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.

References:
  • Hidalgo M. Pancreatic cancer. N Eng J Med 362: 1605-1617, 2012.
  • Neesse A, Krug S, Gress TM et al. Emerging concepts in pancreatic cancer medicine: targeting the tumor stroma. OncoTargets and Therapy 7: 33-43, 2014.
  • Whatcord CJ, Han H, Posner RG, et al. Tumor-stromal interactions in pancreatic cancer. Crit Rev Oncog 18: 135-151, 2013.
  • tan Dem GB, van de Westerlo EMA, Purushothaman A et al. Antibody GD3G7 selected against embryonic glycosaminoglycans defines chondroitin sulfate-E domain highly up-regulated in ovarian cancer and involved in vascular endothelial growth factor binding. Am J Pathol 171:1324-1333, 2007.
  • Sugahara KN, Hirata T, Tanaka T et al. Chondroitin sulfate E fragments enhances CD44 cleavage and CD44-dependent motility in tumor cells. Cancer Res 68: 7191-7199, 2008.
  • Li F, tan Dam GB, Murugan S et al. Involvement of highly sulfated chondroitin sulfate in the metastasis of the Lewis lung carcinoma cells, JBC 283: 34294-34304, 2008.
  • Basappa, Murugan S, Sugahara KN et al. Involvement of chondroitin sulfate E in the liver tumor focal formation of murine osteosarcoma cells. Glycobiology 19: 735-742, 2009.
  • 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.
  • Yamada S and Sugahara K. Potential therapeutic Application of chondroitin sulfate/dermatan sulfate. Current Drug Discovery Technologies 5: 289-301, 2008.
  • 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.

 

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.

 

References:
  • Siersema PD. Treatment option for esophageal strictures. Nature Gastroenterol Hepatol 5: 142-152, 2008.
  • Sami SS, Haboubi N, Ang Y et al. UK guidelines on esophageal dilatation in clinical practice. Gut 67: 1000-1023, 2018.
  • Draganov PV, Wang AY, Othman MO et al. AGA institute clinical practice update: Endoscopic submucosal dissection in the united states. Clin Gastroenterol Hepatol 17: 16-25, 2019.
  • Barret M< Beye S, Leblanc S et al. Systematic review: the prevention of oesophageal stricture after endoscopic resection. Aliment Pharmacol Ther 42: 20-39, 2015.
  • Jain D, Singhal S. Esophageal stricture prevention after endoscopic submucosal dissection. Clin Endosc 49: 241-256, 2016.
  • 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.