Laboratory of Biofunctional Molecular Medicine

1. Key members

2. Background and objectives

*Cancer is currently the leading cause of death in Japan, and the lifetime risk of contracting cancer is one in two men and one in three women, making the development of cancer prevention, diagnosis, and treatment methods and the establishment of personalized medicine an urgent priority. It has become clear that cancer develops and progresses in multiple stages due to the accumulation of genomic (epigenomic) abnormalities. Furthermore, recent innovations in omics technology have led to more detailed elucidation of the molecular mechanisms underlying the onset and progression of cancer. However, it is still not fully understood how the accumulated abnormalities are closely related to each other and lead to the manifestation of abnormal traits called "cancer".

In this project, we aim to elucidate the molecular mechanisms of cancer onset and progression as well as resistance to treatment, including anticancer drugs, by clarifying the in vivo functions of “cancer-related genes” identified through cancer omics analysis, especially those that function specifically in cancer cells, and to develop innovative therapeutic and diagnostic methods through the control of their in vivo functions. We aim to develop innovative therapeutic and diagnostic methods by elucidating the molecular mechanisms of cancer development and resistance to treatment, including anticancer drugs, and by regulating their biological functions.

3. Overview of our research

I. Cancer Drug Discovery for Cancer Suppressor Factors

We are currently focusing on BIG3 (Brefeldin A-Inhibited Guanine nucleotide-exchange protein 3), a novel cancer-specific scaffold protein, as one of cancer-specific functional molecules. BIG3 forms a complex with phosphatase PP1Cα and kinase PKA in the cytoplasm of estrogen receptor-positive breast cancer cells and dephosphorylates the phosphate group of serine residue, which is essential for the inhibitory activity of the tumor suppressor PHB2 (Prohibitin2), and negatively regulates its inhibitory activity. Furthermore, we developed "BIG3-PHB2 interaction inhibitory peptide (ERAP)," which utilizes the activation of the inhibitory function of PHB2 by inhibiting BIG3-PHB2 interaction, and successfully led to in vivo antitumor effects in ER-positive breast cancer (Nat. Communi. 2013, 2017, Sci. Rep 2017). We are currently conducting research and development for clinical application.

II. Cancer Drug Discovery through Functional Analysis of Cancer-Specific Molecules

II-I. Elucidation of cancer microenvironment regulation mechanisms through organelle collaboration

In solid tumors, the cancer microenvironment, such as continuous hypoxia and glucose starvation, which are not found in normal tissues, causes persistent endoplasmic reticulum stress. While persistent ER stress in normal cells causes cell death, the ER stress response in cancer cells is thought to be homeostatically activated to avoid cell death. Such intratumor microenvironmental stress is thought to be an adaptive response of cancer cells to the accumulation of proteins with abnormal folding structures in the endoplasmic reticulum (ER), and is considered to be a "endoplasmic reticulum stress response (UPR)" mechanism, although the molecular mechanism is still poorly understood. We aims to elucidate this cancer cell-specific adaptation mechanism to the microenvironment and to develop new therapeutic strategies targeting this adaptation mechanism.

II-II: Elucidation of molecular mechanisms and drug discovery for triple negative breast cancer, an intractable cancer

The existence of hormone receptor (estrogen receptor, progesterone receptor) negative and HER2 negative triple negative breast cancer (TNBC), which has a high biological grade, poor prognosis, and no therapeutic target, is a serious problem in breast cancer today. TNBC (Triple Negative Breast Cancer) is a serious problem. We are currently conducting comprehensive genomic analysis, including comprehensive gene expression analysis and next-generation sequencing analysis, to identify and functionally analyze molecules related to the carcinogenesis and progression of TNBC in order to elucidate the molecular mechanism of TNBC and to conduct drug discovery research. In particular, we are conducting functional analysis and drug discovery research to elucidate the role of TNBC cell proliferation and the mechanism of chemotherapy resistance based on the regulation of glutamine metabolism.

III. Identification of New Causative Genes for Familial Breast Cancer

Among patients diagnosed with cancer, many of those families in which a large number of cancer patients exist in the same family have cancer due to heredity. In particular, in hereditary breast and ovarian cancer syndrome (HBOC), clinical tests for germline mutations of the causative genes, BRCA1 and BRCA2, are well established. However, HBOC with these mutations account for only about 60% of all hereditary breast cancer patients, and the rest have not yet been identified, although it has long been pointed out that HBOC with other causative genes may exist. Our laboratory aims to identify novel causative genes of familial breast cancer through next-generation sequencing analysis and to develop a diagnostic system.

Ⅳ. Construction of Omics Analysis Platform for Refractory Cancer and Research and Development on Elucidation of Molecular Mechanism of Drug Resistance and its Control (JST Cancer Moonshot Project).

The JST Moonshot Project aims to develop diagnostic and preventive therapies for drug resistance by identifying genes involved in the onset and progression of refractory cancers such as recurrent metastatic breast cancer and pancreatic cancer, from normal to precancerous lesions to early cancer stages, and by identifying novel genes associated with therapeutic resistance and analyzing their functions. For more information about the Moonshot Project, please refer to this URL (https://ms2cancer.org/).

Laboratory of Biofuntional Molecular Medicine