Targeted therapy clinical trials in ovarian cancer: improved outcomes by gene mutation screening.

Epithelial ovarian cancer is the most common and leading cause of death for gynaecologic cancer in the western world. Current standard treatments with limited selection of chemotherapies cannot meet patients' urgent needs. Novel targeted therapies may improve patients' survival rate with less side effects that have been demonstrated by using approved medicines such as poly ADP-ribose polymerase and angiogenesis inhibitors. Many classes of targeted therapies impacting cell signalling pathways related to ovarian cancer tumorigenesis have been investigated in clinical trial studies. Gene mutation screening is a powerful tool for improvement of success rate of the trials for better patient selection and interpretation of clinical outcomes. Increasing number of patients are being screened for genetic alterations particularly in 'basket' trials that are offering new, genetic-oriented therapies to patients. Thus, in this review, we have searched databases of Pubmed and Clinicaltrials.gov for the past and current phase III and selected phase II ovarian cancer clinical trials with focus on gene profiling. Lessons from both successful and failed trials and implications of ongoing trials are discussed.

Mechanism of Human Tubal Ectopic Pregnancy Caused by Cigarette Smoking.

In the past few decades, the smoking rate of women of childbearing age has increased. Epidemiological data has repeatedly shown that smoking women have an increased risk of various reproductive diseases, including ectopic pregnancy (EP), decreased fertility, adverse pregnancy outcomes, and failure of assisted reproduction. The oviduct was the target of cigarette smoke in many in vivo and in vitro studies. The fallopian tube is a well-designed organ. Its function is to collect and transport the ova to the fertilized site and provide a suitable environment for fertilization and early embryonic development. Lastly, the fallopian tube transports the pre-implantation embryo to the uterus. Various biological processes can be studied in the fallopian tubes, making it an excellent model for toxicology. This paper reviews the roles of the fallopian tube in gametes and embryo transportation, and the possible mechanism tobacco smoke contributes to tubal EP. A possible signal pathway might be a model to develop intervention of EP for pregnant women exposed to smoking.

Advanced clinical trials of dendritic cell vaccines in ovarian cancer.

Epithelial ovarian cancer (EOC) is the most common and leading cause of death for gynecologic cancer in the western world. Current standard treatments with limited selection of chemotherapies cannot meet patients' urgent needs. Immunotherapies have recently demonstrated clinical benefits in a variety of solid tumors and may offer a promising frontier for treating EOC. Dendritic cells (DCs) are key coordinators of the innate and adaptive immune system in induction of antitumor immunity. DC-based vaccinations showed clinical benefits and encouraging safety profiles in a few phase II clinical trials for patients with EOC and currently are in a phase III double-blind, randomized, placebo-controlled clinical trial. In this review, we have searched Pubmed and Clinicaltrials. gov databases for past and current phase II or phase III clinical trials with focus on EOC and DC vaccines. Outcomes and implications of the completed and ongoing trials are discussed.

Clinical Trials of Novel Targeted Therapies in Ovarian Cancer: Moving Beyond Poly ADP Ribose Polymerase (PARP) Inhibitors.

BACKGROUND: Epithelial ovarian cancer (EOC) is one of the most common cancers in the female reproductive system and deadliest gynecological cancer in the United States. Standard treatments by surgery and platinum-based chemotherapy are not satisfied for the patients with high risk of relapse. Advances in molecular biology for EOC development have brought several targeted therapies to benefit recurrent patients. Poly-ADP-ribose polymerase inhibitors (PARPi) may be one of the most successful classes of targeted therapies with three approved medicines. For better clinical outcomes and more comprehensive disease management of EOC, more novel classes of targeted therapies are needed. METHOD: We focus on non-PARPi novel targeted therapies that are completed or on-going in phase III clinical trials by searching databases of Pubmed and Clinicaltrials.gov. Keywords of "ovarian cancer, targeted therapy and phase III trial" were used for publications and information from May 2012 to May 2018. RESULTS: There are total 150 viable EOC phase III studies listed in Clinicaltrials.gov., including 20 completed studies with results and 73 on-going studies. Bevacizumab plus chemotherapy is the only medication with government approval for recurrent EOC. Targeted therapies against other growthrelated factors, cytokines and folate receptor are failed in phase III trials or still on-going. CONCLUSION: Implications of on-going phase III trials are: 1) combination therapy of bevacizumab with atezolizumab may be the most anticipated studies for approvals; 2) mirvetuximab soravtansine plus chemotherapy may generate positive results to justify an approval; and 3) Immune therapy for EOC may bring new treatments for the patients.

Global protein expression profiling underlines reciprocal regulation of caveolin 1 and endothelial nitric oxide synthase expression in ovariectomized sheep uterine artery by estrogen/progesterone replacement therapy.

Ovariectomized (OVX) ewes were assigned to receive vehicle, progesterone (P4, 0.9-g controlled internal drug release vaginal implants), estradiol-17beta (E2, 5 microg/kg bolus + 6 microg kg(-1) day(-1)), or P4 + E2 for 10 days (n = 3/group). Uterine artery endothelial proteins were mechanically isolated on Day 10. The samples were used for protein expression profiling by the Ciphergen Proteinchip system and immunoblotting analysis of endothelial nitric oxide synthase (NOS3, also termed eNOS) and caveolin 1. Uterine artery rings were cut and analyzed by immunohistochemistry to localize NOS3 and caveolin 1 expression. With the use of the IMAC3 protein chip with loading as little as 2 microg protein/sample, many protein peaks could be detected. Compared to vehicle controls, a approximately 133.1-kDa protein was identified to be upregulated by 2- to 4-fold in OVX ewes receiving E2, P4, and their combination, whereas a approximately 22.6-kDa protein was downregulated by 2- to 4-fold in OVX ewes receiving E2 and E2/P4, but not P4 treatments. Western blot analysis revealed that E2, P4, and their combination all increased NOS3 protein, whereas E2 and its combination with P4, but not P4 alone, downregulated caveolin 1 expression. Immunohistochemical analysis revealed that NOS3 was mainly localized in the endothelium and upregulated by E2, whereas caveolin 1 was localized in both endothelium and smooth muscle and downregulated by E2. Thus, our data demonstrate that uterine artery endothelial NOS3 and caveolin 1 are regulated reciprocally by estrogen replacement therapy. In keeping with the facts that E2, but not P4, causes uterine vasodilatation and that E2 and P4 increase NOS3 expression, but only E2 decrease caveolin 1 expression, our current study suggests that both increased NOS3 expression and decreased caveolin 1 expression are needed to facilitate estrogen-induced uterine vasodilatation.