-Research Support

  1. Creation of innovative screening methodology for cancer drug discovery based on the reconstituted Rab proteoliposome analysis technique
  2. Development of new therapy for chemo-resistant breast cancer
  3. Development of tumor vessel-injuring CAR-T cell therapy for refractory solid cancer
  4. Development of molecular-targeted therapy for leukemia targeting WT1
  5. Creation of a protein–protein interaction inhibitor screening system
  6. Development of a new anticancer drug inhibiting the intermolecular interaction between PRL3 and CNNM4
  7. Development of anti-aging/cancer treatment methodology that utilizes vascular endothelial stem cell control
  8. Screening of low-molecular-weight compounds targeting the claudin-7 protein and clarification of the pathological conditions of GDLD
  9. Development of a system automatically detecting nausea/malaise induced by antineoplastic agents
  10. Colorectal cancer treatment using a C4.4A-specific (monoclonal) antibody
  11. Exploration of a new molecule responsible for necrotic myocardial cell death using the genome-wide shRNA screening method
  12. Development of new hypolipidemic agents to reduce the residual risk of cardiovascular events

[1] Creation of innovative screening methodology for cancer drug discovery based on the reconstituted Rab proteoliposome analysis technique

Joji Mima (Institute for Protein Research)

[Research overview]
All eukaryotic cells, including those of humans, selectively transport various substances intracellularly and extracellularly. This intracellular substance transport is called intracellular membrane trafficking. The Rab GTPase family (having at least 60 varieties in humans), specifically localized in organelles, is a group of proteins essential for determining the location selectivity for this intracellular membrane trafficking. In addition, recently, Rabs have been reported to be involved in the onset of various types of cancer; therefore, it has a growing potential to become a new target molecule for cancer drug discovery. With the aim of creating a new cancer drug discovery screening system, this research will utilize a group of purified human Rabs and artificial liposomes with a lipid bilayer to develop a reconstituted Rab proteoliposome membrane behavior analysis so that the analysis will be available for a group of cancer-related Rabs. To the best of our knowledge, we are the first to this.

[2] Development of new therapy for chemo-resistant breast cancer

Yoshiaki Taniyama (Graduate School of Medicine)

[Research overview]
Breast cancer is the most frequently occurring cancer among women. Although the therapy for this cancer has been established to some extent, the presence of drug-resistant breast cancer is an extraordinarily serious concern. Meanwhile, epithelial-mesenchymal transition (EMT) has been reported to enhance the undifferentiated character of cancer cells and induce their metastasis to other organs, and it has recently been suggested as one of the major causes of chemo-resistant breast cancer. Therefore, we conducted exhaustive analyses on genes that correlated with eight EMT markers, including SNAIL1/2 and ZEB1, using the Cancer Cell Line Encyclopedia (N = 1036) comprising clinical samples of malignant tumors. We found that periostin is the most strongly correlated. Cases of triple-negative breast cancer (N = 580) were then divided into two groups according to the level of periostin expression, and we found a significant relationship between the prognosis and the expression of the periostin gene (P = 0.0095).

[3] Development of tumor vessel-injuring CAR-T cell therapy for refractory solid cancer

Naoki Okada (Graduate School of Pharmaceutical Sciences)

[Research overview]
Chimeric antigen receptor-expressing T (CAR-T) cells specific to the vascular endothelial growth factor receptor 2 (VEGFR2) exhibit excellent anti-tumor efficacy against various solid cancers owing to their high tumor tissue-accumulating property and tumor vessel-injuring activity. With the aim of using this finding in clinical applications, we optimized the human CAR-T cell preparation technique that used the mRNA electroporation (mRNA-EP) method and evaluated the quality and functionality of prepared CAR-T cells. The mRNA-EP method enabled CAR expression without altering T cell properties; the prepared CAR-T cells did not exhibit sufficient efficacy for clinical use . Based on these achievements, we are currently planning to implement nonclinical studies that use VEGFR2-specific CAR-T cells prepared in accordance with the mRNA-EP method as well as developing a clinical trial protocol.

[4] Development of molecular-targeted therapy for leukemia targeting WT1

Yuusuke Oji (Functional Diagnosis Science, Graduate School of Medicine, Osaka University)

[Research overview]
WT1 gene, isolated as a gene responsible for the pediatric renal tumor Wilms’ tumor, was believed to be an anti-oncogene. However, we have demonstrated that WT1 is overexpressed in almost all leukemia and various solid cancers and that it actually acts as an oncogene. In addition, we have demonstrated that the WT1 protein directly binds with metabolic pathway enzymes to influence the survival of leukemia cells. Molecular-targeted therapy for leukemia is currently being developed targeting this interaction.

[5] Creation of a protein–protein interaction inhibitor screening system

Nobumasa Hino (Graduate School of Pharmaceutical Sciences)

[Research overview]
Disruption in the precisely controlled network of protein–protein interactions (PPI) is responsible for all diseases, and there are numerous interactions that could become a drug discovery target. However, methods for screening agents that inhibit such interactions remain to be established. This research will develop a method of high-efficiency fluorescence resonance energy transfer (FRET) based on the site-specific modification of proteins. A highly sensitive PPI inhibitor screening system will be developed that uses the FRET method.

[6] Development of a new anticancer drug inhibiting the intermolecular interaction between PRL3 and CNNM4

Hiroaki Miki (Research Institute for Microbial Diseases)

[Research overview]
PRL3 is expressed at high levels in colorectal cancer metastases, thereby causing malignant transformation of cancer. It has been shown that PRL3 binds to CNNM4, i.e., the Mg2+ transporter, to become functional. A compound that inhibits this intermolecular interaction between PRL3 and CNNM4 has the potential of an anticancer drug. With the aim of exploring such substances, an experimental system is being developed that can detect PRL3–CNNM4 binding at high throughput as well as enable the functionality of PRL3 to be easily detected in cultured cells.

[7] Development of anti-aging/cancer treatment methodology that utilizes vascular endothelial stem cell control

Nobuyuki Takakura (Research Institute for Microbial Diseases)

[Research overview]
To date, our research group has discovered the presence of endothelial stem cell-like cells that have a high capacity to produce vascular endothelial cells during angiogenesis in existing vessels. These cells can contribute to vessels for prolonged periods of time. By the end of 2017, a method had been developed that used cell surface markers to isolate such vascular endothelial stem cells. In the present research, single cell analyses were conducted on cells of the vascular endothelial stem cell subset isolated as having the aforementioned cell surface markers. The presence of three additional gene-expressed cell groups in this subset were demonstrated.

[8] Screening of low-molecular-weight compounds targeting the claudin-7 protein and clarification of the pathological conditions of GDLD

Satoshi Kawasaki (Graduate School of Medicine)

[Research overview]
Gelatinous drop-like corneal dystrophy (GDLD) is the severest form of hereditary corneal dystrophy. It is characterized by substantially decreased visual acuity, which is caused by amyloid deposition under the corneal epithelium.
This disease advances throughout life, and serious cases often lead to blindness.
Focusing on the intracellular aggregation of claudin-1 and -7, a pathological cell model has been created to develop low-molecular-weight therapeutic agents for GDLD.
Using a pathological cell model, primary screening is currently being conducting with the aim to perform secondary assays to narrow down the compounds that have passed the primary screening. In-vivo efficacy will be studied using disease-model mice to acquire therapeutic agents for GDLD.

[9] Development of a system automatically detecting nausea/malaise induced by antineoplastic agents

Koichi Yamamoto (Graduate School of Medicine)

[Research overview]
The role of the histamine H4 receptor in the onset of delayed nausea induced by antineoplastic agents has been studied. As a result, we found that the increased production of IL-1β in the hypothalamus via the H4 receptor played an important role in the onset of delayed nausea (particularly loss of appetite). In addition, H4 receptor blocker is as therapeutically effective as steroids, which have been used as therapeutic agents to date. These findings have triggered the development of new therapy for delayed nausea targeting the H4 receptor.

[10] Colorectal cancer treatment using a C4.4A-specific (monoclonal) antibody

Hirofumi Yamamoto (Graduate School of Medicine)

[Research overview]
C4.4A is a glycophosphatidylinositol (GPI)-anchored membrane protein isolated from rat metastatic tumors. Peptide fragments of C4.4A have been detected in the urine of patients with colorectal and pancreatic cancer; therefore, its role in human cancer is being investigated. A polyclonal antibody was developed and used to stain primary lesions of colorectal cancer (stages II and III). It was found that 25% of such lesions expressed C4.4A on their cell membranes at the invasive fronts of cancer. Therefore, the polyclonal antibody became a recurrence-prediction marker independent of the lymph node metastasis marker . Finally, we have started developing a monoclonal antibody with potential for clinical application.

[11] Exploration of a new molecule responsible for necrotic myocardial cell death using the genome-wide shRNA screening method

Hiroyuki Nakayama (Graduate School of Pharmaceutical Sciences)

[Research overview]
Calcium ions are secondary messengers involved in various vital phenomena. They control cardiac systole and diastole via the excitation-contraction coupling mechanism as well as play an important role in events such as cardiac hypertrophy and cell death. Cardiac failure is the terminal stage of all cardiac diseases. Although it is believed that calcium ions play an important role in the formation of the pathological condition of cardiac diseases, most of the details of such formation are unknown.
Current research is investigating the perspective of analyzing and controlling the mechanism of cell death to develop new therapies targeting calcium ions.

[12] Development of new hypolipidemic agents to reduce the residual risk of cardiovascular events

Keisuke Tachibana (Graduate School of Pharmaceutical Sciences)

[Research overview]
The nuclear receptor PPARα controls lipid metabolism. When activated, it decreases triglyceride (TG) level and increases high-density lipoprotein level in the blood. Therefore, PPARα activators are used as hypolipidemic agents and are being studied as therapeutic agents for non-alcoholic steatohepatitis (NASH). Using our independently developed PPARα ligand screening system, a new activator compound was discovered from the chemical library . This compound decreased the TG level in the blood of hyperlipidemia-model rats at a lower dose than the existing ligand. Therefore, this research has the potential for developing new therapeutic agents.

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