Synergistic antitumor activity of a DLL4/VEGF bispecific therapeutic antibody in combination with irinotecan in gastric cancer
1
조회
0
다운로드
4
인용
0
참고문헌
키워드
초록
Notch signaling has been identified as a critical pathway in gastric cancer (GC) progression and metastasis, and inhibition of Delta-like ligand 4 (DLL4), a Notch ligand, is suggested as a potent therapeutic approach for GC. Expression of both DLL4 and vascular endothelial growth factor receptor 2 (VEGFR2) was similar in the malignant tissues of GC patients. We focused on vascular endothelial growth factor (VEGF), a known angiogenesis regulator and activator of DLL4. Here, we used ABL001, a DLL4/VEGF bispecific therapeutic antibody, and investigated its therapeutic effect in GC. Treatment with human DLL4 therapeutic antibody (anti-hDLL4) or ABL001 slightly reduced GC cell growth in monolayer culture; however, they significantly inhibited cell growth in 3D-culture, suggesting a reduction in the cancer stem cell population. Treatment with anti-hDLL4 or ABL001 also decreased GC cell migration and invasion. Moreover, the combined treatment of irinotecan with anti-hDLL4 or ABL001 showed synergistic antitumor activity. Both combination treatments further reduced cell growth in 3D-culture as well as cell invasion. Interestingly, the combination treatment of ABL001 with irinotecan synergistically reduced the GC burden in both xenograft and orthotopic mouse models. Collectively, DLL4 inhibition significantly decreased cell motility and stem-like phenotype and the combination treatment of DLL4/VEGF bispecific therapeutic antibody with irinotecan synergistically reduced the GC burden in mouse models. Our data suggest that ABL001 potentially represents a potent agent in GC therapy. Further biochemical and pre-clinical studies are needed for its application in the clinic.
Abstract
Notch signaling has been identified as a critical pathway in gastric cancer (GC) progression and metastasis, and inhibition of Delta-like ligand 4 (DLL4), a Notch ligand, is suggested as a potent therapeutic approach for GC. Expression of both DLL4 and vascular endothelial growth factor receptor 2 (VEGFR2) was similar in the malignant tissues of GC patients. We focused on vascular endothelial growth factor (VEGF), a known angiogenesis regulator and activator of DLL4. Here, we used ABL001, a DLL4/VEGF bispecific therapeutic antibody, and investigated its therapeutic effect in GC. Treatment with human DLL4 therapeutic antibody (anti-hDLL4) or ABL001 slightly reduced GC cell growth in monolayer culture; however, they significantly inhibited cell growth in 3D-culture, suggesting a reduction in the cancer stem cell population. Treatment with anti-hDLL4 or ABL001 also decreased GC cell migration and invasion. Moreover, the combined treatment of irinotecan with anti-hDLL4 or ABL001 showed synergistic antitumor activity. Both combination treatments further reduced cell growth in 3D-culture as well as cell invasion. Interestingly, the combination treatment of ABL001 with irinotecan synergistically reduced the GC burden in both xenograft and orthotopic mouse models. Collectively, DLL4 inhibition significantly decreased cell motility and stem-like phenotype and the combination treatment of DLL4/VEGF bispecific therapeutic antibody with irinotecan synergistically reduced the GC burden in mouse models. Our data suggest that ABL001 potentially represents a potent agent in GC therapy. Further biochemical and pre-clinical studies are needed for its application in the clinic.
참고문헌 (31)
- Russo AE, "Gastric cancer etiology and management in asia and the west", Annu Rev Med, 70, pp.353~367 (2019)
- Sitarz R, "Gastric cancer : epidemiology, prevention, classification, and treatment", Cancer Manag Res, 10, pp.239~248 (2018)
- Kanat O, "Targeted therapy for advanced gastric cancer : A review of current status and future prospects", World J Gastrointest Oncol, 7, pp.401~410 (2015)
- Lin Y, "Gene mutations in gastric cancer : a review of recent next-generation sequencing studies", Tumour Biol, 36, pp.7385~7394 (2015)
- Guruharsha KG, "The Notch signalling system : recent insights into the complexity of a conserved pathway", Nat Rev Genet, 13, pp.654~666 (2012)
- Andersson ER, "Notch signaling : simplicity in design, versatility in function", Development, 138, pp.3593~3612 (2011)
- Hori K, "Notch signaling at a glance", J Cell Sci, 126, pp.2135~2140 (2013)
- Bagheri V, "Isolation and identification of chemotherapy-enriched sphere-forming cells from a patient with gastric cancer", J Cell Physiol, 233, pp.7036~7046 (2018)
- Ishigami S, "Clinical implications of DLL4 expression in gastric cancer", J Exp Clin Cancer Res, 32, pp.46~ (2013)
- Miao ZF, "DLL4 overexpression increases gastric cancer stem", progenitor cell self-renewal ability and correlates with poor clinical outcome via Notch-1 signaling pathway activation, 2017, pp.6, 245~257
- Aster JC, "The Varied Roles of Notch in Cancer", Annu Rev Pathol, 12, pp.245~275 (2017)
- Lee D, "Simultaneous blockade of VEGF and Dll4 by HD105, a bispecific antibody, inhibits tumor progression and angiogenesis", MAbs, 8, pp.892~904 (2016)
- Bailly C, "Irinotecan : 25 years of cancer treatment", Pharmacol Res, 148, pp.104398~ (2019)
- Thuss-Patience PC, "Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)", Eur J Cancer, 47, pp.2306~2314 (2011)
- Pasquini G, "Third-line chemotherapy with irinotecan plus 5-fluorouracil in caucasian metastatic gastric cancer patients", Oncology, 91, pp.311~316 (2016)
- Seo MD, "Irinotecan combined with 5-fluorouracil and leucovorin as second-line chemotherapy for metastatic or relapsed gastric cancer", Jpn J Clin Oncol, 38, pp.589~595 (2008)
- Sweeney TJ, "Visualizing the kinetics of tumor-cell clearance in living animals", Proc Natl Acad Sci U S A, 96, pp.12044~12049 (1999)
- den Dulk M, "The essentials of locoregional control in the treatment of gastric cancer", Scand J Surg, 95, pp.236~242 (2006)
- Reim D, "Prognostic implications of the seventh edition of the international union against cancer classification for patients with gastric cancer : the Western experience of patients treated in a single-center European institution", J Clin Oncol, 31, pp.263~271 (2013)
- Kim IH, "Current status of adjuvant chemotherapy for gastric cancer", World J Gastrointest Oncol, 11, pp.679~685 (2019)
- Fujita K, "Irinotecan, a key chemotherapeutic drug for metastatic colorectal cancer", World J Gastroenterol, 21, pp.12234~12248 (2015)
- Chun JH, "Weekly irinotecan in patients with metastatic gastric cancer failing cisplatinbased chemotherapy", Jpn J Clin Oncol, 34, pp.8~13 (2004)
- Yamao T, "Phase I-II study of irinotecan combined with mitomycin-C in patients with advanced gastric cancer", Ann Oncol, 12, pp.1729~1735 (2001)
- Leslie JD, "Endothelial signalling by the Notch ligand Delta-like 4 restricts angiogenesis", Development, 134, pp.839~844 (2007)
- Shutter JR, "Dll4, a novel Notch ligand expressed in arterial endothelium", Genes Dev, 14, pp.1313~1318 (2000)
- Chatterjee S, "Tumor VEGF : VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer", J Clin Invest, 123, pp.1732~1740 (2013)
- Fu L, "Gastric cancer stem cells : current insights into the immune microenvironment and therapeutic targets", Biomedicines, 8, pp.7~ (2020)
- Katoh M, "Precision medicine for human cancers with Notch signaling dysregulation(Review)", Int J Mol Med, 45, pp.279~297 (2020)
- 백정환, "Kahweol inhibits lipid accumulation and induces Glucose-uptake through activation of AMP-activated protein kinase (AMPK)", BMB Reports, 50(11), pp.566~571 (2017), 생화학분자생물학회
- 김남준, "A PDE1 inhibitor reduces adipogenesis in mice via regulation of lipolysis and adipogenic cell signaling", Experimental and Molecular Medicine, 51, pp.1~15 (2019), 생화학분자생물학회[DOI]
- Cho Y, "Post-translational modification of OCT4 in breast cancer tumorigenesis", Cell Death Differ, 25, pp.1781~1795 (2018)