Drug Discovery and Development Division

Our study aims to further improve the therapeutic effects of cancer chemotherapy.

Research Goals

The therapeutic effects of conventional cytotoxic anticancer drugs are limited. To further improve the outcome of cancer treatment, the development of molecular-targeted therapeutics, which can selectively target dysregulated genes and signaling pathways in each cancer type, is urgently needed. However, currently, only a handful of patients with several tumor types actually benefit from effective molecular-targeted cancer therapeutics.

Therefore, to further expand the range of patients suitable for molecular-targeted therapeutics, we are attempting to develop novel molecular-targeted therapeutics and are exploring novel biomarkers that enable the prediction of therapeutic effects of and resistance to molecular-targeted cancer therapeutics.

Research Tasks (Methods to Achieve the Goals)

(1) Systematic identification of novel functional tumor-specific mutations(a part of Project HOPE)

This project aims to identify mutations with potential either as a therapeutic target causing dysregulation of signaling pathways or as biomarkers for the prediction of therapeutic effects and drug resistance.

We are performing systematic functional analysis of novel tumor-specific mutations detected in the Project HOPE study centering on cancer genome sequencing. Moreover, the effect of those tumor-specific genetic alterations on conformation and the affinity for drugs are also evaluated by molecular dynamics computer simulation. Based on those results of both molecular functional analysis and bioinformatics analysis, we elucidate signature commonly observed in driver mutations, and establish algorism for prediction of deriver mutations. Moreover, this project may contribute to expand the range of patients suitable for molecular-targeted therapeutics by clinical trial-design based on the results of functional classification of mutations.

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(2) Elucidation of mechanisms of resistance to molecular-targeted cancer therapeutics

Molecular-targeted therapeutic drugs are effective against patients harboring abnormalities in genes or signal transduction targeted by each drug. However, the majority of responders eventually develop resistance. In this project, we aim to identify the acquired molecular mechanisms of causes of resistance to molecular targeted therapy and develop therapeutic strategy to overcome its resistance.

(3)Development of metabolic pathway-targeted cancer therapeutics

Metabolic abnormalities are observed in many cancer types and are known to be related to therapeutic effects and drug resistance. Metabolome analysis, which is a technology developed to systematically detect the concentration of metabolites, enables to identify cancer-specific metabolic profiles. In this study, we identify the metabolic pathway, on which tumors are dependent, in terms of energy production for cell growth and acquired resistance to cancer-therapeutics, and we aim to develop molecular-targeted cancer therapeutics against those identified metabolic pathways.

(4)Development of minimally invasive technology to detect tumor-specific genetic alterations as biomarker (Liquid biopsy)

Serial biopsies for detecting genetic alterations as biomarkers are a crucial method for monitoring drug efficacy after the initial treatment of tumors. However, it is highly invasive for several tumor types, such as lung cancer. To develop minimally invasive technology to detect tumor-specific genetic alterations, we focused on circulating-tumor DNA (ctDNA) derived from tumors, which is included in fragmented DNA extracted from the plasma fraction of whole blood (known as circulating-free DNA, cfDNA) in cancer patients. However, its concentration is extremely low. Therefore, we are developing a highly sensitive method, which enables the detection of tumor-specific genetic alterations in cfDNA with digital polymerase chain reaction and next-generation sequencing.

Introduction of Divisions

Introduction of Divisions