scholarly journals Translational Development of A Tumor Junction Opening Technology

2021 ◽  
Author(s):  
Jiho Kim ◽  
Chang Li ◽  
Hongjie Wang ◽  
Swarnendu Kaviraj ◽  
Sanjay Singh ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Resistance Mechanism ◽  
Pegylated Liposomal Doxorubicin ◽  
Treatment Resistance ◽  
Drug Penetration ◽  
Response To Chemotherapy ◽  
Cynomolgus Macaques ◽  
Multiple Cycles ◽  
New Treatment ◽  
Pro Inflammatory Cytokines

Abstract Our goal is to overcome treatment resistance in ovarian cancer patients, which occurs in most cases after an initial positive response to chemotherapy. A central resistance mechanism is the maintenance of desmoglein-2 (DSG2)-positive tight junctions between malignant cells, which prevents drug penetration into the tumor. We generated JO4, a recombinant protein that binds to DSG2, resulting in the transient opening of junctions in epithelial tumors. Here, we present studies on the clinical translation of JO4 in combination with PEGylated liposomal doxorubicin/Doxil® for ovarian cancer therapy. A manufacturing process for cGMP-compliant production of JO4 was developed. GLP toxicology studies using material from this process in DSG2 transgenic mice and cynomolgus macaques showed no treatment-related toxicities after intravenous injection at doses reaching 24 mg/kg. Multiple cycles of intravenous JO4 plus Doxil® (4 cycles, 4 weeks apart, simulating the treatment regimen in the clinical trial) elicited antibodies against JO4 that increased with each cycle and were accompanied by elevation of pro-inflammatory cytokines IL6 and TNF. Pretreatment with steroids and cyclophosphamide reduced the anti-JO4 antibody response and blunted cytokine release. Our data indicate acceptable safety of our new treatment approach if immune reactions are monitored and counteracted with appropriate immune suppression.

scholarly journals Overcoming Platinum and PARP-Inhibitor Resistance in Ovarian Cancer

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1607
Author(s):  
Michelle McMullen ◽  
Katherine Karakasis ◽  
Ainhoa Madariaga ◽  
Amit M. Oza
Keyword(s):  
Ovarian Cancer ◽  
Parp Inhibitor ◽  
Acquired Resistance ◽  
Resistance Mechanism ◽  
Treatment Resistance ◽  
Tumour Microenvironment ◽  
Resistance Mechanisms ◽  
Cell Cycle Checkpoint ◽  
Angiogenic Therapy ◽  
Cycle Checkpoint

Platinum chemotherapy remains the cornerstone of treatment for epithelial ovarian cancer (OC) and Poly (ADP-ribose) polymerase inhibitors (PARPi) now have an established role as maintenance therapy. The mechanisms of action of these agents is, in many ways, complementary, and crucially reliant on the intracellular DNA Damage Repair (DDR) response. Here, we review mechanisms of primary and acquired resistance to treatment with platinum and PARPi, examining the interplay between both classes of agents. A key resistance mechanism appears to be the restoration of the Homologous Recombination (HR) repair pathway, through BRCA reversion mutations and epigenetic upregulation of BRCA1. Alterations in non-homologous end-joint (NHEJ) repair, replication fork protection, upregulation of cellular drug efflux pumps, reduction in PARP1 activity and alterations to the tumour microenvironment have also been described. These resistance mechanisms reveal molecular vulnerabilities, which may be targeted to re-sensitise OC to platinum or PARPi treatment. Promising therapeutic strategies include ATR inhibition, epigenetic re-sensitisation through DNMT inhibition, cell cycle checkpoint inhibition, combination with anti-angiogenic therapy, BET inhibition and G-quadruplex stabilisation. Translational studies to elucidate mechanisms of treatment resistance should be incorporated into future clinical trials, as understanding these biologic mechanisms is crucial to developing new and effective therapeutic approaches in advanced OC.

scholarly journals A phase I study of combined trabectedin and pegylated liposomal doxorubicin therapy for advanced relapsed ovarian cancer

2021 ◽  
Author(s):  
Shunji Takahashi ◽  
Munetaka Takekuma ◽  
Kenji Tamura ◽  
Kazuhiro Takehara ◽  
Hiroyuki Nomura ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Liposomal Doxorubicin ◽  
Advanced Ovarian Cancer ◽  
Pegylated Liposomal Doxorubicin ◽  
Japanese Patients ◽  
Pharmacokinetic Analysis ◽  
Dependent Manner ◽  
Drug Concentrations ◽  
Grade 3

Abstract Background Advanced relapsed ovarian cancer has a poor prognosis, and treatment options are limited. Methods This phase I trial investigated the dosage, safety, pharmacokinetics and efficacy of trabectedin plus pegylated liposomal doxorubicin (PLD) in Japanese patients with advanced relapsed ovarian, fallopian tube, or primary peritoneal cancer. Patients received trabectedin 0.9 or 1.1 mg/m2 immediately after PLD 30 mg/m2; both drugs were given by intravenous infusion. Treatment was repeated every 21 days until disease progression or unacceptable toxicity. The maximum tolerated dose (MTD) was determined in an initial dose escalation phase, and this was used in a subsequent safety assessment phase. Safety and tumor response were monitored throughout the trial, and drug concentrations for pharmacokinetic analysis were measured during cycle 1. Results Eighteen patients were included. The MTD of trabectedin was determined as 1.1 mg/m2. Gastrointestinal adverse events were experienced by all patients, but were mostly grade 1 or 2 in intensity. Most patients had grade ≥ 3 elevations in transaminase levels or grade ≥ 3 reductions in neutrophil count, but these events were generally manageable through dose reduction and/or supportive therapies, as appropriate. There were no deaths during the trial. Trabectedin exposure increased in a dose-dependent manner. The overall response rate was 27.8%. Conclusions Trabectedin, in combination with PLD, may have clinical benefits in Japanese patients with relapsed advanced ovarian cancer. The recommended dosage of trabectedin for further study in this population is 1.1 mg/m2 once every 21 days. Clinical trial registration number: JapicCTI-163164

scholarly journals Molecular imaging and deep learning analysis of uMUC1 expression in response to chemotherapy in an orthotopic model of ovarian cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hongwei Zhao ◽  
Hasaan Hayat ◽  
Xiaohong Ma ◽  
Daguang Fan ◽  
Ping Wang ◽  
...  
Keyword(s):  
Neural Networks ◽  
Ovarian Cancer ◽  
Deep Learning ◽  
Cancer Progression ◽  
In Vivo Imaging ◽  
Near Infrared ◽  
Response To Therapy ◽  
Response To Chemotherapy

Abstract Artificial Intelligence (AI) algorithms including deep learning have recently demonstrated remarkable progress in image-recognition tasks. Here, we utilized AI for monitoring the expression of underglycosylated mucin 1 (uMUC1) tumor antigen, a biomarker for ovarian cancer progression and response to therapy, using contrast-enhanced in vivo imaging. This was done using a dual-modal (magnetic resonance and near infrared optical imaging) uMUC1-specific probe (termed MN-EPPT) consisted of iron-oxide magnetic nanoparticles (MN) conjugated to a uMUC1-specific peptide (EPPT) and labeled with a near-infrared fluorescent dye, Cy5.5. In vitro studies performed in uMUC1-expressing human ovarian cancer cell line SKOV3/Luc and control uMUC1low ES-2 cells showed preferential uptake on the probe by the high expressor (n = 3, p < .05). A decrease in MN-EPPT uptake by SKOV3/Luc cells in vitro due to uMUC1 downregulation after docetaxel therapy was paralleled by in vivo imaging studies that showed a reduction in probe accumulation in the docetaxel treated group (n = 5, p < .05). The imaging data were analyzed using deep learning-enabled segmentation and quantification of the tumor region of interest (ROI) from raw input MRI sequences by applying AI algorithms including a blend of Convolutional Neural Networks (CNN) and Fully Connected Neural Networks. We believe that the algorithms used in this study have the potential to improve studying and monitoring cancer progression, amongst other diseases.

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