The 10th symposium

Speech

Special　Lecture1

“Cancer and Metabolism”
Tomoyoshi Soga, Institute for Advanced Biosciences, Keio University,
Advanced Research and Development Programs for Medical Innovation (AMED-CREST)

Cancer cells are known to shift their metabolism to glycolysis to generate adenosine triphosphate (ATP), which is well-recognized as the Warburg effect. Metabolic pathways specific for cancer, other than glycolysis, have been found in recent years, and drugs targeting such pathways are under aggressive development. However, the molecular mechanisms of cancer cells undergoing metabolic shifts have remained unknown.
We performed multi-omics analyses, including metabolome analysis, gene expression analysis, and mutation analysis of cancer-related genes, to compare normal with cancer tissues in 275 patients with colon cancer. The results revealed that the metabolism changes in the benign stage of tumors and that gene mutations do not affect the metabolism.
Detailed data analyses and cell biology tests demonstrated that MYC, an oncogene product, regulates at least 215 metabolic reactions through 160 metabolic control genes in colon cancer. Additionally, we found that MYC and the pyrimidine metabolic pathway regulated by MYC can be the promising targets in treating colon cancer.
In this lecture, we will discuss our findings on the metabolic control mechanism of colon cancer and would like to approach the nature of the Warburg effect that has been a mystery for the past 100 years.

Special　Lecture2

“Chemically induced liver progenitors as a source for liver regeneration and drug metabolism”
Takahiro Ochiya, Chief, Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo Japan

A challenge for advancing approaches to liver regeneration is loss of functional differentiation capacity when hepatocyte progenitors are maintained in culture. Recent lineage-tracing studies have shown that mature hepatocytes (MHs) convert to an immature state during chronic liver injury, and we investigated whether this conversion could be recapitulated in vitro and whether such converted cells could represent a source of expandable hepatocytes. We report that a cocktail of small molecules can convert rat and mouse MHs in vitro into proliferative bipotent cells, which we term chemically induced liver progenitors (CLiPs) (Katsuda et al., Cell Stem Cell, 2017). CLiPs can differentiate into both MHs and biliary epithelial cells that can form functional ductal structures. CLiPs in long-term culture did not lose their proliferative capacity or their hepatic differentiation ability, and rat CLiPs were shown to extensively repopulate chronically injured liver tissue. Our current progress on generation of human CLiPs and the therapeutic potency for liver diseases as well as potency of drug metabolism will be mentioned.

Case Introduction

“Update on Clinical Experience with Phenylbutyrate”
Masakazu Sawanobori (Director, Gokigen Clinic)

Since our study group was established, we have conducted research on phenylbutyrate, an histone deacetylase (HDAC) inhibitor. As part of the research, the Sanbancho Gokigen Clinic provides treatment with phenylbutyrate, mostly to patients with solid tumors. Among 70 assessable subjects (gender: male/female = 39/31; age: 4 to 82 years; mean age: 60.3 years), 80% (56 cases) had stage 4 disease, and 61% (40 cases) concurrently received the standard of care. As previously reported, adverse reactions included heartburn (14.3%), which was the mostly frequently reported, followed by gastrointestinal symptoms, including nausea (8.6%), stomach upset (7.1%) and constipation (7.1%), and skin rash (2.8%). All the adverse reactions were grade 1 in severity. The following patient was recently treated and showed a good response to phenylbutyrate.

Case) A 64-year-old woman with lung adenocarcinoma and multiple bone and liver metastases
The diagnosis was made in January 2014. The tumor was positive for epidermal growth factor receptor (EGFR) mutation (L858R). Clinical course) Oral treatment with Iressa 250 mg/day was started in March 2014. On April 11, 2014, phenylbutyrate was added to the therapy. The treatment with Iressa was successful, and all the lesions disappeared temporarily. The dose of phenylbutyrate was reduced to 1 g/day to maintain the condition of the patient. While she made favorable progress, radiotherapy had to be started in October 2016 for a relapse in the right hip joint. During the radiotherapy, the dose of phenylbutyrate was increased to 3 g. The bone lesion showed improvement, but in September 2017, metastasis was detected in the hip joint of the other side. Since then, the patient has been receiving Metastron.
It has been 4 years 1 month since the disease was first diagnosed, however, no disease relapse has been observed in the lung or liver throughout the observation period. The patient remains in good general condition, and has been engaged in daily living without any problems. While there is little doubt that Iressa is effective, we believe that concurrent use of phenylbutyrate may produce therapeutic synergy and prevent the development of resistance to Iressa.