Combining old and new concepts in targeting telomerase for cancer therapy: transient, immediate, complete and combinatory attack (TICCA)

Abstract

Telomerase can overcome replicative senescence by elongation of telomeres but is also a specific element in most cancer cells. It is expressed more vastly than any other tumor marker. Telomerase as a tumor target inducing replicative immortality can be overcome by only one other mechanism: alternative lengthening of telomeres (ALT). This limits the probability to develop resistance to treatments. Moreover, telomerase inhibition offers some degree of specificity with a low risk of toxicity in normal cells. Nevertheless, only one telomerase antagonist reached late preclinical studies. The underlying causes, the pitfalls of telomerase-based therapies, and future chances based on recent technical advancements are summarized in this review. Based on new findings and approaches, we propose a concept how long-term survival in telomerase-based cancer therapies can be significantly improved: the TICCA (Transient Immediate Complete and Combinatory Attack) strategy.

Keywords: Cancer; Cancer therapy; TICCA; Telomerase; Telomere; Transient immediate complete and combinatory attack.

Fig. 1

Schematic description of the shelterin complex. Telomeres end with a G-strand 3’ overhang that invades the double-stranded telomeric sequence. A closed structure called telomere loop (T-loop) is formed. The shelterin complex coordinates the T-loop formation and protects the end of the chromosome from damage. Telomeric Repeat Factor 1 and 2 (TRF1 and TRF2) bind to double strand (ds) DNA and form two separate complexes with other proteins. Protection of telomeres protein 1 (POT1) recognizes single-stranded DNA while Repressor/activator protein 1 (RAP1) binds to DNA at the ds-ss joint. TRF1- and TRF2-Interacting Nuclear Protein 2 (TIN2) binds TRF1 and TRF2 spontaneously and protects TRF1 from being degraded. TINT1/PTOP/PIP1 protein (TPP1) and POT1 form a heterodimer. TPP1 also links TIN2 and POT1 and recruits telomerase (TERT) with its telomerase RNA component (TR) to the shelterin complex. TPP1 contains two telomerase binding regions. The CST complex has three components: conserved telomere protection component 1 (CTC1), suppressor of cdc thirteen 1 (STN1) and telomeric pathway with STN1 (TEN1), which are thought to function in telomere lagging-strand synthesis. The CST complex binds to newly synthesized repeats and blocks telomerase activity

Fig. 2

Strategies for telomerase-based treatment of cancer. The figure summarizes the traditional and novel strategies for telomerase-based treatment of cancer: (1) oligonucleotide inhibitors inhibiting telomerase by binding to the mRNA of telomerase components and to turn the gene "off" (1A) or by inactivating the RNA template of the telomerase complex (1B), (2) alternative splicing to induce splicing patterns with inactive variants, (3) quadruplex stabilizers to inhibit telomerase indirectly, (4) small-molecule telomerase inhibitors with a broad variety of targets, (5) dual hybrid telomerase inhibitors with different tumor suppressive effects in one hybrid molecule such as telomerase inhibition plus carboanhydrase (CA) inhibition, (6) immunotherapeutic approaches as vaccine synthesis against telomerase or as adoptive cell therapy by modification of lymphocytes ex vivo, (7) viral vector mediated delivery (of Cas9-sgRNA) for mutational repair (AAV) or oncolytic therapy (HSV) in ALT positive tumors, (8) telomerase-directed gene therapy by directly addressing the telomerase gene and promotor and selective induction of high concentrations of cytotoxic and oncolytic proteins, (9) phytochemicals and various other substances with a broad range of mechanisms, and (10) direct attack of the shelterin complex. These strategies might be combined with novel technologies such telomere deprotection, Crisp/Cas9 induced abrupt telomere attrition and use of transiently effective vector systems to avoid negative effects of the conventional methods such as long start-up time and negative side-effects on the immune system with long-term treatment

Fig. 3

Combination of classical tumor therapies with targeted modulation of telomeres. The combination of old and new telomerase modifying technologies with conventional chemotherapies may allow (i) transient telomerase inhibition, thus keeping telomere length short, but not critically short, (ii) attack of alternative targets inducing telomere deprotection and (iii) immediate and complete telomere cleavage. Altogether these strategies may help to turn cancer, even if not curable, into a more chronic disease with a long survival time. A Conventional therapies alone, B Conventional therapies in combination with transient and targeted telomerase inhibition strategies C. The parallel monitoring of telomere length and structure by methods such as qPCR, TESLA or TERRA to prevent falling below critical telomere lengths and to avoid genetic instability. The lines indicate the levels of classical tumor markers such as proteins, peptides and carbohydrates found in blood, urine or tissues or novel markers such as cell-free nucleic acids and circulating tumor cells from peripheral blood (liquid biopsy). The color-coded therapies in this figure are only intended as examples and must be individually tailored to the respective tumor and patient. Different conventional therapies may be applied sequentially over a long period of time. Also, the timing of telomerase-based therapy may vary depending on the tumor and future studies.