Proceedings of the Japan Academy, Series B

We review the current understanding of the cosmological evolution of supermassive black holes in galactic centers elucidated by X-ray surveys of active galactic nuclei (AGNs). Hard X-ray observations at energies above 2 keV are the most efficient and complete tools to find “obscured” AGNs, which are dominant populations among all AGNs. Combinations of surveys with various flux limits and survey area have enabled us to determine the space number density and obscuration properties of AGNs as a function of luminosity and redshift. The results have essentially solved the origin of the X-ray background in the energy band below ∼10 keV. The downsizing (or anti-hierarchical) evolution that more luminous AGNs have the space-density peak at higher redshifts has been discovered, challenging theories of galaxy and black hole formation. Finally, we summarize unresolved issues on AGN evolution and prospects for future X-ray missions.

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Targeting of essential growth drivers represents an ideal approach to cancer treatment. To identify such molecules in clinical specimens, we developed a highly sensitive functional screening system based on the preparation of retroviral cDNA expression libraries. By screening such a library of lung adenocarcinoma with a focus formation assay, we discovered the EML4-ALK fusion-type oncogene. A small chromosomal inversion thus leads to fusion of the amino-terminal portion of the microtubule-associated protein EML4 to the intracellular kinase domain of ALK, a receptor-type protein tyrosine kinase. Constitutive dimerization of EML4-ALK mediated by a dimerization motif of EML4 results in kinase activation. Specific inhibitors of the kinase activity of ALK have been developed as therapeutic drugs for EML4-ALK–positive lung cancer, three of which (crizotinib, ceritinib, and alectinib) have already been approved for clinical use. An overall clinical response rate of 93.5% for alectinib has shown that agents that target essential growth drivers can become magic bullets for cancer treatment.

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