Targeting XPO1 and PAK4 in 8505C Anaplastic Thyroid Cancer Cells: Putative Implications for Overcoming Lenvatinib Therapy Resistance.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) that shows improved median progression-free survival (PFS) in patients with thyroid carcinomas. However, virtually all patients ultimately progress, indicating the need for a better understanding of the mechanisms of resistance. Here, we examined the molecular profile of anaplastic thyroid cancer cells (8505C) exposed to lenvatinib and found that long-term exposure to lenvatinib caused phenotypic changes. Consistent with change toward mesenchymal morphology, activation of pro-survival signaling, nuclear exporter protein exportin 1 (XPO1) and Rho GTPase effector p21 activated kinases (PAK) was also observed. RNA-seq analysis showed that prolonged lenvatinib treatment caused alterations in numerous cellular pathways and several oncogenes such as CEACAM (carcinoembryonic antigen-related cell adhesion molecule) and NUPR1 (Nuclear protein 1) were also upregulated. Further, we evaluated the impact of XPO1 and PAK4 inhibition in the presence or absence of lenvatinib. Targeted inhibition of XPO1 and PAK4 could sensitize the 8505C cells to lenvatinib. Both XPO1 and PAK4 inhibitors, when combined with lenvatinib, showed superior anti-tumor activity in 8505C sub-cutaneous xenograft. These studies bring forward novel drug combinations to complement lenvatinib for treating anaplastic thyroid cancer. Such combinations may possibly reduce the chances of lenvatinib resistance in thyroid cancer patients.

Syringe plunger contamination by hazardous drugs: a comparative study.

AIM: The purpose of this study was to perform a comparative cyclophosphamide contamination level test with Becton Dickinson® syringe plungers with Phaseal® Closed System Transfer Devices and Equashield® syringe plungers under routine oncological compounding conditions. METHOD: The ChemoGlo™ sampling kit and analysis services were used to test for cyclophosphamide contamination levels on the syringe plungers of Becton Dickinson® Phaseal and Equashield® syringes that underwent cycles of drug transfer in a Forma Class II, 2A Biological Safety Cabinet. Prior to testing, the syringes were divided into three equal groups for the Equashield® and Becton Dickinson® syringes. A 50 mL aliquot of cyclophosphamide was drawn into each syringe and then injected back into the cyclophosphamide vial. This drug transfer procedure was immediately repeated twice for the syringes in group 1, four times for group 2, and eight times for group 3. After the completion of the drug transfers with the Equashield® and Becton Dickinson® Phaseal syringes, the plungers were retracted back to the nominal syringe marking, and a wipe test of the exposed plunger was done using the ChemoGlo™ sampling kit. RESULTS: Significant contamination levels of 2000 ng and greater were detected on most Becton Dickinson® syringe plungers with Phaseal® Closed System Transfer Devices, whereas all Equashield® syringes remained uncontaminated at undetectable levels.

Calcium Release-Activated Calcium (CRAC) Channel Inhibition Suppresses Pancreatic Ductal Adenocarcinoma Cell Proliferation and Patient-Derived Tumor Growth.

Pancreatic ductal adenocarcinoma (PDAC) remains an unmet clinical problem in urgent need of newer molecularly driven treatment modalities. Calcium signals, particularly those associated with calcium release-activated calcium (CRAC) channels, are known to influence the development, growth, and metastasis of many cancers. This is the first study investigating the impact of CRAC channel inhibition on PDAC cell lines and patient-derived tumor models. PDAC cell lines were exposed to a novel CRAC channel inhibitor, RP4010, in the presence or absence of standard of care drugs such as gemcitabine and nab-paclitaxel. The in vivo efficacy of RP4010 was evaluated in a hyaluronan-positive PDAC patient-derived xenograft (PDx) in the presence or absence of chemotherapeutic agents. Treatment of PDAC cell lines with single-agent RP4010 decreased cell growth, while the combination with gemcitabine/nab-paclitaxel exhibited synergy at certain dose combinations. Molecular analysis showed that RP4010 modulated the levels of markers associated with CRAC channel signaling pathways. Further, the combination treatment was observed to accentuate the effect of RP4010 on molecular markers of CRAC signaling. Anti-tumor activity of RP4010 was enhanced in the presence of gemcitabine/nab-paclitaxel in a PDAC PDx model. Our study indicates that targeting CRAC channel could be a viable therapeutic option in PDAC that warrants further clinical evaluation.

Low-grade gliomas in adults.

Making treatment decisions for patients with infiltrating low-grade gliomas (LGGs) is challenging. Patients frequently present with seizures and usually have little or no neurologic deficit. In this younger and relatively well patient population, despite the potential for significant morbidity, we believe that surgical resection, radiation therapy, and chemotherapy each play an important role in the optimal management of these tumors. Randomized clinical trials have begun to address some of the many questions about prognosis, natural history, and treatment, but most questions have yet to be answered. We believe that, when possible, a maximal surgical resection consistent with preservation of neurologic function should be performed, even though it is likely that no randomized clinical trial will ever be done to demonstrate a survival advantage for this approach. External beam radiation therapy is most often given to a total dose of 50.4 or 54 Gy in 1.8-Gy fractions. The role of chemotherapy is less certain, but a growing body of evidence suggests that temozolomide, a generally well-tolerated drug, is active in the treatment of LGGs. In recent years, loss of heterozygosity of chromosome 1p and 19q, as well as silencing of the MGMT gene, have been identified as promising predictors of response to adjuvant therapy in gliomas. Although randomized trials have not yet shown a survival benefit for early radiation therapy or chemotherapy, one study by the European Organisation for Research and Treatment of Cancer did show an improvement in time to tumor progression with the earlier use of radiation therapy. In addition, a trial by the Radiation Therapy Oncology Group (soon to be analyzed and reported) is comparing radiation alone with radiation followed by a year (six cycles) of standard-dose PCV chemotherapy (procarbazine, CCNU, and vincristine); this trial may shed light on the use of chemotherapy in conjunction with radiation therapy for the initial treatment of LGGs. Because patients remain at risk for tumor progression for the remainder of their lives, we recommend lifelong follow-up with MRI scans, even for patients without documented tumor regrowth over long intervals. To give clinicians a more solid basis for guiding therapy recommendations, we encourage participation in large cooperative group clinical trials.