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 at least through mechanism regulating the secretion of sCD44v6. To investigate optimal treatment dose and schedule, Phase 1/2a study is now conducted as ITT in Japan.

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Esophageal stricture post-endoscopic therapy for esophageal cancer ~A “new disease” associated with technical improvement for endoscopic curative treatment of esophageal cancer as well as Barrett’s esophagus.

Endoscopic therapy represents less invasive approach against esophageal diseases including esophageal cancer and Barrett’s esophagus. Rapid technical improvement, especially, endoscopic submucosal dissection (ESD) during 21st century has dramatically changed patient life as a curative, first-choice treatment even in patients with large disease lesion.

However, in parallel with the technical improvement, “new disease condition” has arisen such as benign esophageal stricture post-endoscopic therapy. Especially, over 75% circumference ESD provides curative treatment but induces esophageal stricture that leads severe dysphagia and increases the risk of surgery. Despite intensive balloon dilatation, restenosis frequently occurs, leading to impaired QOL for patients despite complete removal of cancer.

Local injection of corticosteroid (CS) is currently used to prevent esophageal stricture. However, CS has a risk of severe infection [mediastinal abscess etc] and late onset perforation probably by muscle destruction. Moreover,the effect of CS is quite limited against esophageal stricture post more than 75% circumference ESD. As excessive fibrotic response causes esophageal stricture post-endoscopic therapy, new and safe treatment approach that regulate fibrotic microenvironment is required.

CHST15 dsRNA was shown to repress esophageal stricture in pig ESD model without adverse effects, so would be a novel therapeutic approach to control this new disease condition.


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  • Hashimoto S, Kobayashi M, Takeuchi M, et al. The efficacy of endoscopic triamcinolone injection for the prevention of esophageal stricture after endoscopic submucosal dissection. Gastrointest Endosc 74: 1389-1393, 2011.
  • Yamashita S, Kato M, Fujimoto A, et al. Inadequate steroid injection after esophageal ESD might cause mural necrosis. Endosc int Open 7: E115-E121. 2019.
  • Sato H, Sagara S, Nakajima N, et al. Prevention of esophageal stricture after endoscopic submucosal dissection using RNA-based silencing of carbohydrate sulfotransferse 15 in a pig model. Endoscopy 49: 1-9, 2017.