Tumor-specific environment (tumor microenvironment) is a promising target for novel cancer therapy. For example, in most types of solid tumors, uncontrolled tumor growth and immature blood vessels during angiogenesis often generate hypoxic microenvironment. Under hypoxic conditions, hypoxia-inducible factors are activated, inducing a vast array of gene products that promote both tumor progression and resistant to therapies. Thus, tumor hypoxia can be novel “microenvironmental target” for cancer therapy (Adv Drug Deliv Rev 2009, 61, 623). We have addressed a novel strategy to target hypoxic cancer cells by using fusion protein drugs (TOP3, POP33) that selectively kill the HIF-active cancer cells (Cancer Res 2002, 62, 2013, Clin Cancer Res 2009, 15, 3433, Can Sci 2016, 107. 1151). We currently optimize treatment protocol for combination therapy and preparation of fusion protein drugs for clinical test on patients with pancreatic cancers.
Peptides that have high affinity for target molecules on the surface of cancer cells are crucial for the development of targeted cancer therapies. Although peptide-display techniques are commonly used to screen target-binding peptides, a most of the selected peptides were not functional as expected in vivo. One possible explanation for this discrepancy is that the displayed peptides are not structurally constrained and thus have flexible conformations, causing reduced specificity and affinity for target molecules. Thus, we constructed protein scaffold for presenting structurally constrained peptides. Now, we are screening clinically applicable target-binding peptides using the scaffold. (PLoS One 2014, 9(8), e103397)
The enhanced delivery of drugs from the blood vessels into tumor tissue improves therapeutic outcome in cancer therapy. Macromolecules can seep from blood vessels and accumulate within the tumor by enhanced permeability and retention (EPR) effect. In addition, some studies have demonstrated that synthetic peptides can increase vascular permeability by stimulating the permeability-regulating receptor, neuropilin-1 (NRP1). Recently, we found that cell penetrating peptide/protein transduction domain (CPP/PTD) can facilitate the extravasation of fused proteins by binding to NRP1. Therefore, we are trying to develop the novel drug delivery system using CPP/PTDs. (J Control Release 2015, 201, 14-21)
It is increasingly recognized that tumor-specific microenvironment critically direct tumor malignant processes. Understanding of microenvironmental regulation of tumor malignancy would pave the way to develop novel therapeutic strategies. However, traditional “static” biological assays are not sufficient to precisely dissect the mechanisms regulated by “dynamic” tumor microenvironment (TME). We thus have developed imaging tools to noninvasively monitor TME such as intratumoral hypoxia (PLoS ONE 2010, 5, e15736, PLoS ONE 2011, 6, e26640, Nat Commun 2016, 7, 11856, Sci Rep 2016, 6, 34331). We currently work on development of new bioluminescence imaging tools which allow for multifaceted approaches to understand tumor malignancy process regulated by TME.
Metastasis remains a major cause of death from solid tumors. Understanding of critical mechanisms regulating metastasis holds a promise to improve prognosis of patients and overcome cancer diseases in the future. Metastasis is highly complex process including multi-step cascade. To fully understand this process, interactions between cancer cells and stromal environments are critically important as well as genetic characterizations of cancer cells. To address this issue, we have combined traditional biological approaches with noninvasive imaging, unique animal models and bioinformatics (Cancer Sci 2014, 105, 553). In particular, we currently study on lung metastasis of osteosarcoma and bone metastasis of prostate cancers.
We have active collaborations with following research groups: National Cancer Center Hospital East, Sakurai Lab (Tokyo Tech), Ueno Lab (Tokyo Tech), Omata Lab (Tokyo Tech), Inoue Lab (Research Institute, Osaka Medical Center for Cancer and Cardiovascular Diseases), Seo Lab (Kyoto Sangyo University), Sato Lab (Tohoku University), Maki Lab (The University of Electro-Communications)、Medigear International Corporation (Yokohama). Through the collaboration works, we aim to develop interdisciplinary approaches in cancer research field.