervix liver metastasis

Synchronous ovarian and uterine cervix malignancies are extremely rare gynecologic neoplasia. In the meantime the presence of hepatic metastases originating from cervical cancer is another rare situation, the liver being more often a common site of metastases for ovarian malignancies. We present the case of a 63-year-old patient who was diagnosed with a moderately differentiated squamous cell cervical tumor with urinary bladder invasion associated with an ovarian tumorand liver metastases. An anterior exenteration and atypical liver resection were performed; the histopathological studies revealed the presence of a moderately differentiated squamous cell uterine cervix carcinoma and a well differentiated serous epithelial ovarian adenocarcinoma; the histopathological examination of the liver lesions confirmed the presence of a squamous cell type originating from the uterine cervix neoplasm.

Clinicopathological heterogeneity in ovarian clear cell adenocarcinoma: a study on individual therapy practice.

Ovarian clear cell adenocarcinoma (CCA) has been believed to be a lethal histological subtype of an epithelial ovarian adenocarcinoma (EOA); its precursor has been assumed to be endometriosis. However, it has been reported that CCAs occasionally exhibit different clinical behaviors, suggesting that CCAs might not belong to a single category. We focused on CCAs combined with other histological types of EOAs; we re-evaluated the pathology of 46 CCAs and divided them into two subgroups: 35 CCAs alone (pure-type CCAs); and 11 CCAs with other histological types, endometrioid adenocarcinomas (EAs) or/and serous adenocarcinomas (SAs) (mixed-type CCAs). Immunohistochemical analysis for expression of ARID1A, p53, PTEN, Annexin 4, hepatocyte nuclear factor-1β (HNF-1β), and WT-1 was employed. We identified that patients with endometriosis were younger than those without endometriosis in pure-type CCAs (P < 0.005). In mixed-type CCAs, the immunohistochemical-staining patterns revealed internal transition of each histological component. In pure-type CCAs, expressions of ARID1A and p53 were mutually altered, and altered expression of p53 was associated with worse prognosis than that of ARID1A (P < 0.001). Our results provide evidence that CCAs would have clinicopathological heterogeneity, determining the patient's prognosis. Furthermore, immunohistochemical analysis may shed light on the selection of appropriate treatment, including chemotherapy.

Menadione induces the formation of reactive oxygen species and depletion of GSH-mediated apoptosis and inhibits the FAK-mediated cell invasion

Menadione induces apoptosis in tumor cells. However, the mechanism of apoptosis in ovarian cancer cells exposed to menadione is not clear. In addition, it is unclear whether menadione-induced apoptosis is mediated by the depletion of glutathione (GSH) contents that is associated with the formation of reactive oxygen species. Furthermore, the effect of menadione on the invasion and migration of human epithelial ovarian cancer cells has not been studied. Therefore, we investigated the effects of menadione exposure on apoptosis, cell adhesion, and cell migration using the human epithelial ovarian carcinoma cell lines OVCAR-3 and SK-OV-3. The results suggest that menadione may induce apoptotic cell death in ovarian carcinoma cell lines by activating the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The apoptotic effect of menadione appears to be mediated by the formation of reactive oxygen species and the depletion of GSH. Menadione inhibited fetal-bovine-serum-induced cell adhesion and migration of OVCAR-3 cells, possibly through the suppression the focal adhesion kinase (FAK)-dependent activation of cytoskeletal-associated components. Therefore, menadione might be beneficial in the treatment of epithelial ovarian adenocarcinoma and combination therapy.

P0147 Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis at st luke’s medical center: 2-Year experience from a pilot study

Background Cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS + HIPEC) is an evolving treatment option for peritoneal carcinomatosis. Several large centres have consistently shown a significant survival advantage in patients subjected to this aggressive procedure despite its associated morbidity. We present the survival outcomes of patients with peritoneal carcinomatosis who were treated with CRS + HIPEC at St Luke’s Medical Center as an early experience in the Philippines. Methods This prospective, phase 2 single-institution study was done on a series of patients with peritoneal carcinomatosis from primary or recurrent epithelial ovarian cancer, colorectal, and appendiceal adenocarcinoma. Patients underwent CRS with or without HIPEC from January 2012 to December 2013. Patient demographics, tumour histology, peritoneal carcinomatosis index, surgical details, and clinical outcomes were prospectively recorded and reviewed. Findings A total of 35 patients were enrolled with 38 cytoreductive surgeries (35 primary, three secondary) with 28 HIPEC procedures. There were 25 patients with gynaecological peritoneal carcinomatosis (23 ovarian, two tubal), seven with colorectal peritoneal carcinomatosis (three appendiceal), and three patients with sarcomatosis. Cytoreduction was completed in 31 patients with a median PCI of 20. Mean operating time was 7.87 h with an average of four major resections/CRS. Major morbidity was observed in 34.29% which included anastomotic leaks, fistulae, and abscesses with a 17.14% reoperation rate. Mortality rate is 5.7% due to cardiogenic shock and pulmonary embolism. With a median follow-up of 7 months, mean overall survival was 16.38 ± 1.89 months with a median disease free survival of 13 months (95% confidence interval 5.65–20.82). The overall 1 year survival rate was 73% (ovarian peritoneal carcinomatosis 73%, colorectal peritoneal carcinomatosis 67%, and appendiceal peritoneal carcinomatosis 100%). Interpretation Long-term survival of patients with peritoneal carcinomatosis is only achieved with CRS + HIPEC, which carries a significant but acceptable morbidity. The clinical outcomes observed in this early experience approximate those reported in the literature.

Radical surgical cytoreduction in the treatment of ovarian carcinosarcoma

ObjectiveCarcinosarcomas are rare and aggressive ovarian malignancies. Treatment recommendations, which include surgical cytoreduction followed by platinum based chemotherapy, have been based on small amounts of retrospective data or extrapolated from experience with high-grade epithelial ovarian adenocarcinoma. Our objective was to determine the effects of radical primary cytoreduction on progression-free survival (PFS) and overall survival (OS). MethodsFollowing IRB approval, records of women with ovarian carcinosarcomas diagnosed between 2000 and 2012 at our institution were reviewed. Demographics, tumor characteristics, treatments, PFS, and OS were collected. Patients were divided into three groups based on the amount of residual disease: >1cm of disease, ≤1cm of disease, or no visible disease. Chi-square and student's t-test were used to compare variables among groups. Kaplan–Meier survival curves were generated and compared with the log-rank test. Results51 patients with ovarian carcinosarcoma were identified and all underwent primary cytoreductive surgery. Following surgical cytoreduction, 18 patients (35%) had no visible disease, 20 (39%) had ≤1cm of disease, and 13 (25%) had >1cm of residual disease. Median PFS varied significantly among groups: 29 vs. 21 vs. 2months (p=0.036) as did median OS: 57 vs. 32 vs. 11months (p=0.015). When patients with stage 3 disease were analyzed separately, median OS still varied significantly among groups: 57 versus 31 versus 3months (p=0.009). ConclusionDegree of surgical cytoreduction appears to correlate with PFS and OS. Radical surgery resulting in no visible disease is recommended for the upfront surgical treatment of ovarian carcinosarcoma.

Parthenolide induces apoptosis by activating the mitochondrial and death receptor pathways and inhibits FAK-mediated cell invasion

The natural product parthenolide induces apoptosis in cancer cells. However, the mechanism of apoptosis in ovarian cancer cells exposed to parthenolide is not clear. In addition, it is unclear whether parthenolide-induced apoptosis is mediated by the formation of reactive oxygen species and the depletion of GSH contents, and the effect of parthenolide on the invasion and migration of human epithelial ovarian cancer cells has not been studied. Therefore, we investigated the effects of parthenolide exposure on apoptosis, cell adhesion, and migration using the human epithelial ovarian carcinoma cell lines OVCAR-3 and SK-OV-3. The results suggest that parthenolide may induce apoptotic cell death in ovarian carcinoma cell lines by activating the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The apoptotic effect of parthenolide appears to be mediated by the formation of reactive oxygen species and the depletion of GSH. Parthenolide inhibited fetal bovine serum-induced cell adhesion and migration of OVCAR-3 cells, possibly through the suppression the focal adhesion kinase-dependent activation of cytoskeletal-associated components. Therefore, parthenolide might be beneficial in the treatment of epithelial ovarian adenocarcinoma and combination therapy.

Radical surgical cytoreduction in the treatment of ovarian carcinosarcoma

Abstract Objective Carcinosarcomas are rare and aggressive ovarian malignancies. Treatment recommendations, which include surgical cytoreduction followed by platinum based chemotherapy, have been based on small amounts of retrospective data or extrapolated from experience with high-grade epithelial ovarian adenocarcinoma. Our objective was to determine the effects of radical primary cytoreduction on progression-free survival (PFS) and overall survival (OS). Methods Following IRB approval, records of women with ovarian carcinosarcomas diagnosed between 2000 and 2012 at our institution were reviewed. Demographics, tumor characteristics, treatments, PFS, and OS were collected. Patients were divided into three groups based on the amount of residual disease: >1cm of disease, ≤1cm of disease, or no visible disease. Chi-square and student's t-test were used to compare variables among groups. Kaplan–Meier survival curves were generated and compared with the log-rank test. Results 51 patients with ovarian carcinosarcoma were identified and all underwent primary cytoreductive surgery. Following surgical cytoreduction, 18 patients (35%) had no visible disease, 20 (39%) had ≤1cm of disease, and 13 (25%) had >1cm of residual disease. Median PFS varied significantly among groups: 29 vs. 21 vs. 2months (p=0.036) as did median OS: 57 vs. 32 vs. 11months (p=0.015). When patients with stage 3 disease were analyzed separately, median OS still varied significantly among groups: 57 versus 31 versus 3months (p=0.009). Conclusion Degree of surgical cytoreduction appears to correlate with PFS and OS. Radical surgery resulting in no visible disease is recommended for the upfront surgical treatment of ovarian carcinosarcoma.