Identification of tumors harboring the <i>ALK^F1174L</i> mutation in <i>MYCN</i>-driven transgenic mice with intrinsic susceptibility MRI.

<p><b>A</b>) Anatomical transverse T₂*-weighted MR images acquired at TE = 6.8 and 15.6 ms from representative Th-<i>ALK^F1174L</i>/Th-<i>MYCN</i> and Th-<i>MYCN</i> mice with abdominal neuroblastoma during initial air breathing, and at TE = 15.6 ms after 5 minutes of continuous inhalation of 100% oxygen. <b>B</b>) Corresponding parametric tumor transverse relaxation rate R₂* maps calculated during initial air breathing and after 3 minutes of continuous inhalation of 100% oxygen. <b>C</b>) Resulting parametric tumor ΔR₂*_oxygen-air (R₂*_oxygen−R₂*_air) maps. <b>D</b>) Tumor R₂* during initial air breathing, <b>E</b>) tumor R₂* after 5 minutes of breathing 100% oxygen, and <b>F</b>) tumor ΔR₂*_oxygen-air (R₂*_oxygen−R₂*_air) were determined from Th-<i>ALK^F1174L</i>/Th-<i>MYCN</i> and Th-<i>MYCN</i> mice with abdominal neuroblastoma. Individual data points represent the mean of the median values determined from all three imaging slices for each animal, as well as the mean ±1 s.e.m, p, Student's 2-tailed unpaired t-test with a 5% level of significance.</p

Pathological comparison of tumors from Th-<i>ALK^F1174L</i>/Th-<i>MYCN</i> and Th-<i>MYCN</i> mice with abdominal neuroblastoma.

<p><b>A</b>) Gross pathology, <b>B</b>) composite images, and <b>C</b>) high magnification (x200) images from hematoxylin and eosin stained sections. Note the presence of large hemorrhagic regions filled with aggregated erythrocytes (*, blood lakes) extravasated from blood vessels (arrowed) in the tumor from the Th-<i>MYCN</i> mouse. <b>D</b>) Composite fluorescence images of uptake of the perfusion marker Hoechst 33342 into tumors from Th-<i>ALK^F1174L</i>/Th-<i>MYCN</i> and Th-<i>MYCN</i> mice with abdominal neuroblastoma. <b>E</b>) Quantitation of Hoechst 33342 uptake revealed significantly lower functionally perfused vasculature in tumors of Th-<i>ALK^F1174L</i>/Th-<i>MYCN</i> mice (n = 5) compared with tumors in Th-<i>MYCN</i> mice (n = 5). Data are mean ±1 s.e.m, p, Student's 2-tailed unpaired t-test with a 5% level of significance.</p

Discovery of Inhibitors That Overcome the G1202R Anaplastic Lymphoma Kinase Resistance Mutation

The treatment of patients with advanced non-small-cell lung cancer harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small-molecule inhibitor of ALK, ROS1, and MET. However, resistance to crizotinib inevitably develops through a variety of mechanisms, leading to relapse both systemically and in the central nervous system (CNS). This has motivated the development of “second-generation” ALK inhibitors, including alectinib and ceritinib, that overcome some of the mutations leading to resistance. However, most of the reported ALK inhibitors do not show inhibition of the G1202R mutant, which is one of the most common mutations. Herein, we report the development of a structural analogue of alectinib (JH-VIII-157-02) that is potent against the G1202R mutant as well as a variety of other frequently observed mutants. In addition, JH-VIII-157-02 is capable of penetrating the CNS of mice following oral dosing

Discovery of Inhibitors That Overcome the G1202R Anaplastic Lymphoma Kinase Resistance Mutation

The treatment of patients with advanced non-small-cell lung cancer harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small-molecule inhibitor of ALK, ROS1, and MET. However, resistance to crizotinib inevitably develops through a variety of mechanisms, leading to relapse both systemically and in the central nervous system (CNS). This has motivated the development of “second-generation” ALK inhibitors, including alectinib and ceritinib, that overcome some of the mutations leading to resistance. However, most of the reported ALK inhibitors do not show inhibition of the G1202R mutant, which is one of the most common mutations. Herein, we report the development of a structural analogue of alectinib (JH-VIII-157-02) that is potent against the G1202R mutant as well as a variety of other frequently observed mutants. In addition, JH-VIII-157-02 is capable of penetrating the CNS of mice following oral dosing

Radiological comparison of the Th-<i>ALK^F1174L</i>/Th-<i>MYCN</i> and Th-<i>MYCN</i> mice with abdominal neuroblastoma.

<p><b>A</b>) Anatomical transverse T₂-weighted MR images acquired with a rapid acquisition with refocused echoes (RARE) sequence and <b>B</b>) anatomical transverse T₂*-weighted MR images acquired at increasing gradient echo times as indicated, from representative presenting with abdominal neuroblastoma. <b>C</b>) Note the rapidly decaying tumor signal intensity in the Th-MYCN mouse, compared to the more sustained tumor signal observed in the Th-<i>ALK^F1174L</i>/Th-<i>MYCN</i> mouse.</p

Supplemtary table: Association of polymorphisms in ARRB2 (B-Arrestin2) and clinical response to methadone for pain in advanced cancer

Supplementary Table 1. Multiple regression analysis for patient characteristic variables for study population for methadone dose and pain score </div