scholarly journals An Orally Available Small-Molecule Inhibitor of c-Met, PF-2341066, Reduces Tumor Burden and Metastasis in a Preclinical Model of Ovarian Cancer Metastasis

Neoplasia ◽  
2010 ◽  
Vol 12 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Marion Zillhardt ◽  
James G. Christensen ◽  
Ernst Lengyel
Keyword(s):  
Ovarian Cancer ◽  
Small Molecule ◽  
Cancer Metastasis ◽  
Small Molecule Inhibitor ◽  
Tumor Burden ◽  
Preclinical Model ◽  
Molecule Inhibitor

scholarly journals Abdominal FLASH irradiation reduces radiation-induced gastrointestinal toxicity for the treatment of ovarian cancer in mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Karen Levy ◽  
Suchitra Natarajan ◽  
Jinghui Wang ◽  
Stephanie Chow ◽  
Joshua T. Eggold ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Radiation Therapy ◽  
Dose Rate ◽  
Cancer Metastasis ◽  
Therapeutic Index ◽  
Similar Efficacy ◽  
High Dose Rate ◽  
Tumor Burden ◽  
Preclinical Model ◽  
High Dose

AbstractRadiation therapy is the most effective cytotoxic therapy for localized tumors. However, normal tissue toxicity limits the radiation dose and the curative potential of radiation therapy when treating larger target volumes. In particular, the highly radiosensitive intestine limits the use of radiation for patients with intra-abdominal tumors. In metastatic ovarian cancer, total abdominal irradiation (TAI) was used as an effective postsurgical adjuvant therapy in the management of abdominal metastases. However, TAI fell out of favor due to high toxicity of the intestine. Here we utilized an innovative preclinical irradiation platform to compare the safety and efficacy of TAI ultra-high dose rate FLASH irradiation to conventional dose rate (CONV) irradiation in mice. We demonstrate that single high dose TAI-FLASH produced less mortality from gastrointestinal syndrome, spared gut function and epithelial integrity, and spared cell death in crypt base columnar cells compared to TAI-CONV irradiation. Importantly, TAI-FLASH and TAI-CONV irradiation had similar efficacy in reducing tumor burden while improving intestinal function in a preclinical model of ovarian cancer metastasis. These findings suggest that FLASH irradiation may be an effective strategy to enhance the therapeutic index of abdominal radiotherapy, with potential application to metastatic ovarian cancer.

scholarly journals In silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Z. Ping Lin ◽  
Nour N. Al Zouabi ◽  
Mark L. Xu ◽  
Nicole E. Bowen ◽  
Terence L. Wu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Small Molecule ◽  
In Silico ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Small Molecule Inhibitor ◽  
Wild Type ◽  
In Silico Screening ◽  
Molecule Inhibitor ◽  
Inhibitor Resistance

AbstractPoly ADP-ribose polymerase (PARP) inhibitors are promising targeted therapy for epithelial ovarian cancer (EOC) with BRCA mutations or defective homologous recombination (HR) repair. However, reversion of BRCA mutation and restoration of HR repair in EOC lead to PARP inhibitor resistance and reduced clinical efficacy of PARP inhibitors. We have previously shown that triapine, a small molecule inhibitor of ribonucleotide reductase (RNR), impaired HR repair and sensitized HR repair-proficient EOC to PARP inhibitors. In this study, we performed in silico screening of small molecule libraries to identify novel compounds that bind to the triapine-binding pocket on the R2 subunit of RNR and inhibit RNR in EOC cells. Following experimental validation of selected top-ranking in silico hits for inhibition of dNTP and DNA synthesis, we identified, DB4, a putative RNR pocket-binding inhibitor markedly abrogated HR repair and sensitized BRCA-wild-type EOC cells to the PARP inhibitor olaparib. Furthermore, we demonstrated that the combination of DB4 and olaparib deterred the progression of BRCA-wild type EOC xenografts and significantly prolonged the survival time of tumor-bearing mice. Herein we report the discovery of a putative small molecule inhibitor of RNR and HR repair for combination with PARP inhibitors to treat PARP inhibitor-resistant and HR repair-proficient EOC.

scholarly journals Coupling Metastasis to pH-Sensing GPR68 Using a Novel Small Molecule Inhibitor

2019 ◽  
Author(s):  
Charles H. Williams ◽  
Leif R. Neitzel ◽  
Pratap Karki ◽  
Brittany D. Keyser ◽  
Timothy E. Thayer ◽  
...  
Keyword(s):  
Neural Crest ◽  
Cancer Progression ◽  
Small Molecule ◽  
Cancer Metastasis ◽  
Association Studies ◽  
Small Molecule Inhibitor ◽  
Migration And Invasion ◽  
Ph Sensing ◽  
Molecule Inhibitor

AbstractAn acidic milieu is a hallmark of the glycolytic metabolism that occurs in cancerous cells. The acidic environment is known to promote cancer progression, but the underlying signaling and cell biological underpinnings of these phenomena are not well understood. Here, we describe ogremorphin, a first-in-class small-molecule inhibitor of GPR68, an extracellular proton-sensing and mechanosensing G protein–coupled receptor. Ogremorphin was discovered in a chemical genetic zebrafish screen for its ability to perturb neural crest development, which shares basic cell behaviors of migration and invasion with cancer metastasis. Ogremorphin also inhibited migration and invasive behavior of neural crest–derived human melanoma cells in vitro. Furthermore, in phenome-wide association studies (PheWAS), we identified an aberrantly activated variant of GPR68, which is associated with cancer metastasis in vivo and promotes invasive phenotypes of cancer cells in vitro. Thus, extracellular proton-sensing GPR68 signaling promotes cell migration and invasion during embryonic development and may do likewise in cancer progression.

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