Variations in telomere maintenance and the role of telomerase inhibition in gastrointestinal cancer

Figures & data

Figure 1 Telomeres and telomerase as therapeutic targets.

Notes: (A) Telomeres display a single-stranded G-rich 3′ overhang that is bound by telomeric proteins and forms higher-order structures of telomerase such as T-loop and G-quadruplex that are required for proper telomere maintenance and protection of chromosomal integrity. In addition, a D-loop structure can be observed serving as the primer for telomerase during elongation of telomeres. Six telomere-associated proteins form the shelterin complex that serves as a telomere cap and is involved in the regulation of telomere length. In this context, TRF1 serves as a negative regulator of telomeres that prevents telomerase from telomere access. Therapeutic strategies targeting telomere structures are depicted at their respective site of action. (B) Telomerase comprises the catalytic subunit hTERT and the intrinsic RNA moiety hTER, which serves as a template for the synthesis of telomeric DNA. Telomerase inhibition can be either achieved by blocking of the active site of the enzyme (BIBR1532) or by targeting the RNA template of the enzyme with an antisense oligonucleotide (GRN163L).
Abbreviations: hTER, human telomerase RNA; hTERT, human telomerase reverse transcriptase; PARP, poly (ADP-ribose) polymerase.

Table 1 Therapeutic strategies targeting telomeres and telomerase

Therapeutic approach	Target	Mechanism	Agents	Preclinical data in GI cancer	Clinical data in GI cancer
Antisense oligonucleotides	hTER	Inhibition of RNA template	GRN163L	Esophageal cancer^Citation82	–
				Induction of senescence/apoptosis
				Inhibition of proliferation
				Significant reduction in tumor size (subcutaneous xenograft model) HCC^Citation84
				Inhibition of tumor cell growth
				Induction of apoptosis
				I ncreased sensitivity to doxorubicin treatment
				Pancreatic cancer^Citation85
				Reduction of tumor-initiating cells
				Reduction in tumor engraftment
Immunotherapy	hTERT	Induction of CD4^+ and CD8^+ immune response	GV1001, GRNVAC 1/2, VX-001	n/a	HCC^Citation87
					45.9% patients with stable disease after 6 months, but no effect on time to progression in combination with cyclophosphamide
					Pancreatic cancer^Citation88,Citation90
					Phase I/II
					Immune responses in 75% of patients 8.6 months median survival 1-year survival of 25%
					Phase III
					No effect on overall survival in combination with gemcitabine or capecitabine
Small molecule inhibitors	hTERT	Enzyme inhibition via active site binding	BIBR1532	–	–
Gene therapy	hTERT	hTERT promoter-driven tumor cell lysis	Telomelysin hTERT-Ad	HCC^Citation91,Citation92	–
				Effective in orthotopic HCC xenografts
G-quadruplex stabilizers	Telomere	Blocking access to telomeres	BRACO19, telomestatin	–	–
Manipulation of telomere- and telomerase-associated proteins	HSP90, TRF1	Disruption of telomere–telomerase interaction	Geldanamycin, PARP inhibitors	Nonspecific targeting of telomerase: Geldanamycin^Citation93
				Antineoplastic effects on gastric, pancreatic, and colon cancer cell lines
				PARP inhibitors^Citation94,Citation95
				Preclinical and early clinical trials indicate efficacy against BRCA-associated pancreatic cancer

Abbreviations: GI, gastrointestinal; hTER, human telomerase RNA; hTERT, human telomerase reverse transcriptase; hTERT-Ad, human telomerase reverse transcriptase-adenovirus; HCC, hepatocellular carcinoma, HSP90, heat shock protein 90; PARP, poly (ADP-ribose) polymerase; n/a, not applicable.

ShammasMAQaziABatchuRBTelomere maintenance in laser capture microdissection-purified Barrett’s adenocarcinoma cells and effect of telomerase inhibition in vivoClin Cancer Res200814154971498018676772

 PubMed Web of Science ®Google Scholar

DjojosubrotoMWChinACGoNTelomerase antagonists GRN163 and GRN163L inhibit tumor growth and increase chemosensitivity of human hepatomaHepatology20054251127113616114043

 PubMed Web of Science ®Google Scholar

JosephITresslerRBassettEThe telomerase inhibitor imetelstat depletes cancer stem cells in breast and pancreatic cancer cell linesCancer Res201070229494950421062983

 PubMed Web of Science ®Google Scholar

GretenTFFornerAKorangyFA phase II open label trial evaluating safety and efficacy of a telomerase peptide vaccination in patients with advanced hepatocellular carcinomaBMC Cancer20101020920478057

 PubMed Web of Science ®Google Scholar

BernhardtSLGjertsenMKTrachselSTelomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II studyBr J Cancer200695111474148217060934

 PubMed Web of Science ®Google Scholar

MiddletonGSilcocksPCoxTGemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trialLancet Oncol201415882984024954781

 PubMed Web of Science ®Google Scholar

LinWHYehSHYangWJTelomerase-specific oncolytic adenoviral therapy for orthotopic hepatocellular carcinoma in HBx transgenic miceInt J Cancer201313261451146222886913

 PubMed Web of Science ®Google Scholar

WirthTKühnelFFleischmann-MundtBTelomerase-dependent virotherapy overcomes resistance of hepatocellular carcinomas against chemotherapy and tumor necrosis factor-related apoptosis-inducing ligand by elimination of Mcl-1Cancer Res200565167393740216103092

 PubMed Web of Science ®Google Scholar

MoserCLangSAStoeltzingOHeat-shock protein 90 (Hsp90) as a molecular target for therapy of gastrointestinal cancerAnticancer Res20092962031204219528462

 PubMed Web of Science ®Google Scholar

JavleMCurtinNJThe role of PARP in DNA repair and its therapeutic exploitationBr J Cancer201110581114112221989215

 PubMed Web of Science ®Google Scholar

WaalerJMachonOTumovaLA novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant miceCancer Res201272112822283222440753

 PubMed Web of Science ®Google Scholar