The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN.

The first-in-class inhibitor of ALK, c-MET and ROS1, crizotinib (Xalkori), has shown remarkable clinical efficacy in treatment of ALK-positive non-small cell lung cancer. However, in neuroblastoma, activating mutations in the ALK kinase domain are typically refractory to crizotinib treatment, highlighting the need for more potent inhibitors. The next-generation ALK inhibitor PF-06463922 is predicted to exhibit increased affinity for ALK mutants prevalent in neuroblastoma. We examined PF-06463922 activity in ALK-driven neuroblastoma models in vitro and in vivo In vitro kinase assays and cell-based experiments examining ALK mutations of increasing potency show that PF-06463922 is an effective inhibitor of ALK with greater activity towards ALK neuroblastoma mutants. In contrast to crizotinib, single agent administration of PF-06463922 caused dramatic tumor inhibition in both subcutaneous and orthotopic xenografts as well as a mouse model of high-risk neuroblastoma driven by Th-ALK(F1174L)/MYCN Taken together, our results suggest PF-06463922 is a potent inhibitor of crizotinib-resistant ALK mutations, and highlights an important new treatment option for neuroblastoma patients.

Screening for BRCA1 large genomic rearrangements in female Egyptian hereditary breast cancer patients.

Approximately 5%-10% of all breast cancers are inherited as the result of germline mutations in the BRCAl gene. Large genomic rearrangements (LGRs) in BRCA1 have not been well-researched in the Egyptian population. Using multiplex ligation-dependent probe amplification, we showed BRCA1 rearrangements in 4/22 cases (18.2%) of familial breast cancer. No influence of having multiple breast cancer cases within the family was observed in patients diagnosed at or=45 years and having BRCAl-positive LGRs. However, focusing on cases with first- and second-degree relatives affected, we observed a significant difference between the percentage of patients with BRCA1-positive versus BRCAl-negative LGRs. Our results provide the first evidence that LGRs in BRCA1 exist in the Egyptian population. Screening for these alterations may be desirable when breast cancer patients are diagnosed at an early age, especially if these cases have first- and second-degree of relatives with breast cancer.

Detection and semiquantitative determination of nickel with dimethylglyoxime-loaded foam.

Rapid, sensitive and selective detection and semiquantitative determination of nickel in aqueous solution can be obtained by using dimethylglyoxime loaded on polyurethane foam, either by batch or column extractions, the detection limits being 0.05 and 0.01 ppm respectively.