Numazu Branch

Research Outline

Our research focuses on “cancer.” We are studying cancer biology at the molecular level in order to identify new therapeutic targets and strategies for cancer. Furthermore, based on our findings, we are developing new candidates for anticancer drugs by screening for bioactive natural compounds in microbial cultures using our original experimental systems.

Furthermore, we apply microbes to environmental field and also isolate entomophathogenic fungi as a new screening source.

Theme outline

1. Development of inhibitors of the ubiquitin–proteasome pathway

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.

Fig.1 Ubiquitin-proteasome 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. We are presently developing orally active proteasome inhibitors using in vivo imaging system.

Fig.2 In vivo imaging of proteasome inhibition in tumors

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.

2. Development of tumor microenvironment-oriented anticancer drugs

The tumor microenvironment has an important influence on cancer progression, particularly in cases where large areas of a tumor are nutrientstarved and hypoxic because of a disorganized vascular system. Because chronic deprivation of nutrients or hypoxia is rare in normal tissues, nutrientdeprived 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.

Fig.3 Tumor microenvironment

3. 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 androgenindependent 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.

Fig.4 Prostate cancer progression

4. Searching for new treatment strategies against small-cell lung cancer by using an original orthotopic metastasis model

Small-cell lung cancer (SCLC) accounts for approximately 20% of lung cancer cases and is one of the most aggressive cancers due to its ability to form early and widespread metastases. The overall survival of SCLC at five years has been approximately 10% over the last several decades. Hence, the development of novel strategies for the treatment of SCLC is urgently required. However, the details of SCLC biology, which is important for the development of novel SCLC treatments remains unclear. Recently, we have successfully established a new orthotopic transplantation model of SCLC in nude mice. Our model has a superior distant metastases-forming ability compared with that of other orthotopic SCLC models. Using this model, we are currently addressing several projects as follows: (1) the analysis of the molecular mechanisms of distant metastases formation of SCLC (particularly brain metastasis), (2) searching for novel molecular targets for the treatment of SCLC, and (3) searching for parent-compounds of drugs against SCLC.

Fig.5 A new orthotopic metastasis model for SCLC

5. Application of microbes to microenvironments

We applied microbes to environmental improvement and promoted a procedure to degrade jellyfish, which is difficult to process in thermal and nuclear power plants (Figure 6). We developed an original processing system of jellyfish, which included enzymatic degradation and brine waste water processing by a single ciliate. We also developed this methodology for application to marine waste.

Fig.6 Flow of jellyfish degradation

6. Screening of bioactive compounds from entomopathogenic fungi

We have isolated Cordyceps and related entomopathogenic fungi as screening resources for drug discovery. Entomopathogenic fungi are known to produce various bioactive molecules in it’s life cycle, infection process of insects, proliferation and death of insects. The molecules produced by these microbes are expected to possess unique structures and biological functions and may represent seed compounds for drugs. We screen bioactive molecules focusing on antitumor compounds and furthermore investigate the activation of fungal secondary metabolism to broaden diversity of metabolites.

Fig.7 Photographs of Cordyceps