[Current Status and Issues in Drug Development for Rare Cancers].

Since 1993, the"R & D Promotion System for Orphan Drugs and Orphan Medical Devices"has been in operation to support the development of orphan drugs in Japan. Various supportive measures are in place for indications that target less than 50,000 patients, have high medical needs and high probability of successful development(which means regulatory approval). However, recently a trend was observed that the designation for orphan drugs occurred most often in late phase of development, because clinical data for late stage clinical studies were required to show the high probability of successful regulatory approval. The Ministry of Health, Labour and Welfare are trying to make efforts to expand the orphan drug designation, and have made the decision to include the related expenses will be included in the FY 2023 budget request. It is expected that the expansion of orphan drug designation will lead to promote drug development in rare disease area. On the other hand, fundamental reform is considered necessary for this system. Among the approved anti-cancer drugs that obtained orphan designation in the U. S. and EU as of 2020, there are 24 drugs that have not been approved in Japan. Of these, there are at least 16 drugs approved in either China, Taiwan, and South Korea. From viewpoint of development pathway of an orphan drug, participation in a multi-regional clinical trial(MRCT)is useful, but there are cases that Japan cannot join MRCT in time due to the requirement of Japanese safety data prior to the participation. In that case, it is impossible to conduct a separate clinical trial to obtain Japan regulatory approval due to very limited patients(eg several to several tens of Ultra-Orphan). A review system that allows earlier patient access is desired.

Antisense activity of 2',4'-BNA targeted to PPAR gamma in THP-1 and HCT116 cells.

2'-O,4'-C-methylene bridged nucleic acid (2',4'-BNA) is a nucleic acid analogue that has high affinity binding to its complementary RNA. Peroxisome proliferator-activated receptor (PPAR) y belongs to the nuclear hormone receptor superfamily and is a drug target in the treatment of type 2 diabetes. Here, we show the antisense effects of 2',4'-BNA oligonucleotides against PPARy in the human monocytic leukaemia cell line THP-1 and the human colorectal tumor cell line HCT116.

Gene expression profiling of potential peroxisome proliferator-activated receptor (PPAR) target genes in human hepatoblastoma cell lines inducibly expressing different PPAR isoforms.

BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors and commonly play an important role in the regulation of lipid homeostasis. To identify human PPARs-responsive genes, we established tetracycline-regulated human hepatoblastoma cell lines that can be induced to express each human PPAR and investigated the gene expression profiles of these cells. RESULTS: The expression of each introduced PPAR gene was investigated using the various concentrations of doxycycline in the culture media. We found that the expression of each PPAR subtype was tightly controlled by the concentration of doxycycline in these established cell lines. DNA microarray analyses using these cell lines were performed with or without adding each subtype ligand and provided much important information on the PPAR target genes involved in lipid metabolism, transport, storage and other activities. Interestingly, it was noted that while ligand-activated PPARdelta induced target gene expression, unliganded PPARdelta repressed these genes. The real-time RT-PCR was used to verify the altered expression of selected genes by PPARs and we found that these genes were induced to express in the same pattern as detected in the microarray analyses. Furthermore, we analysed the 5'-flanking region of the human adipose differentiation-related protein (adrp) gene that responded to all subtypes of PPARs. From the detailed analyses by reporter assays, the EMSAs, and ChIP assays, we determined the functional PPRE of the human adrp gene. CONCLUSION: The results suggest that these cell lines are important tools used to identify the human PPARs-responsive genes.