crizotinib and Ovarian-Neoplasms

Poor outcomes for patients with ovarian cancer relate to dormant, drug-resistant cancer cells that survive after primary surgery and chemotherapy. Ovarian cancer (OvCa) cells persist in poorly vascularized scars on the peritoneal surface and depend on autophagy to survive nutrient deprivation. The authors have sought drugs that target autophagic cancer cells selectively to eliminate residual disease.. By using unbiased small-interfering RNA (siRNA) screens, the authors observed that knockdown of anaplastic lymphoma kinase (ALK) reduced the survival of autophagic OvCa cells. Small-molecule ALK inhibitors were evaluated for their selective toxicity against autophagic OvCa cell lines and xenografts. Autophagy was induced by reexpression of GTP-binding protein Di-Ras3 (DIRAS3) or serum starvation and was evaluated with Western blot analysis, fluorescence imaging, and transmission electron microscopy. Signaling pathways required for crizotinib-induced apoptosis of autophagic cells were explored with flow cytometric analysis, Western blot analysis, short-hairpin RNA knockdown of autophagic proteins, and small-molecule inhibitors of STAT3 and BCL-2.. Induction of autophagy by reexpression of DIRAS3 or serum starvation in multiple OvCa cell lines significantly reduced the 50% inhibitory concentration of crizotinib and other ALK inhibitors. In 2 human OvCa xenograft models, the DIRAS3-expressing tumors treated with crizotinib had significantly decreased tumor burden and long-term survival in 67% to 79% of mice. Crizotinib treatment of autophagic cancer cells further enhanced autophagy and induced autophagy-mediated apoptosis by decreasing phosphorylated STAT3 and BCL-2 signaling.. Crizotinib may eliminate dormant, autophagic, drug-resistant OvCa cells that remain after conventional cytoreductive surgery and combination chemotherapy. A clinical trial of ALK inhibitors as maintenance therapy after second-look operations should be seriously considered.

Topics: Anaplastic Lymphoma Kinase; Animals; Autophagy; Cell Line, Tumor; Cell Lineage; Cell Survival; Crizotinib; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Mice; Ovarian Neoplasms; Protein Kinase Inhibitors; rho GTP-Binding Proteins; RNA, Small Interfering; Signal Transduction; STAT3 Transcription Factor

Recently, multiple poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated excellent efficacy among patients with ovarian cancer with or without BRCA mutations. However, alternative therapeutic options are urgently required for patients who cannot benefit from conventional chemotherapy or PARP inhibitors.. A patient with high-grade serous ovarian carcinoma presented to our clinic after developing resistance to chemotherapy. Paired tumor-normal next-generation sequencing (NGS) was performed using peripheral blood to identify potential actionable mutations. NGS revealed the patient harboring a GOPC-ROS1 fusion, which was subsequently verified using a reverse transcription polymerase chain reaction assay. No germline or somatic mutation in BRCA1/2 or mismatch repair genes was detected. Therefore, the patient received crizotinib treatment. A rapid, favorable clinical response (partial response at 1 month) was observed, with further pathological response monitored and evaluated in follow-up interrogation.. This study suggested that crizotinib was an off-the-shelf, practical, and ostensibly effective treatment option for patients with ovarian cancer with ROS1 rearrangement. NGS-based genetic testing may guide to plan therapeutic paradigms, and render precision medicine promising in ovarian cancer treatment.. Despite the previous report of ROS1 fusion in patients with ovarian cancer, it remains unknown whether patients can benefit from targeted therapeutic drugs. This study reports a GOPC-ROS1 fusion identified by next-generation sequencing in a patient with chemotherapy-resistant ovarian cancer. The patient was administered crizotinib and showed rapid, remarkable response. This study suggests that comprehensive sequencing should be offered for patients with ovarian cancer without effective therapeutic strategies, and crizotinib can be used to treat ROS1-rearranged ovarian carcinomas.

Topics: Adaptor Proteins, Signal Transducing; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Golgi Matrix Proteins; Humans; Oncogene Proteins, Fusion; Ovarian Neoplasms; Protein-Tyrosine Kinases; Proto-Oncogene Proteins

Glycogen synthase kinase 3β (GSK 3β) is a highly conserved serine/threonine kinase, and its roles in cancer remain controversial. Cumulative evidence supported that GSK 3β inhibitors could suppress ovarian cancer (OC) development in vitro and made a new direction for ovarian cancer treatment. Here, we reported a series of novel substituted benzothiazinones as non-ATP competitive inhibitors of GSK 3β. Further studies showed that most of them had antiproliferative activities in ovarian cancer cell lines in vitro. As the most promising candidate of them, compound 20g induced cells apoptosis, arrested the cell cycle at the G1 phase in the A2780 cell line and showed moderate suppression efficacy in a female BALB/C nude mice model. All of the results demonstrated that compound 20g, as the first reported non-ATP competitive small molecule inhibitor of GSK 3β with suppression efficacy on ovarian cancer both in vitro and in vivo, might represent a potential candidate for the treatment of OC.

Topics: Animals; Benzothiazoles; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Discovery; Female; Glycogen Synthase Kinase 3 beta; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Ovarian Neoplasms; Protein Kinase Inhibitors; Structure-Activity Relationship; Tumor Cells, Cultured

Ovarian metastasis is an exceptionally rare condition in lung adenocarcinoma patients and is often difficult to distinguish from primary ovarian carcinoma. ALK (anaplastic lymphoma kinase) tyrosine kinase inhibitors elicit a significant objective response rate and are well-tolerated in advanced ALK-positive lung cancer. Hence, we report a case of a 41-year-old woman with ovarian metastases from NSCLC. After receiving a 6 course first line chemotherapy and 8 course maintenance therapy, the patient suffered acute abdominal pain, so surgery was performed. ALK rearrangement was detected by next generation sequencing, with a 13% abundance of ALK fusion. Crizotinib was administered, and the disease remained stable after 10 months of crizotinib therapy. Further, we reviewed the literature related to characteristics of metastatic ovarian malignancies that form from lung tumors, the utility of ALK inhibition for treating ALK-positive NSCLC, the molecular diagnosis of ALK rearrangement and the role of next generation sequencing for ALK rearrangement detection.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adult; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; High-Throughput Nucleotide Sequencing; Humans; Lung Neoplasms; Mutation; Ovarian Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

Lung cancer with ovarian metastasis or adnexal metastasis harboring anaplastic lymphoma kinase (ALK) gene translocation is rare. Crizotinib, a novel ALK tyrosine kinase inhibitor, has already shown an impressive single-agent activity in ALK positive lung cancer.. To summarize the case of clinical data and treatment of a 33-year-old woman with pelvic adnexal metastasis NSCLC.. Histological examination of the tumors showed lung adenocarcinoma. The right lung biopsy tissue and left adnexal mass biopsy tissue both revealed the presence of an ALK rearrangement by Ventana (D5F3) ALK immunohistochemistry assay (Ventana Medical Systems, Roche, Inc., Tuscon, AZ). The patient experienced a remarkable tumor response to crizotinib treatment.. Although the adnexal location is an uncommon metastasis site from lung cancer, oncologists should be aware of the possibility of such metastasis for female patients with ALK rearrangement NSCLC. Considering this remarkable response, we conclude that the presence of adnexal metastasis in NSCLC patients with ALK rearrangement should be attentive.

Topics: Adenocarcinoma; Adult; Biomarkers, Tumor; Biopsy; Crizotinib; Female; Humans; Immunohistochemistry; Lung Neoplasms; Neoplasm Staging; Oncogene Proteins, Fusion; Ovarian Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Tomography, X-Ray Computed; Translocation, Genetic

In this study, we investigated the therapeutic effects of c-MET inhibition in ovarian clear cell carcinoma (OCCC). Expression levels of c-MET in the epithelial ovarian cancers (EOCs) and normal ovarian tissues were evaluated using real-time PCR. To test the effects of c-MET inhibitors in OCCC cell lines, we performed MTT and apoptosis assays. We used Western blots to evaluate the expression of c-MET and its down-stream pathway. In vivo experiments were performed to test the effects of c-MET inhibitor on tumor growth in orthotopic mouse xenografts of OCCC cell line RMG1 and a patient-derived tumor xenograft (PDX) model of OCCC. c-MET expression was significantly greater in OCCCs compared with serous carcinomas and normal ovarian tissues (p < 0.001). In in vitro study, inhibition of c-MET using c-MET inhibitors (SU11274 or crizotinib) significantly decreased the proliferation, and increased the apoptosis of OCCC cells. SU11274 decreased expression of the p-c-MET proteins and blocked the phosphorylation of down-stream proteins Akt and Erk. Furthermore, SU11274 treatment significantly decreased the in vivo tumor weight in xenograft models of RMG1 cell and a PDX model for OCCC compared to control (p = 0.004 and p = 0.009, respectively).

Topics: Adenocarcinoma, Clear Cell; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Crizotinib; Female; Gene Expression Regulation, Neoplastic; Humans; Indoles; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Neoplasm Proteins; Ovarian Neoplasms; Phosphorylation; Piperazines; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Signal Transduction; Sulfonamides; Xenograft Model Antitumor Assays

Deregulated expression of the hepatocyte growth factor (HGF) receptor, c-Met, in cancer contributes to tumor progression and metastasis. The objective of this study was to determine whether blocking c-Met with an orally available c-Met inhibitor, PF-2341066, reduces tumor burden and increases survival in a xenograft model of ovarian cancer metastasis. Treatment of mice injected interperitoneally with SKOV3ip1 cells showed reduced overall tumor burden. Tumor weight and the number of metastases were reduced by 55% (P < .0005) and 62% (P < .0001), respectively. Treatment also increased median survival from 45 to 62 days (P = .0003). In vitro, PF-2341066 reduced HGF-stimulated phosphorylation of c-Met in the tyrosine kinase domain as well as phosphorylation of the downstream signaling effectors, Akt and Erk. It was apparent that inhibition of the pathways was functionally important because HGF-induced branching morphogenesis was also inhibited. In addition, proliferation and adhesion to various extracellular matrices were inhibited by treatment with PF-2341066, and the activity of matrix metalloproteinases was decreased in tumor tissue from treated mice compared with those receiving vehicle. Overall, these data indicate that PF-2341066 effectively reduces tumor burden in an in vivo model of ovarian cancer metastasis and may be a good therapeutic candidate in the treatment of patients with ovarian cancer.

Topics: Animals; Apoptosis; Blotting, Western; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Crizotinib; Female; Hepatocyte Growth Factor; Humans; Immunohistochemistry; Mice; Mice, Nude; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neoplasm Metastasis; Ovarian Neoplasms; Phosphorylation; Piperidines; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Signal Transduction; Survival Analysis; Tumor Burden; Xenograft Model Antitumor Assays