Our aim is to develop novel therapeutics that regulate “tumor microenvironment (TME)” for the treatment of unresectable pancreatic cancer, esophageal stricture post-endoscopic therapy against esophageal cancer, etc.
Our main approach is to develop oligonucleotide compounds that inhibit the expression of several glycogenes, which are involved in tissue remodeling in various disease microenvironment including cancer and fibrosis.
Pancreatic cancer~ One of the most lethal tumor.
Rich tumor stroma is one of the causes for drug resistance of pacreatic cancer. A novel therapeutic approach other than typical anticancer agents is required to regulate tumor stroma/microenvironment of pancreatic cancer. Various stromal proteoglycans are paid attention as important modulators of tumor microenvironment.
Chondroitin sulfate E (CS-E) is known to promote tumor invasion by cleaving CD44 on pancreatic cancer cells. The biosynthesis of CS-E is mediated by specific enzyme carbohydrate sulfotransferase 15 (CHST15) that is reported to correlate with poor prognosis in several types of cancer.
CHST15 dsRNA oligonucleotide is an attractive approach to selectively inhibit CHST15 gene expression and thereby, CS-E biosynthesis. CHST15 dsRNA was shown to inhibit the expression of CHST15 mRNA on PANC-1 cells in vitro, which was associated with reduced secretion of soluble CD44 variant 6 (sCD44v6). Intratumoral injection with CHST15 dsRNA inhibited tumor growth and induced necrosis in PANC-1 xenograft model in mice.
An open-labeled investigator’s initiated trial (IIT) through EUS-guided intratumoral injection in patients with unresectable pancreatic cancer was conducted. STNM01 (CHST15 dsRNA) was injected into the tumor under EUS guidance in 6 unresectable pancreatic cancer patients. CHST15 was highly expressed at baseline, with 2 patients showing large reductions of CHST15 at week 4. The mean OS of these patients was 15 months while it was 5.7 months for the other 4 patients. This was associated with reduction of serum sCD44v6 level.
Based on the IIT findings, the potential of CHST15 as a new therapeutic target for pancreatic cancer was suggested, then investigators conducted larger team to perform Phase 1/2a clinical study under support by AMED.
The phase 1/2a study for unresectable pancreatic cancer was completed and its follow-up clinical study is now conducted in Japan. Top-line results were presented by investigators at DDW and ASCO 2022.
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- Mizumoto S, Takahashi J, Sugahara K. Involvement of advanced glycation end products (RAGE) functions as receptor for specific sulfated glycosaminoglycans, and anti-RAGE antibody or sulfated glycosaminoglycans delivered in vivo inhibit pulmonary metastasis of tumor cells. JBC 287: 18985-18994, 2012.
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- Nishimura M, Matsukawa M, Fujii Y, et al. Effects of endoscopic ultrasound-guided intratumoral injection of oligonucleotide STNM01 on tumor growth, histology and overall survival in patients with unresectable pancreatic cancer. Gastrointest Endoscopy 87: 1126-1131, 2018.