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Ovarian cancer target drugs

Han-Wei Lin, Ying-Cheng Chiang, Nai-Yun Sun, Yu-Li Chen, Chi-Fang Chang, Yi-Jou Tai, Chi-An Chen, Wen-Fang Cheng
The role of chitinase-3-like protein 1 (CHI3L1) in ovarian cancer and the possible mechanisms were elucidated. CHI3L1 is a secreted glycoprotein and associated with inflammation, fibrosis, asthma, extracellular tissue remodeling and solid tumors. Our previous study showed CHI3L1 could be a potential prognostic biomarker for epithelial ovarian cancer and protect cancer cells from apoptosis. Therefore, clinical data and quantitation of CHI3L1 of ovarian cancer patients, tumor spheroid formation, side-population assays, Aldefluor and apoptotic assays, ELISA, RT-PCR, immunoblotting, and animal experiments were performed in two ovarian cancer cells lines, OVCAR3 and CA5171, and their CHI3L1-overexpressing and knockdown transfectants...
August 18, 2018: Endocrine-related Cancer
Seema C Parte, Surinder K Batra, Sham S Kakar
BACKGROUND: Ovarian cancer is a complicated malady associated with cancer stem cells (CSCs) contributing to 238,700 estimated new cases and 151,900 deaths per year, worldwide. CSCs comprise a tiny fraction of tumor-bulk responsible for cancer recurrence and eventual mortality. CSCs or tumor initiating cells are responsible for self-renewal, differentiation and proliferative potential, tumor initiation capability, its progression, drug resistance and metastatic spread. Although several biomarkers are implicated in these processes, their distribution within the ovary and association with single cell type has neither been established nor demonstrated across ovarian tumor developmental stages...
August 18, 2018: Journal of Ovarian Research
Abhilash Samykutty, William E Grizzle, Benjamin L Fouts, Molly W McNally, Phillip Chuong, Alexandra Thomas, Akiko Chiba, Dennis Otali, Anna Woloszynska, Neveen Said, Peter J Frederick, Jacek Jasinski, Jie Liu, Lacey R McNally
At the intersection of the newly emerging fields of optoacoustic imaging and theranostic nanomedicine, promising clinical progress can be made in dismal prognosis of ovarian cancer. An acidic pH targeted wormhole mesoporous silica nanoparticle (V7-RUBY) was developed to serve as a novel tumor specific theranostic nanoparticle detectable using multispectral optoacoustic tomographic (MSOT) imaging. We report the synthesis of a small, < 40 nm, biocompatible asymmetric wormhole pore mesoporous silica core particle that has both large loading capacity and favorable release kinetics combined with tumor-specific targeting and gatekeeping...
August 4, 2018: Biomaterials
Yeongseon Byeon, Jeong-Won Lee, Wahn Soo Choi, Ji Eun Won, Ga Hee Kim, Min Gi Kim, Tae In Wi, Jae Myeong Lee, Tae Heung Kang, In Duk Jung, Young-Jae Cho, Hyung Jun Ahn, Byung Cheol Shin, Young Joo Lee, Anil K Sood, Hee Dong Han, Yeong-Min Park
Chemotherapy is commonly used in the treatment of ovarian cancer, yet most ovarian cancers harbor inherent resistance or develop acquired resistance. Therefore, novel therapeutic approaches to overcome chemoresistance are required. In this study, we developed a hyaluronic acid-labeled poly(d,l-lactide-co-glycolide) nanoparticle (HA-PLGA-NP) encapsulating both paclitaxel (PTX) and focal adhesion kinase (FAK) siRNA as a selective delivery system against chemoresistant ovarian cancer. The mean size and zeta potential of the HA-PLGA-NP were 220 nm and -7...
August 16, 2018: Cancer Research
Daniela Loessner, Peter Goettig, Sarah Preis, Johanna Felber, Holger Bronger, Judith A Clements, Julia Dorn, Viktor Magdolen
Aberrant levels of kallikrein-related peptidases (KLK1-15) have been linked to cancer cell proliferation, invasion and metastasis. In ovarian cancer, the KLK proteolytic network has a crucial role in the tissue and tumor microenvironment. Publically available ovarian cancer genome and expression data from multiple patient cohorts show an upregulation of most KLKs. Areas covered: Here, we review the expression levels of all 15 members of this family in normal and ovarian cancer tissues, categorizing them into highly and moderately or weakly expressed KLKs, and their association with patient prognosis and survival...
August 17, 2018: Expert Opinion on Therapeutic Targets
Luca Gambini, Ahmed F Salem, Parima Udompholkul, Xiao-Feng Tan, Carlo Baggio, Neh Shah, Alexander Aronson, Jikui Song, Maurizio Pellecchia
EphA2 overexpression is invariably associated with poor prognosis and development of aggressive metastatic cancers in pancreatic, prostate, lung, ovarian and breast cancers, and melanoma. Recent efforts from our laboratories identified a number of agonistic peptides targeting the ligand-binding domain of the EphA2 receptor. The individual agents, however, were still relatively weak in affinities (micromolar range) that precluded detailed structural studies on the mode of action. Using a systematic optimization of the 12-mer peptide mimetic 123B9, we were able to first derive an agent that displayed a sub-micromolar affinity for the receptor...
August 15, 2018: ACS Chemical Biology
Radoslav Chekerov, Felix Hilpert, Sven Mahner, Ahmed El-Balat, Philipp Harter, Nikolaus De Gregorio, Claudius Fridrich, Susanne Markmann, Jochem Potenberg, Ralf Lorenz, Guelten Oskay-Oezcelik, Marcus Schmidt, Petra Krabisch, Hans-Joachim Lueck, Rolf Richter, Elena Ioana Braicu, Andreas du Bois, Jalid Sehouli
BACKGROUND: Antiangiogenic therapy has known activity in ovarian cancer. The investigator-initiated randomised phase 2 TRIAS trial assessed the multi-kinase inhibitor sorafenib combined with topotecan and continued as maintenance therapy for platinum-resistant or platinum-refractory ovarian cancer. METHODS: We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 trial at 20 sites in Germany. Patients (≥18 years) with platinum-resistant ovarian cancer previously treated with two or fewer chemotherapy lines for recurrent disease were stratified (first vs later relapse) in block sizes of four and randomly assigned (1:1) using a web-generated response system to topotecan (1·25 mg/m2 on days 1-5) plus either oral sorafenib 400 mg or placebo twice daily on days 6-15, repeated every 21 days for six cycles, followed by daily maintenance sorafenib or placebo for up to 1 year in patients without progression...
August 9, 2018: Lancet Oncology
Laura R Hardy, Amrita Salvi, Joanna E Burdette
High-grade serous ovarian cancer is a deadly disease that can originate from the fallopian tube or the ovarian surface epithelium. The PAX (paired box) genes PAX2 and PAX8 are lineage-specific transcription factors required during development of the fallopian tube but not in the development of the ovary. PAX2 expression is lost early in serous cancer progression, while PAX8 is expressed ubiquitously. These proteins are implicated in migration, invasion, proliferation, cell survival, stem cell maintenance, and tumor growth...
August 8, 2018: Cancers
Antonious Hazim, Vinay Prasad
BACKGROUND: There is widespread interest in cancer basket trials. However, to date, there has been no formal analysis of all published basket trials. METHODS: We performed a systematic review to identify all published basket trials in cancer medicine. We included studies that (1) did not place restriction on tumour type and (2) used a biomarker for the basis of enrolment (3) administered at least one anti-cancer agent in prospective fashion and (4) reported responses by each tumour type included...
August 7, 2018: European Journal of Cancer
Kathleen N Moore, David M O'Malley, Ignace Vergote, Lainie P Martin, Antonio Gonzalez-Martin, Karim Malek, Michael J Birrer
PURPOSE: To evaluate the safety profile and preliminary antitumor activity of mirvetuximab soravtansine when administered in combination with carboplatin to relapsed ovarian cancer patients. METHODS: Patients with recurrent, platinum-sensitive epithelial ovarian or fallopian tube cancer were enrolled. Eligibility included a minimum requirement of tumor FRα positivity (≥25% of cells with ≥2+ staining intensity). Patients received escalating doses of mirvetuximab soravtansine and carboplatin on day 1 of a 21-day cycle (once every 3 weeks)...
August 6, 2018: Gynecologic Oncology
Ai Ai, Ying Xiong, Beiling Wu, Jiajia Lin, Yongyi Huang, Yilin Cao, Te Liu
Tripterygium glycosides (TGs) are chemotherapeutic drugs and immunosuppressant agents for the treatment of cancer and autoimmune diseases. We have previously reported that TGs induces premature ovarian failure (POF) by inducing cytotoxicity in ovarian granulosa cells (OGCs). Hence, we report that TGs suppress the expression of the Hippo-YAP/TAZ pathway in murine OGCs in vitro and in vivo. We found that the expressions of miR-181b, miR-15a, and miR-30d, were elevated significantly in the POF. Luciferase reporter assays confirmed that miR-15a targets Lats1 through a miR-15a binding site in the Lats1 3'UTR...
August 6, 2018: Gene
Chengqiong Mao, Yan Zhao, Fang Li, Zibo Li, Shaomin Tian, Waldemar Debinski, Xin Ming
Drug resistance remains a formidable challenge to cancer therapy. P-glycoprotein (Pgp) contributes to multidrug resistance in numerous cancers by preventing accumulation of anticancer drugs in cancer cells. Strategies to overcome this resistance have been vigorously sought for over 3 decades, yet clinical solutions do not exist. The main reason for the failure is lack of cancer specificity of small-molecule Pgp inhibitors, thus causing severe toxicity in normal tissues. In this study, Pgp-targeted photodynamic therapy (PDT) was developed to achieve superior cancer specificity through antibody targeting plus locoregional light activation...
August 3, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Lidija Covic, Athan Kuliopulos
The G-protein coupled receptors (GPCRs) belong to a large family of diverse receptors that are well recognized as pharmacological targets. However, very few of these receptors have been pursued as oncology drug targets. The Protease-activated receptor 1 (PAR1), which is a G-protein coupled receptor, has been shown to act as an oncogene and is an emerging anti-cancer drug target. In this paper, we provide an overview of PAR1's biased signaling role in metastatic cancers of the breast, lungs, and ovaries and describe the development of PAR1 inhibitors that are currently in clinical use to treat acute coronary syndromes...
July 31, 2018: International Journal of Molecular Sciences
Keita Togashi, Masashi Okada, Masahiro Yamamoto, Shuhei Suzuki, Tomomi Sanomachi, Shizuka Seino, Hidetoshi Yamashita, Chifumi Kitanaka
BACKGROUND: Chemoresistance of cancer stem cells (CSCs) is considered a major cause of post-treatment recurrence that negatively impacts the prognosis of patients with ovarian cancer. MATERIALS AND METHODS: Using CSCs derived from two different ovarian cancer cell lines, we searched for molecules implicated in the chemoresistance of ovarian CSCs and also drugs with which to target those molecules. RESULTS: Knockdown of survivin overexpressed in ovarian CSCs resulted in increased sensitivity to paclitaxel...
August 2018: Anticancer Research
Nicola S Meagher, Klaus Schuster, Andreas Voss, Timothy Budden, Chi Nam Ignatius Pang, Anna deFazio, Susan J Ramus, Michael L Friedlander
OBJECTIVE: Advanced stage mucinous ovarian cancers are diagnostically and therapeutically challenging. Histotype specific trials have failed due to low recruitment after excluding non-ovarian primaries. Mucinous ovarian cancers are commonly metastatic from other sites however lack definitive diagnostic markers. We suggest a classification of mucinous ovarian cancers of uncertain primary origin 'MO-CUPs' in clinical trials. This study aims to identify drug targets to guide treatment and future trials...
July 24, 2018: Gynecologic Oncology
David A Eavarone, Linah Al-Alem, Alexey Lugovskoy, Jillian M Prendergast, Rawan I Nazer, Jenna N Stein, Daniel T Dransfield, Jeff Behrens, Bo R Rueda
The expression of Sialyl-Tn (STn) in tumors is associated with metastatic disease, poor prognosis, and reduced overall survival. STn is expressed on ovarian cancer biomarkers including CA-125 (MUC16) and MUC1, and elevated serum levels of STn in ovarian cancer patients correlate with lower five-year survival rates. In the current study, we humanized novel anti-STn antibodies and demonstrated the retention of nanomolar (nM) target affinity while maintaining STn antigen selectivity. STn antibodies conjugated to Monomethyl Auristatin E (MMAE-ADCs) demonstrated in vitro cytotoxicity specific to STn-expressing ovarian cancer cell lines and tumor growth inhibition in vivo with both ovarian cancer cell line- and patient-derived xenograft models...
2018: PloS One
Hitoshi Sase, Yoshito Nakanishi, Satoshi Aida, Kana Horiguchi-Takei, Nukinori Akiyama, Toshihiko Fujii, Kiyoaki Sakata, Toshiyuki Mio, Masahiro Aoki, Nobuya Ishii
Fibroblast growth factor receptor 2 (FGFR2) gene is frequently amplified in gastric cancer. Recently, targeting FGFR2 has drawn attention as a form of gastric cancer therapy, and FGFR-selective inhibitors have shown promising efficacy in clinical studies. Because overcoming acquired resistance is a common problem with molecular targeting drugs, we investigated a resistant mechanism of FGFR inhibitors using the gastric cancer cell line SNU-16, which harbors FGFR2 amplification. We established single cell clones of FGFR inhibitor-resistant SNU-16 (AZD-R) by continuous exposure to AZD4547, a selective FGFR inhibitor...
July 25, 2018: Molecular Cancer Therapeutics
Lei Liu, Xiaoyuan Xiong, Ming Shen, Dan Ru, Pei Gao, Xiangyu Zhang, Can Huang, Ying Sun, He Li, Yourong Duan
Triptolide has proven to possess anticancer potential and been widely used for anti-cancer research. However, the liver and kidney toxicity has limited its application in cancer treatment. In this study, a drug delivery system based on mPEG-DPPE/calcium phosphate was developed to co-load triptolide and curcumin (TP and Curc-NPs). The coefficient of drug interaction (CDI) was calculated to determine the optimal concentration of the two drugs. When the concentration of triptolide was 25.22 ng/mL and the concentration of curcumin was 6...
October 1, 2018: Journal of Biomedical Nanotechnology
Aneta Rogalska, Arkadiusz Gajek, Małgorzata Łukawska, Irena Oszczapowicz, Agnieszka Marczak
Chemical modification of known, effective drugs are one method to improve the chemotherapy of tumors. We reported ability of oxazoline analogs of doxorubicin (O-DOX) and daunorubicin (O-DAU) to induce apoptosis and autophagy in ovarian and liver cancer cells. Reactive oxygen and nitrogen species (ROS and RNS, respectively), together with intracellular calcium-mediated downstream signaling, are essential for the anticancer effect of these new anthracycline analogs. The changes of mitochondrial membrane potential and induction of the ceramide pathway suggests that these compounds induce cell death by apoptosis...
2018: PloS One
Peixin Dong, Ying Xiong, Junming Yue, Sharon J B Hanley, Hidemichi Watari
B7H3 (also known as CD276, an immune checkpoint molecule) is aberrantly overexpressed in many types of cancer, and such upregulation is generally associated with a poor clinical prognosis. Recent discoveries indicate a crucial role for B7H3 in promoting carcinogenesis and metastasis. This review will focus on the latest developments relating specifically to the oncogenic activity of B7H3 and will describe the upstream regulators and downstream effectors of B7H3 in cancer. Finally, we discuss the emerging roles of microRNAs (miRNAs) in inhibiting B7H3-mediated tumor promotion...
2018: Frontiers in Oncology
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