The targeted SMAC mimetic SW IV-134 augments platinum-based chemotherapy in pre-clinical models of ovarian cancer

Background: Ovarian cancer is initially responsive to frontline chemotherapy. Unfortunately, it often recurs and becomes resistant to available therapies and the survival rate for advanced and recurrent ovarian cancer is unacceptably low. We thus hypothesized that it would be possible to achieve more durable treatment responses by combining cisplatin chemotherapy with SW IV-134, a cancer-targeted peptide mimetic and inducer of cell death. SW IV-134 is a recently developed small molecule conjugate linking a sigma-2 ligand with a peptide analog (mimetic) of the intrinsic death pathway activator SMAC (second-mitochondria activator of caspases). The sigma-2 receptor is overexpressed in ovarian cancer and the sigma-2 ligand portion of the conjugate facilitates cancer selectivity. The effector portion of the conjugate is expected to synergize with cisplatin chemotherapy and the cancer selectivity is expected to reduce putative off-target toxicities. Methods: Ovarian cancer cell lines were treated with cisplatin alone, SW IV-134 alone and a combination of the two drugs. Treatment efficacy was determined using luminescent cell viability assays. Caspase-3/7,-8 and-9 activities were measured as complementary indicators of death pathway activation. Syngeneic mouse models and patient-derived xenograft (PDX) models of human ovarian cancer were studied for response to SW IV-134 and cisplatin monotherapy as well as combination therapy. Efficacy of the therapy was measured by tumor growth rate and survival as the primary readouts. Potential drug related toxicities were assessed at necropsy. Results: The combination treatment was consistently superior in multiple cell lines when compared to the single agents in vitro. The expected mechanism of tumor cell death, such as caspase activation, was confirmed using luminescent and flow cytometry-based assay systems. Combination therapy proved to be superior in both syngeneic and PDX-based murine models of ovarian cancer. Most notably, combination therapy resulted in a complete resolution of established tumors in all study animals in a patient-derived xenograft model of ovarian cancer. Conclusions: The addition of SW IV-134 in combination with cisplatin chemotherapy represents a promising treatment option that warrants further pre-clinical development and evaluation as a therapy for women with advanced ovarian cancer.

Visceral Obesity Determined by CT As a Predictor of Short-term Postoperative Complications in Ovarian Cancer

Objective: To explore the association between visceral obesity and short-term postoperative complications in patients with advanced ovarian cancer undergoing cytoreductive surgery.Methods: Medical records were reviewed for patients with ovarian cancer. Visceral fat area, subcutaneous fat area and total fat area were measured on a single slice at the level of L3/4 of a preoperative CT scan. Univariable and multivariable analyses were performed to investigate the correlation between visceral obesity and short-term complications and to analyze the risk factors for complications after surgery.Results: Of the 130 patients, 53.8% (70/130) were presented visceral obesity. Patients with visceral obesity were older than those with nonvisceral obesity (58.3 years old vs. 52.3 years old, p = 0.001). The proportion of patients with hypertension was slightly higher (37.1% vs. 11.7%, p = 0.001). The total fat area and subcutaneous fat area were higher in patients with visceral obesity (296.9 ± 72.1 vs. 173.1 ± 67.3, p < 0.001; 168.8 ± 55.5 vs. 121.6 ± 54.3, p < 0.001). Compared with patients in the nonvisceral obese group, patients in the visceral obese group were more likely to have postoperative fever (21/70 30.0% vs. 8/60 1.25%, p = 0.023), leading to a longer length of hospital stay (21 days vs. 17 days, p = 0.009). Time from surgery to adjuvant chemotherapy for patients with visceral obesity has been delayed (24 days vs. 20 days, p = 0.037). Multivariate analysis showed that visceral obesity (OR 4.770, p < 0.001) and operation time (OR 1.008, p < 0.001) were independent predictors of postoperative complications. Conclusion: Visceral obesity is an important risk factor for short-term postoperative complications in patients with advanced ovarian cancer undergoing cytoreductive surgery.

Role of MRI in Pre-Operative Assessment of Patients with Advanced Ovarian Cancer Candidate for Cytoreductive Surgery, A Brief Review

When it comes to gynecologic cancer, ovarian cancer with no doubt is the deadliest and most challenging. The reason often falls into the late presentation, in fact the clinical symptoms are not prominent until the disease is disseminated In patients with advanced ovarian cancer cytoreductive surgery procedure is the key element in treatment plan. One of the best tools to predict successful and complete cytoreductive surgery is using prior imaging. Magnetic resonance imaging is one of the newly described imaging modality for advanced ovarian cancer patients selected for cytoreductive surgery. Here we discussed the application of MRI in advanced ovarian cancer underwent cytoreductive surgery.

Carrier-Free Multifunctional Nanomedicine For Intraperitoneal Disseminated Ovarian Cancer Therapy

Background: Ovarian cancer is the most lethal gynecological cancer which is characterized by extensive peritoneal implantation metastasis and malignant ascites. Despite advances in diagnosis and treatment in recent years, the five-year survival rate is only 25 - 30%. Therefore, developing multifunctional nanomedicine with abilities of promoting apoptosis and inhibiting migration on tumor cells would be a promising strategy to improve the antitumor effect.Methods and results: In this study, we developed a novel ACaT nanomedicine composed of alendronate, calcium ions and cyclin-dependent kinase 7 (CDK7) inhibitor THZ1. With the average size of 164 nm and zeta potential of 12.4 mV, the spherical ACaT nanoparticles were selectively internalized by tumor cells and effectively accumulated in the tumor site. Results of RNA-sequencing and in vitro experiments showed that ACaT promoted tumor cell apoptosis and inhibited tumor cell migration by arresting the cell cycle, increasing ROS and affecting calcium homeostasis. Weekly intraperitoneally administered of ACaT for 8 cycles significantly inhibited the growth of tumor and prolonged the survival of intraperitoneal xenograft mice.Conclusion: In summary, this study presents a new self-assembly nanomedicine with favorable tumor targeting, antitumor activity and good biocompatibility, providing a novel therapeutic strategy for advanced ovarian cancer.