Division of Refractory and Advanced Cancer

Ryuichi Sakai, Hideki Yamaguchi, Masato Enari, Takuya Shirakihara, Katsuhiko Nakashima, Ryo Otomo, Emi Saito, Yuko Nagamura, Yuko Hibiya, Tomoko Shoji

Introduction

In patients with advanced stages of cancers, the control of metastasis, invasion and drug resistance is crucial for maintaining quality of life (QOL) in addition to prolonged survival. Cancer cells acquire numbers of abnormal properties during the progression of cancers which enable cells to survive in unsuitable conditions caused by distant metastasis or anticancer drug administration. To overcome the malignant characteristics of cancers, it is crucial to understand the molecular mechanism associated with these abnormal biological properties.

Our team and what we do

Our main focus is to clarify the molecular mechanisms of tumor progression in refractory cancers including lung cancer and gastric cancer, and to develop various novel therapeutic strategies. Signals from activated tyrosine kinases are mediated through phosphorylation of substrate molecules to modulate cell characteristics during tumor proliferation and metastasis. The p53 pathway is also involved in the regulation of invasiveness, metastatic activity, and drug resistance.

One of the goals of our research is to establish models of novel therapy to overcome these malignant characteristics of progressed cancers by targeting critical proteins and signals involved in these procedures.

Research activities

1.Molecules and Signals regulating Metastasis and Invasion of Cancers

Scirrhous gastric carcinoma (SGC) shows rapid expansion through progressive invasion, peritoneal dissemination, and frequent metastasis to lymph nodes. Receptor tyrosine kinases such as fibroblast growth factor receptors (FGFRs) and Met are frequently activated in SGC and the contribution of signaling from these kinases to unique clinical aspects of SGC are suggested. A novel signaling protein called PLEKHA5 was identified by the analysis. PLEKHA5 was required for growth and peritoneal dissemination of scirrhous gastric carcinoma cells, indicating that PLEKHA5 is a novel therapeutic target.

Actinin-4 is an actin bundling protein identified at the National Cancer Center (NCC) as a protein associated with cancer malignancies. We revealed that actinin-4 regulates the formation of invadopodia that are cellular structures required for cancer invasion and metastasis.

CDCP1 is a critical regulator of anoikis resistance, distant metastasis, and peritoneal dissemination of cancer cells. Therapeutic antibodies and chemicals which block the CDCP1-mediated signaling are being screened and several candidates were obtained.

In collaboration with Kanazawa University, we found that the expression of the CD74-NRG1 fusion protein promoted cancer-stem cell-like properties in lung cancer cells and that the inhibition of ErbB2, PI3K, NF-κB, or IGF2 suppressed CD74-NRG1-induced tumor sphere formation.

2.Role of ALK and p53 in cancer progression

It was revealed that the combination of the ALK inhibitor with the p53 activator attenuated the resistance of ALK-positive neuroblastoma to the ALK inhibitor. In addition, the combination treatment of the ALK inhibitor with the p53 activator was also effective in the ALK fusion-positive lung cancer and ALK fusion-positive gastric cancer.

It was shown that SHP2 is tyrosine-phosphorylated by ALK and appears to mediate the ALK-dependent oncogenic property of NB-39-nu neuroblastoma cells, while SHP2 induces dephosphorylation of ALK protein. Our findings suggest that the loss of FLOT1-mediated regulation of ALK or enhanced expression of SHP2 contributes to malignancy of clinical neuroblastoma cases and those cases might be sensitive to ALK inhibitors even without the genetic alteration of ALK.

Tumor suppressor p53 pathway is inactivated by mutation or perturbation of its regulatory pathways in most cancers. We discovered various small molecular compounds that re-activate the p53 pathway in cancer cells. From in vitro and in vivo experiments, we found that these compounds inhibited the proliferation of cancer cells and suppressed tumor growth.

Education

We accept students or graduate students as trainees from various institutes including Tokyo University of Pharmacy and Life Sciences and educate future basic cancer researchers. We also make efforts in the education of young post-doctoral researchers.

Future prospects

Our approach to elucidate the underling mechanism of these malignant characteristics of cancers will give us ways to develop novel therapeutic strategies for advanced cancers. Especially, identification of molecules and signals involved in drug resistance and cancer-stromal interaction will be intensively studied to find novel approaches to overcome refractory cancers.