Characterization Human Disorders with a High-throughput Analysis of the Regulatory Mechanism for Gene Expression

Hiroyuki Mano (Professor of the Center for Molecular Medicine, Jichi Medical University)

Research Area: Basic Technology to Establishing Tailor-Made Medicine by Utilizing Genome Information (FY2002-2007)
The gene responsible for lung cancer EML4-ALK was discovered.
Revolutionary for lung cancer: The "being cured of cancer using pills" era has arrived.

Research Overview
Lung cancer remains the leading cause of cancer deaths, with an annual incidence of 1.3 millions worldwide, and 66,000 in Japan. Here, a novel functional screening system for cDNAs in clinical specimens has been developed, and used to discover a novel oncogene EML4-ALK in lung cancer. Based on this finding, both of molecular diagnosis of EML4-ALK-positive lung cancer and a highly effective molecular targeted therapy against this disorder have been achieved.
Moreover, the following results with this gene have been achieved: (1) Highly sensitive diagnosis of lung cancer from sputum and (2) Completely new medicine for treating lung cancer.

Impact of Research Achievements
■ Solid tumors such as lung cancer have been proved to be generated through chromosome rearrangements.
■ Although normal ALK is an enzyme to induce transient cell growth, a fusion event to EML4 leads to a marked elevation in its enzymatic activity, and thus induces cancer. Compounds to suppress ALK activity are presumed to become effective drugs against EML4-ALK-positive cancer, and are under development by many pharmaceutical companies.
A dramatic therapeutic effect of such inhibitors has been demonstrated already for patients with EML4-ALK. This discovery may thus help the survival of tens of thousands of patients every year.
■ The market size of the EML4-ALK molecular-targeted agent is estimated to be around 300 billion yen.

Transplantation of an own-oral-mucosa cell sheet for ocular pemphigoid
A chromosome rearrangement, inv(2p),
generates the EML4-ALK fusion gene.
Cell sheet desorbed by temperature change only
Hundreds of lung cancer nodules are generated in the lungs of EML4-ALK-transgenic mice, but disappear by an oral administration of an ALK inhibitor.