Search

Objective: Evaluate the antitumor activity and safety profile of the triplet combination of mirvetuximab soravtansine (MIRV), carboplatin, and bevacizumab in recurrent, platinum-sensitive ovarian cancer., Methods: Participants with recurrent, platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer (1-2 prior lines of therapy) received MIRV (6 mg/kg adjusted ideal body weight), carboplatin (AUC5), and bevacizumab (15 mg/kg) once every 3 weeks. Carboplatin could be discontinued after 6 cycles per investigator discretion; continuation of MIRV+bevacizumab as maintenance therapy was permitted. Eligibility included folate receptor alpha (FRα) expression by immunohistochemistry (≥50% of cells with ≥2+ intensity; PS2+ scoring); prior bevacizumab was allowed. Tumor response, duration of response (DOR), progression-free survival (PFS), and adverse events (AEs) were assessed., Results: Forty-one participants received triplet therapy, with a median of 6, 12, and 13 cycles of carboplatin, MIRV, and bevacizumab, respectively. The confirmed objective response rate was 83% (9 complete and 25 partial responses). The median DOR was 10.9 months; median PFS was 13.5 months. AEs (any grade) occurred as expected, based on each agent's safety profile; most common were diarrhea (83%), nausea (76%), fatigue (73%), thrombocytopenia (71%), and blurred vision (68%). Most cases were mild to moderate (grade ≤2), except for thrombocytopenia, for which most drug-related discontinuations occurred, and neutropenia., Conclusions: This triplet regimen (MIRV+carboplatin+bevacizumab) was highly active, with a tolerable AE profile in participants with recurrent, platinum-sensitive, FRα-expressing ovarian cancer. Thrombocytopenia was the primary cause of dose modifications. These outcomes compare favorably to historical data reported for platinum-based chemotherapy plus bevacizumab regimens in similar patient populations., Competing Interests: Declaration of competing interest DMO reports institutional research funding from AbbVie, Inc., Advaxis Inc., Agenus Inc., Alkermes plc, Aravive, Inc., Arcus Biosciences, Inc., AstraZeneca plc, BeiGene USA, Inc., Boston Biomedical, Inc., Bristol-Myers Squibb Co., Clovis Oncology, Deciphera Pharmaceuticals, Inc., Eisai Co. Ltd., EMD Serono, Inc., Exelixis, Inc., Genentech Inc., Genmab A/S, GlaxoSmithKline plc., GOG Foundation, Inc., F. Hoffmann-La Roche Ltd., Incyte Corporation, IOVANCE Biotherapeutics, Inc., Karyopharm Therapeutics, Leap Therapeutics, Inc., Ludwig Institute for Cancer Research, Merck & Co. Inc., Merck Sharp & Dohme Corp., Mersana Therapeutics, Inc., National Cancer Institute, Novartis AG, NovoCure GmbH, NRG Oncology, OncoC4, Inc., OncoQuest Inc., Pfizer Inc., Precision Therapeutics, Inc., Prelude Therapeutics, Regeneron Pharmaceuticals, Inc., Radiation Therapy Oncology Group, Rubius Therapeutics, SeaGen, Inc., Sutro Biopharma, Inc., SWOG, TESARO Inc., Verastem, Inc.; personal consulting and/or advisory board fees from AbbVie, Inc., AdaptImmune Therapeutics PLC, Agenus, Inc., Arquer Diagnostics Ltd., Arcus Biosciences, Inc., AstraZeneca plc, Atossa Therapeutics, Inc., Boston Biomedical, Inc., Cardiff Oncology, Inc., Celcuity, Inc., Clovis Oncology, Corcept Therapeutics, Inc., Duality Biologics Co. Ltd., Eisai Co. Ltd., Elevar Therapeutics, Genentech Inc., Genelux Corporation, GlaxoSmithKline plc, GOG Foundation, F. Hoffmann-La Roche Ltd., ImmunoGen, Inc., Imvax, Inc., InterVenn Biosciences, INXMED, IOVANCE Biotherapeutics Inc., Janssen Pharmaceuticals, Jazz Pharmaceuticals, Inc., Laekna Therapeutics, Leap Therapeutics, Inc., Luzsana Biotechnology, Merck & Co, Inc., Merck Sharp & Dohme Corp., Mersana Therapeutics, Inc., Myriad, Novartis, NovoCure GmbH, OncoC4, Inc., Onconova Therapeutics, Inc., Regeneron Pharmaceuticals, Inc., Replimmune Group, Inc., R Pharm, SeaGen Inc., Sorrento Therapeutics, Inc., Tarveda Therapeutics, Inc., Toray Medical Co. Ltd., Trillium Therapeutics, Umoja Biopharma, VBL Therapeutics, Ltd., Verastem Oncology, VBL Therapeutics, Vincerx Pharma, Inc., Xencor Inc., Zentalis Pharmaceuticals, Inc.; data safety monitoring board participation for Watermark; and a leadership role on the GOG Foundation Board. DLR reports institutional research funding for multiple trials from ImmunoGen, Inc.; institutional funding for research from Roche/Genentech, Inc., Mersana Therapeutics, Inc., Deciphera Pharmaceuticals, Inc., Aravive, Inc., CanariaBio, Celsion Corporation, Eli Lilly and Company, Fujifilm, Shattuck Labs, Inc., Plexxikon, ProfoundBio, Syros Pharmaceuticals, Inc., Arch Oncology, Inc., Harpoon Therapeutics, Clovis Oncology, Hookipa Pharma Inc., Karyopharm Therapeutics, Inc., and grants received from TESARO Inc./GlaxoSmithKline plc; individual consulting fees from Mersana, AstraZeneca plc, ProfoundBio, Eisai Co., Ltd., GlaxoSmithKline PLC., ImmunoGen, Inc.; personal fees from Great Debates and Updates PeerView; participation on a steering committee from Karyopharm Therapeutics, Inc., and leadership role as VP Board of Directors for National Ovarian Cancer Committee, and Board of Directors for Society of Gynecologic Oncology. KNM reports institution research funding from PTC Therapeutics, Eli Lilly and Company, Clovis Oncology, Genentech, Inc./Roche, GlaxoSmithKline plc/TESARO Inc., and Verastem Oncology; consulting fees for advisory board participation from AstraZeneca plc, Aravive, Inc., Aadi Global, Inc., Blueprint Medicines Corporation, Clovis Oncology, Caris Eisai, GlaxoSmithKline plc/TESARO Inc., Genentech Inc./Roche, Jiangsu Hengrui Pharmaceuticals Co. Ltd., ImmunoGen, Inc., Inxmed, I-Mab, Iovance Biotherapeutics, Eli Lilly and Company, Mereo, Mersana, Merck & Co., Inc., Myriad Genetics, Inc., Novartis, Novocure GmbH, Ltd., Panavance Therapeutics, OncXerna Therapeutics, Inc., Onconova Therapeutics, Inc., Tarveda Therapeutics, Inc., VBL Therapeutics, Verastem Oncology; individual payment from AstraZeneca plc, GlaxoSmithKline plc, ImmunoGen, Inc., PRIME, RTP, Medscape, Inc., Great Debates and Updates; support for attending meetings from AstraZeneca; and a leadership role as Associate Director for GOG-P. IV reports contracted research via KU Leuven from Oncoinvent AS, corporate-sponsored research from Amgen Inc. and Genentech Inc./Roche; personal fees from Agenus Inc., Akeso Inc., AstraZeneca plc, Bristol-Myers Squibb Company, Deciphera Pharmaceuticals, Inc., Eisai Co., Ltd., Elevar Therapeutics, Inc., Exelixis, F. Hoffmann-La Roche Ltd., Genmab A/S, GlaxoSmithKline plc, ImmunoGen, Inc., Jazz Pharmaceuticals, Inc., Karyopharm Therapeutics Inc., Mersana Therapeutics, Inc., Merck & Co., Inc., Novocure GmbH, Novartis, OncXerna Therapeutics, Inc., Regeneron Pharmaceuticals, Inc., Sanofi S.A., Seagen Inc., Sotio Biotech BV, Verastem Oncology, and Zentalis Pharmaceuticals; and travel expenses from Karyopharm Therapeutics Inc., Genmab A/S, and Novocure GmbH. LG reports institutional funding from AstraZeneca plc, Merck Sharp & Dohme, Karyopharm Therapeutics Inc., TESARO Inc., IMV Inc., Alkermes plc, F. Hoffmann-La Roche AG, ImmunoGen, Inc., Esperas Pharma Inc., Novocure GmbH, K-Group Beta, Inc., OncoQuest Pharmaceuticals; consulting fees from Merck & Co. Inc., GlaxoSmithKline plc; payment from Merck & Co. Inc.; and advisory board participation from AstraZeneca plc, Alkermes plc, Merck & Co. Inc., Eisai Co., Ltd., GS, and Novocure GmbH. LPM reports institutional funding for clinical trial activities from Agenusbio, Inc., AstraZeneca plc, Sutro Biopharma, Inc., ImmunoGen, Inc., Mersana Therapeutics, and Xencor, Inc., and advisory board participation for Elucida Oncology, Inc., Sutro Biopharma, Inc., and ImmunoGen, Inc. GMMS reports advisory board participation for MIRASOL study from ImmunoGen, Inc. CMC reports consulting fees from Qiagen, Inc., Teladoc Health, Inc., and InfiniteMD. DP reports institutional research funding from Exactis Innovation and consulting fees and advisory board participation from AstraZeneca plc, Merck & Co. Inc., and GlaxoSmithKline plc. UAM reports consulting fees from Merck & Co. Inc., GlaxoSmithKline plc, AstraZeneca plc, and Pfizer Inc.; personal fees from Med Learning Group; travel fees from ImmunoGen, Inc.; advisory board participation with Allarity Therapeutics, Inc., NextCure, Inc., Trillium, Inc., Agenus, Inc., ProfoundBio, Novartis, C.H. Boehringer Sohn AG & Co. KG, Rivkin Center, Ovarian Cancer Research Alliance, Clearity Foundation, MorphoSys AG, CureLab Oncology Inc., and Eisai Co., Ltd.; and data safety monitoring board participation with Alkermes plc and Symphogen A/S. JS reports employment by ImmunoGen, Inc. YW reports employment by ImmunoGen, Inc. MM reports employment by ImmunoGen, Inc., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Type 1 endometrial cancer (EC) survivors who are overweight or obese are at increased risk of comorbidities and reduced quality of life. Lifestyle modification interventions (e.g., healthy eating, exercise) may help these women reduce excess weight and improve their quality of life. However, existing interventions have shown limited success. Guided by Self-Determination Theory, the proposed study sought to identify factors associated with perceived importance of weight loss and exercise as well as interest in lifestyle modification interventions (components of extrinsic and intrinsic motivation) among EC survivors with overweight or obesity to inform future intervention development., Methods: One hundred type 1 EC survivors [body mass index (BMI) ≥ 25 kg/m 2 ] completed a cross-sectional survey assessing sociodemographics, medical factors, exercise, risk perceptions and provider communication, quality of life, barriers to dieting and exercise, perceived importance of healthy lifestyles, and desired intervention content., Results: EC survivors who were aware obesity is a risk factor for EC were significantly more likely to perceive weight loss as important and were interested in weight loss programs and receiving information about exercise ( ps  < 0.05). Additionally, EC survivors who reported their provider discussed the importance of a healthy weight after their diagnosis were significantly more likely to perceive exercise as important and were interested in receiving dieting information., Conclusions: EC survivors expressed interest in lifestyle modification interventions. Increasing awareness about the risk of obesity and provider discussions about healthy weight during routine appointments may motivate EC survivors to engage in lifestyle modification interventions., Competing Interests: David B. Sarwer has grant funding from the National Institutes of Health (National Institute for Diabetes, Digestive, and Kidney Disease R01 DK108628 and National Institute of Dental and Craniofacial Research R01 DE026603) as well as PA CURE Funds from the Commonwealth of Pennsylvania and is a consultant for Ethicon and Novo Nordisk. All other authors declare no competing interests., (© 2023 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Purpose: Evaluate the antitumor activity and safety profile of the combination of mirvetuximab soravtansine and bevacizumab in patients with platinum-resistant ovarian cancer., Methods: Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, whose most recent platinum-free interval was ≤6 months, were administered mirvetuximab soravtansine (6 mg/kg adjusted ideal body weight) and bevacizumab (15 mg/kg), intravenously, once every 3 weeks. Eligibility included FRα expression by immunohistochemistry (IHC; ≥25% of cells with ≥2+ intensity). Prior bevacizumab and/or PARP inhibitor (PARPi) treatment were permitted. The primary endpoint was confirmed objective response rate (ORR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and safety., Results: Ninety-four patients received combination treatment with mirvetuximab soravtansine and bevacizumab. Median age was 62 years (range, 39-81). Fifty-two percent had ≥3 prior therapies; 59% had prior bevacizumab; and 27% had prior PARPi. ORR was 44% (95% CI 33, 54) with 5 complete responses, median DOR 9.7 months (95% CI 6.9, 14.1), and median PFS 8.2 months (95% CI 6.8, 10.0). Treatment-related adverse events were consistent with the profiles of each agent, with the most common being blurred vision (all grades 57%; grade 3, 1%), diarrhea (54%; grade 3, 1%), and nausea (51%; grade 3, 1%)., Conclusion: The mirvetuximab soravtansine plus bevacizumab doublet is an active and well-tolerated regimen in patients with FRα-expressing platinum-resistant ovarian cancer. Promising activity was observed for patients regardless of level of FRα expression or prior bevacizumab. These data underscore the potential for mirvetuximab soravtansine as the combination partner of choice for bevacizumab in this setting., Competing Interests: Declaration of Competing Interest LG reports personal fees from Merck and GSK; advisory board participation with AstraZeneca, Alkermes, Merck, Eisai, Eisai-Merck, GSK, and Novocure; institutional funding from OncoQuest Pharmaceuticals, Novocure GmbH, Alkermes Inc., ImmunoGen Inc., AstraZeneca, Esperas Pharma Inc., K-Group Beta Inc., Merck Sharp & Dohme, Roche, Karyopharm, Tesaro, and IMV Inc. AO reports personal fees from AstraZeneca, Doctaforum Servicios S.L, Edizioni Minerva Medica SpA, ESMO, PharmaMar, and Roche; advisory board participation with Agenus, AstraZeneca, Clovis Oncology, Inc., Corcept Therapeutics, Deciphera Pharmaceutical, Eisai Europe Limited, EMD Serono, Inc., F. Hoffmann-La Roche, GlaxoSmithKline, ImmunoGen, KL Logistics, Medison Pharma, Merck Sharp & Dohme de España, Mersana Therapeutics, Novocure GmbH, PharmaMar, prIME Oncology, ROCHE FARMA, Sattucklabs, and Sutro Biopharma, Inc.; funding from AbbVie Deutschland Gmbh & Co Hg, Ability Pharmaceuticals, Advaxis, Agenus, Aprea Therapeutics AB, AstraZeneca AB, Beigene USA, Inc., Belgian Gynaecological Oncology Group (BGOG), Bristol-Myers Squibb International Corporation, Clovis Oncology, Corcept Therapeutics, Eisai, Eli Lilly and Company, F. Hoffmann-La Roche, Grupo Español de Investigación en Cáncer de Ovario (GEICO), ImmunoGen, Iovance Biotherapeutics, Medimmune, Merck Healthcare, Merck Sharp & Dohme, Millennium Pharmaceuticals, Mundipharma Research, Novartis Farmacéutica, Regeneron Pharmaceuticals, Seagen, Seattle Genetics, Sutro Biopharma, Tesaro, University Health Network, and Verastem. UAM reports consulting fees from Merck, GSK, and AstraZeneca; personal fees from Med Learning Group; advisory board participation with 2× Oncology, NextCure, Trillium, Agenus, ImmunoGen, Novartis, Boehringer Ingelheim, Rivkin Foundation, Ovarian Cancer Research Alliance, Clearity Foundation, and Morphosys; data safety monitoring board participation with Alkermes and Symphogen. GMMS reports advisory board participation with ImmunoGen. PCL reports no disclosures. CMC reports personal fees from Qiagen, Inc., Teladoc Health, and InfiniteMD. DP reports no disclosures. SM reports no disclosures. MM reports employment and stock options with ImmunoGen Inc. JW reports employment and stock options with ImmunoGen Inc. KNM reports personal fees from AbbVie, Alkemeres, Aravive, AstraZeneca, Blueprint Pharma, Bristol Myers Squibb, Eisai, Elevar, GSK/Tesaro, Genentech/Roche, iMab, ImmunoGen, Merck, Mereo, Mersana, Myriad, OncXerna, Oncomed, Rubius, Sorrento, Tarveda, Vavotar, and VBL Therapeutics; advisory board participation with Abbvie, Alkemeres, Aravive, AstraZeneca, Blueprint Pharmaceuticals, Eisai, Elevar, Genetech/Roche, GSK/Tesaro, ImmunoGen, Merck, Mereo, Mersana, Myriad, Onco Med, OncXerna, Rubius, Sorrento, Tarveda, Vavotar, VBL Therapeutics; funding from Genentech/Roche, GSK/Tesaro, ImmunoGen, Lilly, Merck, and PTC Therapeutics. DMO reports receiving grants or contracts from AbbVie Inc., Agenus Inc., Ajinomoto Co Inc., Amgen Inc., Array BioPharma Inc., AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Clovis Oncology, Dare Bioscience, Eisai Inc., EMD Serono Inc., Ergomed Plc, Genentech, Genmab, GOG Foundation Inc., ImmunoGen Inc., Iovance Biotherapeutics, Janssen Biotech Inc., Johnson & Johnson Pharmaceuticals, Ludwig Institute for Cancer Research Ltd., Merck, Merck Serono, Mersana Therapeutics, New Mexico Cancer Care Alliance, Novocure Inc., PRA Health Sciences, Regeneron Pharmaceuticals Inc., Seagen Inc., Stemcentrx, Sumitomo, Dainippon Pharma Oncology Inc., Syneos Health, Tesaro, TRACON Pharmaceuticals, VentiRX Pharmaceuticals Inc., and Yale University; data safety monitoring board and/or advisory board participation with AbbVie Inc., Ambry Genetics, Amgen Inc., Arquer Diagnostics, AstraZeneca Pharmacueticals LP, Celsion Corporation, Clovis Oncology, Corcept Therapeutics, Eisai Inc., Elevar Therapeutics, Genentech, GOG Foundation Inc., ImmunoGen Inc., InxMed, Iovance Biotherapeutics, Janssen Biotech Inc., Johnson and Johnson Pharmaceuticals, Merck, Mersana Therapeutics Inc., Novartis, Novocure Inc., Regeneron Pharmaceuticals Inc., Roche Diagnostics MSA, Seagen Inc., Sorrento Therapeutics, Sumitomo Danippon Pharma Oncology Inc., Takeda Pharmaceuticals USA Inc., Tesaro, and Tora; other financial or nonfinancial interests with Agenus Inc., Myriad Genetic Laboratories Inc., Rubis, and Tarveda Therapeutics., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Non-Gestational Ovarian Choriocarcinoma (NGOC) is an extremely rare ovarian tumor, with an incidence of less than 0.6% of malignant ovarian germ cell tumors. Its close pathologic resemblance to Gestational Ovarian Choriocarcinoma (GOC), however, requires special attention as the treatments differ greatly. NGOC typically affects patients in late adolescence or early reproductive years. As a result, NGOCs are often misdiagnosed as ectopic pregnancies due to their common presentation of bleeding, abdominal pain, adnexal mass, and positive serum beta-HCG. On pathologic examination, the tumor is indistinguishable from GOC, and only after review of tissue for paternal genetic components can the diagnosis of NGOC be made. Imaging studies often show highly vascular lesions with further investigation with computer topography (CT) sometimes showing metastatic lesions in the lungs, pelvis, vagina, and liver. These lesions are often hemorrhagic and can lead to catastrophic bleeding. Treatment is vastly different from GOC; NGOC requires treatment with both surgical resection and chemotherapy, with Bleomycin, Etoposide, and Cisplatin (BEP) being the most used regimen. With correct diagnosis and treatment, patients can often receive fertility sparing treatment with long term survival.

Endometrial carcinoma (EC) is the most common gynecologic malignancy in the United States, with limited effective targeted therapies. Endometrial tumors exhibit frequent alterations in protein kinases, yet only a small fraction of the kinome has been therapeutically explored. To identify kinase therapeutic avenues for EC, we profiled the kinome of endometrial tumors and normal endometrial tissues using Multiplexed Inhibitor Beads and Mass Spectrometry (MIB-MS). Our proteomics analysis identified a network of kinases overexpressed in tumors, including Serine/Arginine-Rich Splicing Factor Kinase 1 (SRPK1). Immunohistochemical (IHC) analysis of endometrial tumors confirmed MIB-MS findings and showed SRPK1 protein levels were highly expressed in endometrioid and uterine serous cancer (USC) histological subtypes. Moreover, querying large-scale genomics studies of EC tumors revealed high expression of SRPK1 correlated with poor survival. Loss-of-function studies targeting SRPK1 in an established USC cell line demonstrated SRPK1 was integral for RNA splicing, as well as cell cycle progression and survival under nutrient deficient conditions. Profiling of USC cells identified a compensatory response to SRPK1 inhibition that involved EGFR and the up-regulation of IGF1R and downstream AKT signaling. Co-targeting SRPK1 and EGFR or IGF1R synergistically enhanced growth inhibition in serous and endometrioid cell lines, representing a promising combination therapy for EC., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (© 2020 Kurimchak et al.)

Purpose: To evaluate the safety and clinical activity of mirvetuximab soravtansine, an antibody-drug conjugate comprising a humanized anti-folate receptor alpha (FRα) monoclonal antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent, in combination with bevacizumab in patients with FRα-positive, platinum-resistant ovarian cancer., Methods: Patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer were administered mirvetuximab soravtansine (6 mg/kg, adjusted ideal body weight) and bevacizumab (15 mg/kg) once every 3 weeks. Eligibility included FRα positivity by immunochemistry and prior bevacizumab exposure was permitted. Adverse events, tumor response, and progression-free survival (PFS) were determined., Results: Sixty-six patients, with a median of 3 prior lines of therapy (range, 1-8), received the combination of mirvetuximab soravtansine and bevacizumab at full dosing during the escalation and expansion stages of the study. Adverse events were generally mild-to-moderate (≤grade 2) with diarrhea, blurred vision, nausea, and fatigue being the most common treatment-related toxicities. Six cases of pneumonitis (9%; all grade 1 or 2), an adverse event of special interest, were observed. The confirmed objective response rate (ORR) was 39%, including 5 complete responses and 21 partial responses, and the median PFS was 6.9 months. The combination was particularly active in the subset of patients (n = 16) who were bevacizumab-naïve, less heavily pretreated (1-2 prior lines), and whose tumors exhibited medium/high FRα expression (ORR, 56% with a median duration of response of 12 months; PFS, 9.9 months)., Conclusion: The combination of mirvetuximab soravtansine with bevacizumab is well tolerated in patients with platinum-resistant, recurrent ovarian cancer. The encouraging efficacy measures compare favorably to reported outcomes for bevacizumab combined with standard chemotherapy in similar patient populations., Competing Interests: Declaration of competing interest This study was supported by ImmunoGen, Inc. Karim Malek is an employee of ImmunoGen. There are no other conflicts of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecological cancer with few effective, targeted therapies. HGSOC tumors exhibit genomic instability with frequent alterations in the protein kinome; however, only a small fraction of the kinome has been therapeutically targeted in HGSOC. Using multiplexed inhibitor beads and mass spectrometry, we mapped the kinome landscape of HGSOC tumors from patients and patient-derived xenograft models. The data revealed a prevalent signature consisting of established HGSOC driver kinases, as well as several kinases previously unexplored in HGSOC. Loss-of-function analysis of these kinases in HGSOC cells indicated MRCKA (also known as CDC42BPA) as a putative therapeutic target. Characterization of the effects of MRCKA knockdown in established HGSOC cell lines demonstrated that MRCKA was integral to signaling that regulated the cell cycle checkpoint, focal adhesion, and actin remodeling, as well as cell migration, proliferation, and survival. Moreover, inhibition of MRCKA using the small-molecule BDP9066 decreased cell proliferation and spheroid formation and induced apoptosis in HGSOC cells, suggesting that MRCKA may be a promising therapeutic target for the treatment of HGSOC., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Purpose: High-grade serous ovarian cancer (HGSOC) is an aggressive disease with few available targeted therapies. Despite high expression of estrogen receptor-alpha (ERα) in approximately 80% of HGSOC and some small but promising clinical trials of endocrine therapy, ERα has been understudied as a target in this disease. We sought to identify hormone-responsive, ERα-dependent HGSOC. Experimental Design: We characterized endocrine response in HGSOC cells across culture conditions [ two-dimensional (2D), three-dimensional (3D), forced suspension] and in patient-derived xenograft (PDX) explants, assessing proliferation and gene expression. Estrogen-regulated transcriptome data were overlapped with public datasets to develop a comprehensive panel of ERα target genes. Expression of this panel and ERα H-score were assessed in HGSOC samples from patients who received endocrine therapy. Time on endocrine therapy was used as a surrogate for clinical response. Results: Proliferation is ERα-regulated in HGSOC cells in vitro and in vivo , and is partly dependent on 3D context. Transcriptomic studies identified genes shared by cell lines and PDX explants as ERα targets. The selective ERα downregulator (SERD) fulvestrant is more effective than tamoxifen in blocking ERα action. ERα H-score is predictive of efficacy of endocrine therapy, and this prediction is further improved by inclusion of target gene expression, particularly IGFBP3 Conclusions: Laboratory models corroborate intertumor heterogeneity of endocrine response in HGSOC but identify features associated with functional ERα and endocrine responsiveness. Assessing ERα function (e.g., IGFBP3 expression) in conjunction with H-score may help select patients who would benefit from endocrine therapy. Preclinical data suggest that SERDs might be more effective than tamoxifen. Clin Cancer Res; 23(14); 3802-12. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Objectives: The purpose of this study was to examine the impact of adjuvant radiation on overall survival (OS) and cancer specific survival (CSS) in patients with lymph node (LN) positive endometrial cancer., Methods: We analyzed all women diagnosed with FIGO stage IIIC endometrial adenocarcinoma in the Surveillance, Epidemiology, and End Results database from 2004 to 2012 (n=2177). Patients not undergoing surgery or with missing treatment information were excluded. Chi-squared tests were used to compare predictors of treatment received. Cox proportional hazards model and Kaplan-Meier method were used to assess OS and CSS., Results: The median age was 60 (27-84) and the median follow-up was 31months (2-107). Adjuvant radiation was administered to 1248 (60.3%) patients. A total of 1363 (65.9%) patients had pelvic LN involvement while 658 (31.8%) had para-aortic involvement. The 3-year actuarial OS for patients with and without radiation was 80.5% and 67.6%, respectively (p<0.001). The 3-year actuarial CSS for patients with and without radiation was 83.4% and 73%, respectively (p<0.001). On multivariable analysis, receipt of radiotherapy remained associated with OS (HR 0.61 95% CI 0.51-0.74) and CSS (HR 0.65, 95% CI 0.53-0.80). After propensity matching, radiotherapy continued to be associated with an improved OS (HR 0.65 95% CI 0.54-0.78) and CSS (HR 0.65 95% CI 0.53-0.81). The addition of brachytherapy was not associated with OS or CSS., Conclusions: In this large population registry analysis, adjuvant radiation was associated with improved OS and CSS in patients with LN positive endometrial cancer. Prospective data is needed to confirm these findings., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Dendritic cells are the professional antigen-presenting cells of the innate immune system with the potential to generate robust antigen-specific T cell immune responses. Immunotherapeutic strategies have attempted to monopolize on this ability of dendritic cells to deliver antigens as a means of therapeutic vaccination in individuals with advanced malignancies. Since the publication of the first clinical trial in melanoma patients in 1995, therapeutic dendritic cell cancer vaccines have been extensively studied in numerous phase I and II trials. While advances have been encountered (especially with prostate cancer), there are still considerable challenges that need to be addressed in future clinical trials. In this review, we describe the current methodology and highlight trials which have contributed to the development of dendritic cell vaccines. We then review strategies to optimize dendritic cell vaccines in order to improve antitumor responses in cancer patients.

Purpose: Whole tumor lysates are promising antigen sources for dendritic cell (DC) therapy as they contain many relevant immunogenic epitopes to help prevent tumor escape. Two common methods of tumor lysate preparations are freeze-thaw processing and UVB irradiation to induce necrosis and apoptosis, respectively. Hypochlorous acid (HOCl) oxidation is a new method for inducing primary necrosis and enhancing the immunogenicity of tumor cells., Experimental Design: We compared the ability of DCs to engulf three different tumor lysate preparations, produce T-helper 1 (TH1)-priming cytokines and chemokines, stimulate mixed leukocyte reactions (MLR), and finally elicit T-cell responses capable of controlling tumor growth in vivo., Results: We showed that DCs engulfed HOCl-oxidized lysate most efficiently stimulated robust MLRs, and elicited strong tumor-specific IFN-γ secretions in autologous T cells. These DCs produced the highest levels of TH1-priming cytokines and chemokines, including interleukin (IL)-12. Mice vaccinated with HOCl-oxidized ID8-ova lysate-pulsed DCs developed T-cell responses that effectively controlled tumor growth. Safety, immunogenicity of autologous DCs pulsed with HOCl-oxidized autologous tumor lysate (OCDC vaccine), clinical efficacy, and progression-free survival (PFS) were evaluated in a pilot study of five subjects with recurrent ovarian cancer. OCDC vaccination produced few grade 1 toxicities and elicited potent T-cell responses against known ovarian tumor antigens. Circulating regulatory T cells and serum IL-10 were also reduced. Two subjects experienced durable PFS of 24 months or more after OCDC., Conclusions: This is the first study showing the potential efficacy of a DC vaccine pulsed with HOCl-oxidized tumor lysate, a novel approach in preparing DC vaccine that is potentially applicable to many cancers., (©2013 AACR.)

•Ovarian cancer patients receiving bevacizumab treatment can experience significant adverse events.•We report a case of vertebral artery dissection associated with bevacizumab treatment.

Ovarian cancer is the most deadly gynecologic malignancy, with more than 15,000 deaths anticipated in 2012. While approximately 80% of patients will respond to frontline chemotherapy, more than 60% of patients will experience disease recurrence and only 44% will be alive at 5 y. Host anti-tumor immune responses are associated with a significant improvement in overall survival for women with ovarian cancer. By bolstering these responses, it may therefore be possible to significantly influence the prognosis of women with this lethal disease. In this review, we will focus on innovative immune-based strategies which are currently being investigated in the treatment of ovarian cancer.

With advances in surgical techniques and chemotherapeutic agents, mortality rates from epithelial ovarian cancer (EOC) have slightly decreased over the last 30 years. However, EOC still ranks as the most deadly gynecologic cancer with an overall 5-year survival rate of 45%. Prognosis is especially disappointing for women with platinum-resistant disease, where 80% of patients will fail to respond to available therapies. Emerging treatment strategies have sub-sequently focused on targets which are integral to tumor growth and metastasis. In this review, we will focus on those innovative agents currently under investigation in clinical trials.