1. Cancer research targeting tumor–stroma interactions

Most of the solid tumors originate from epithelial layers, and the tumor tissues consist of not only tumor cells but also stroma surrounding the tumor cells. Stroma includes various types of components such as blood vessels, macrophages, fibroblasts, and extracellular matrix. The stroma regulates tumor development through diffusible factors and direct adhesion. Thus, these tumor–stroma interactions are closely associated with the growth and metastasis of tumor cells. It is noteworthy that tumor–stroma interactions can both accelerate and suppress tumor growth. We hypothesized that manipulation of the interactions between tumor cells and non-tumor host cells such as stroma results in the suppression of tumors. In order to achieve our goal, we are conducting experiments for the following: (a) regulation of tumor–stromal cell interactions, (b) relationship between chronic inflammation and tumors, (c) augmentation of innate immunity, and (d) development of experimental animal models.

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2. Development of inhibitors of the ubiquitin–proteasome pathway

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The ubiquitin–proteasome pathway is involved in many biological processes. It degrades numerous regulatory proteins critical for tumor growth. We are presently attempting to identify the inhibitors of this pathway.

• Proteasome inhibitors: The proteasome is an abundant multi-enzyme complex that has protease activities. Proteasome inhibitors can stabilize numerous regulatory proteins and cause apoptosis, thereby limiting tumor development. Therefore, proteasome inhibition is an attractive therapeutic strategy for human malignancy.
• IAP inhibitors: IAPs act as E3 ubiquitin ligases for caspase; furthermore, they act as inhibitors of caspase activities. Inhibition of IAP–caspase interaction activates the caspase cascade leading to enhanced apoptosis.
• Mdm2 inhibitors: Mdm2 functions as an E3 ubiquitin ligase for p53 tumor suppression and as an inhibitor of p53 transcriptional activation. Inhibition of Mdm2–p53 interaction activates the p53-dependent apoptosis pathway and induces inhibition of tumor growth.

3. Development of tumor microenvironment-oriented anticancer drugs

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The tumor microenvironment has an important influence on cancer progression, particularly in cases where large areas of a tumor are nutrient-starved and hypoxic because of a disorganized vascular system. Because chronic deprivation of nutrients or hypoxia is rare in normal tissues, nutrient-deprived or hypoxic cancer cells are potential targets for new anticancer agents. We are presently screening cytotoxic agents that function preferentially under nutrient-deprived or hypoxic conditions.

4. Development of androgen receptor inhibitors

Prostate cancer initially occurs as an androgen-dependent tumor and responds favorably to androgen ablation therapy. However, prostate cancer progresses from an androgen-dependent to an androgen-independent stage and acquires resistance to androgen ablation therapy. Most androgen-independent prostate cancer cells still express androgen receptors (ARs), indicating that these cells maintain the AR signaling pathway. Therefore, we are currently attempting to identify novel AR inhibitors that could be potential drugs for treating advanced prostate cancer.

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