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TELOMERASE TARGETING IN CANCER Hari Krishnan R*1 *1Student,
Department of Biotechnology, SRM institute of Science and Technology, Chennai, India.
ABSTRACT Telomerase is a terminal transferase ribonucleo protein that is responsible for maintaining telomere length. This is a feature of nearly 85% of the cancers where cell immortality is achieved by increased expression of telomerase enzyme responsible for the addition of telomere repeat sequences at the 3’ end of the chromosomes after every replication cycle thereby maintaining telomere length. Telomerase is generally active in germ cells and stem cells but is undetectable in normal cells. This makes telomerase inhibitors a potential target in cancer immunotherapy. The telomerase holoenzyme contains two major subunits, the telomerase reverse transcriptase (hTERT) which is the catalytical subunit, and the telomerase RNA (hTR) which provides a template RNA with its sequence complementary to the telomere repeat sequence (“5’-dTTAGGG-3’”). These two subunits are considered important in the telomerase inhibitors studies. Other telomerase inhibitor targets are tankyrase 1 and 2 which is responsible for telomere homeostasis, HSP 90 inhibitors, and 3’ telomere overhang sequence (T-oligos), etc. Inhibition of telomerase will lead to loss of telomeres in cancer cells thereby disabling its immortality feature and enabling replicative senescence and hence acting as a tumor suppressor mechanism. In this review paper, we discuss the recent advances in telomerase inhibition and focus on the future perspectives. Keywords: cell immortality, hTERT, immunotherapy, T-Oligos, replicative senescence.
I.
INTRODUCTION
Telomeres are DNA sequences consisting of hexameric 5′-TTAGGG-3′ tandem repeats capped at the ends of the eukaryotic chromosomes. During eukaryotic cell division, the telomeres shorten with each division as a result of the reduced expression of telomerase enzyme and after about 50 divisions the telomere length becomes critically shortened thereby inducing replicative senescence. The tandem repeats are associated with a complex protein called shelterin. Shelterin consists of six subunits, TRF1, TRF2, Rap1, TIN2, TPP1, and POT1 which binds to the telomere sequences to ensure stability [1]. Telomere prevents the ends of the chromosome to be misrecognized as DNA breaks thereby preventing DNA damage responses that lead to apoptosis and senescence.[2] Telomere shortening occurs due to a process known as ‘end replication problem’, where the DNA polymerase responsible for polymerization does not completely replicate the strand [3]. At some point when the telomere length reaches its threshold, the DNA damage repair system recognizes this as DNA breaks and activates the p53 pathway inducing apoptosis [4]. Telomerase expression is highly regulated from cell to cell, its activity is generally high in cells with proliferative potential like germ cells, self-renewing stem cells. In other tissues, telomerase is inactivated in the gestation stage. A major factor in the molecular basis of telomerase regulation is transcriptional and translational regulation of the hTERT catalytical domain. Due to its overexpression in cancer cells and minimal expression in normal cells, telomerase activity (TA) is considered to be a unique cancer biomarker. Telomerase activity is high in cancer cells during early tumorigenesis and procedures such as telomeric repeat amplification protocol (TRAP) assay is being used for cancer diagnosis as this method can detect trace amounts of this enzyme [5]. In less than 15% of cancers, telomere length is maintained by a homologous recombination-mediated mechanism called the ALT pathway. These cells replenish telomeres in a telomerase independent pathway and thereby are resistant to telomerase-based therapies.
II.
TARGETING hTERT and hTR
The telomerase reverse transcriptase (TERT) and the telomerase RNA(TR) are the two subunits of Telomerase which are responsible for telomere lengthening and telomerase activity (TA) thereby making
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these two sites a potential target for therapy. Over the years various methods have been studied which exclusively target hTERT and hTR subunits and have obtained a positive response. 2.1 RNA INTERFERENCE RNA interference (RNAi) also known as post-transcriptional gene silencing (PTGS), is an emerging process used in the treatment of a variety of diseases including cancer. This method uses short doublestranded RNA sequences which degrades the target mRNA and inhibits gene expression. Currently, numerous studies are going on where hTERT and hTR are targeted using the RNAi mechanism. Kosciolek et al. were the first to inhibit telomerase using RNAi in 2003 [6]. They used 21 nucleotides long small interfering RNA (siRNA) as constructs and used viral expression vectors and performed an in vitro analysis by transfecting human carcinoma cells with siRNA directed against hTR and hTERT. They obtained a very promising result where siRNA directed against hTR showed a 75% decrease in telomerase activity and siRNA against hTERT showed a 65% decrease in the telomerase activity. The difference is probably because the RNAi of the RNA subunit(hTR) may be more efficient than that of the RNAi of the protein subunit (hTERT). To get a view of the long-term effects of RNAi a hairpin structured DNA construct against hTR was used to transfect HeLa cells. After 75days it was found that 80% of the transfected cells had reduced telomere length which makes it clear that RNAi inhibited telomerase activity [6]. Oesophageal adenocarcinoma cell line SEG-1 (Barrett’s adenocarcinoma cells) were transfected with two siRNA duplex directed against two regions of hTERT and the loss of telomerase activity were observed as early as day 1 and was completely inhibited by day 3. When comparing to the control 95% of the cells did not have telomerase protein expression. Of these cells 86% underwent apoptosis and greater than 40% of cells underwent senescence. The treated cells had a considerable change in their gene expression with the upregulation of tumor suppressor genes (p63, p73, E2F1), cell cycle arrest genes (GADD45,p21,p16). Death receptor activators responsible for apoptosis-like FasL, Fas, caspase 8 had elevated expression. CARD9 responsible for activation of caspase 9 also had increased expression when compared to the control cells.[7] Another study was performed using HeLa cells where retroviral-vectors were used to deliver a short hairpin RNA(shRNA) targeting hTERT mRNA degradation [8,9]. Telomerase activity is generally high during the S phase of the cell cycle, the introduction of these shRNAs during this stage disrupted the telomerase activity and slowed down their proliferation when compared to the control cells. It was found out that this treatment enhanced the sensitivity of cells towards conventional DNA double-strand breaking agents like bleomycin, topoisomerase inhibitors, UV radiation. A similar study was performed where shRNA was targeted against hTR and the results were highly efficient and inhibition was observed immediately after infection-causing apoptosis and cell growth inhibition [10].
III.
TARGETING TANKYRASE
hTERT and hTR are two telomerase components which are usually targeted for therapy, but other than that there are few proteins associated with telomerase which are also targeted, one of which is tankyrase a telomeric poly (ADP-ribose) polymerase (PARP) which is responsible for various functions in the celllike telomere homeostasis, glucose metabolism, and cell cycle regulation. A study was conducted in 2009 where BRCA associated cancer cells were subjected to tankyrase 1 inhibitors and the results showed a lethal immune response in the cells subjected to tankyrase inhibitors.[11]
IV.
IMMUNOTHERAPIES
Immunotherapy is the process where an individual's immune system is boosted to increase its ability to fight diseases. This therapy relies on the presence of antigens present on the tumor surface which is detected by their specific antibodies which then acts as a marker to the immune cells and hence activates an immune response. Studies have shown that telomerase derived molecules and peptide efficiently binds
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to MHC(Major Histocompatibility Complex) class I activating CD8+ T cells and class II activating CD4+ T cells [1]. 4.1 PEPTIDE VACCINES During an adaptive immune response, the antigen is processed inside antigen-presenting cells where they are broken down into small peptides and presented onto an MHC molecule. This is then identified by T cells leading to its activation. In the case of Telomerase, nearly 30 different peptide antigens are known to target the hTERT catalytic domain [1,13]. 4.1.1 GV1001 GV1001 is the first and one of the most effective vaccines targeted against hTERT. Various clinical trials have proved the efficacy of this vaccine in treating various cancers like (non-small cell lung cancer) NSCLC, melanoma, pancreatic cancer. This vaccine consists of 16 amino acids from the catalytic sites of hTERT (611–626, EARPALLTSRLRFIPK) [1,12,14]. GM-CSF is required as an adjuvant for this vaccine because it is found to activate macrophages, natural killer cells, neutrophils, and recruit dendritic cells (DC) [15]. GV1001 can activate both CD8+ and CD4+ response hence it can be administered without the HLA typing of patients[1,16]. GV1001 is a cell-penetrating peptide where it crosses the plasma membrane and localizes in the cytoplasm and down-regulates various heat shock proteins including HSP 70, HSP 90 leading to a higher anti-cancer response. In tumors under hypoxic conditions, this peptide reduces the expression of hypoxia-inducible factor (HIF)-1α, and vascular endothelial growth factor (VEGF). GV1001 inhibits angiogenesis thereby leading to apoptosis of the cancer cells [17]. It is also known to have antiviral [18], anti-inflammatory[20] features along with blocking neurotoxicity in the central nervous system [19] A study with lung cancer patients demonstrated that GV1001 administration induced both CD8+ and CD4+ responses[16]. In another phase I/II study, three doses of GV1001 with GM-CSF adjuvant was administered to patients with advanced non- resectable pancreatic cancer, and 63% of administered patients showed immune responses, and patients administered with intermediate-dose survived for longer [21]. The idea of combining GV1001 with chemotherapy was demonstrated in a study where 23 Patients with melanoma were subjected to a clinical trial where GV1001 was administered in combination with temozolomide, an alkylating agent and 78% of the administrated patients showed an immune response, five of them showed signs of tumor regression and one showed signs of complete remission [22]. 4.1.2 UV-1 A study of CD4+ T cells of long-term cancer survivors with GV1001 administration shows the presence of three hTERT derived peptides (peptide 652–665, peptide 660–689, and peptide 691–705) for which a second-generation telomerase vaccine UV-1 was developed. A phase I/II trial of this vaccine in patients with prostate cancer showed an immune response in nearly 86% of patients and 64% of patients had a regulated level of prostate-specific antigen (PSA) and 45% of patients showed no signs of the disease [23]. Clinical trials are being done to check the efficacy of UV-1 in association with checkpoint inhibitors. One of the examples is, UV-1 associated with a CTLA4 inhibitor (Ipilimumab). 4.1.3 GX301 GX301 is a dual adjuvant vaccine with four immunogenic hTERT peptides (peptide 540–548, peptide 611–626, peptide 672–686, and peptide 766–780). Similar to GV1001, GX301 can bind to both MHCI and MHC II molecules. Unlike other peptides, GX301 is associated with 2 adjuvants, Imiquimod and Montanide ISA-51 [24]. Imiquimod induces activation and maturation of Dendritic cells (DC) by activating TLR 7 and 8. Montanide protects the peptides from proteases in the microenvironment by forming a water-oil emulsion and causes an increase in uptake by the Dendritic cells. This in turn causes the dendritic cells to
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release IFNÎł which increases the expression of MHC molecules on the surface of the tumor cells and hence increases immunogenicity [24,25] A phase I study including patients with end-stage prostate and kidney cancer was administered with GX301 and 100% of the patients showed an immunogenic response to at least one of the peptides, suggesting that multi-peptide vaccines like GX301 are more effective in inducing immune response than single peptide vaccines [26]. 4.1.4 Vx-001 The Vx-001 vaccine is the first anti-cancer vaccine that uses cryptic hTERT peptides, the low-affinity hTERT peptide (RLFFYRKSV) containing arginine as the first amino acid and an optimized variant hTERT peptide (YLFFYRKSV) where the first amino acid is replaced by tyrosine [27]. The optimized hTERT peptide is administered first followed by the native peptide. The mutant hTERT peptide due to the presence of a tyrosine group has an increased affinity towards MHC I molecules. Bolonaki and co-workers in 2006 performed the first test on this vaccine to assess its safety and it was found that 93% of patients administered with the vaccine showed high CD8+ response [28]. The next year the same team studied the prolonged effect of the vaccine in non-small cell lung carcinoma patients and found out that 76% of the patients showed early T cell activity after two vaccinations and 91% of the patients showed T cell activity after six vaccinations [29]. TABLE 1- Clinical trials of telomerase-targeted peptide vaccines VACCINE NAME GV1001+ GM-CSF
CLINICAL TRIAL PHASE Phase I/II
CANCER TYPE
Pancreatic cancer Melanoma
IMMUNE RESPONSE
REFERENCE
Response in 63% patients
[21]
Immune response in 18/23 patients
[22]
GV1001+ temozolomide
Phase I/II
UV-1
Phase I/IIa
Prostate cancer
Reponse in 86% of patients
[23]
GX301+ Imiquimod +Montanide ISA51.
Phase I
Prostate and kidney cancer
Well-tolerated immune response in all patients
[26]
Phase I
Various solid tumors
Vx-001 Phase I/II
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NSCLC
93% patients showed immune response Response in 76% of patients (after 2 vaccinations ) and in 91% of patients ( after 6 vaccinations)
[28]
[29]
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4.2 DENDRITIC CELL VACCINESDC’s are immune cells responsible for the activation of T cells and hence initiate an adaptive immune response. They can process and present antigen on its MHC molecules which are then recognized by T cells thereby inducing an immune response. Recently many studies are going on where DC’s are used as a tool to induce an anti-tumor immune response and one such vaccine, sipuleucel-T was approved by the FDA for patients with metastatic prostate cancer [30]. 4.2.1 GRNVAC1 GRNVAC1 is a DC-based vaccine where DC containing hTERT mRNA and a chimeric lysosomal associated membrane protein (LAMP1) are transfected into patients [14,31]. LAMP1 induces lysosomal degradation of the hTERT proteins into smaller antigen peptides which are then presented on the MHC II surface receptor of the DC thereby activating CD4+ T cells to elicit an immune response [12]. When compared to the peptide vaccine these vaccines have numerous advantages as they are not restricted by the HLA typing of patients. A long-term study involving acute myeloid leukemia (AML) patients were administered with GRNVAC1 and after 52 months it was found out that 11 out of 19 patients who were in complete remission were free of disease recurrence [14,32]. 4.2.2 TAPCells Tumor antigen-presenting cells (TAPCells) is a DC-like cell which is used as a vaccine against advanced cancers. Concholepas concholepas hemocyanin (CCH) is used as an adjuvant that is capable of eliciting an immune response. This vaccine was tested for more than 120 patients with stage IV melanoma and 20 patients with advanced prostate cancer and it was found that the vaccine increased the doubling time of PSA, and elicited T cell responses in prostate cancer patients, and increased the survival rate of melanoma patients.[14,33] 4.3 DNA VACCINESDNA vaccines are one of the cost-effective approach used in cancer immunotherapy. To increase the efficacy of antigen processing and presentation to T cells, various recombinant DNA techniques are used performed in the hTERT coding regions of the genome [14]. 4.3.1 INVAC-1 INVAC-1 is an optimized plasmid DNA containing sequence which codes for an inactive form of hTERT. This vaccine is administered via intradermal injection using electroporation. Studies performed with mouse models found out that INVAC-1 induced T cell responses specific to hTERT. A 50% survival rate was found in a study where melanoma patients were administered with INVAC-1 [34]. 4.3.2 phTERT phTERT is synthetic electroporation delivered full-length DNA vaccine which encodes for hTERT. A study with mice and non-human primates (NHP) with phTERT administration showed the increased expression of CD8+ T cell responses specific to hTERT. This study also showed increased expression of CD107a, IFNγ, and TNF-α in T Cells. Reduced tumor growth and increased survival were observed in an HPV-16 associated study with phTERT administration [35]. 4.4 ADOPTIVE T-CELL THERAPY
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Adoptive T-cell therapy or Gene modified T-cell therapy is a technique where T-cells are genetically engineered to produce T-cell receptors (TCRs) that are specific to the tumor antigens [36,37]. The T-cells are first isolated from the patient or another individual with similar HLA typing and these are genetically modified in-vitro to produce TCRs that recognize tumor antigens and then its implanted in the patient. There are two methods of generating tumor-specific T-Cells, one is using chimeric antigen receptor (CAR), which contains light and heavy chain regions specific to a tumor surface antigen. The other method is by using tumor-specific T-cells isolated from the tumor microenvironment which is then activated invitro and transplanted to the patient [38,39]. This method is called Tumour Infiltrating lymphocyte (TIL) therapy and is known to have a higher effect on tumor cells. Studies have been done where TCRs are targeted against telomerase hTERT but the results are limited [40].
V.
CONCLUSIONS
Telomerase is expressed in a huge-varieties of cancer makes it a potential target in cancer therapy. In this review, we discussed various telomerase inhibiting strategies and it can be inferred that the presence of hTERT and hTR has opened a wide opportunity to develop different strategies for telomerase inhibition. Various clinical trials have demonstrated that hTERT derived peptides attached to MHC molecules can activate T- cell response. This concept has helped the field of immunotherapy in taking a big leap by introducing various T-cell mediated therapies. Studies today are focusing on precision medicine where different types of targeted therapies, immunotherapies, and chemotherapies are combined to improve the prognosis of patients at an individual level. The introduction of such new techniques and tools will be at the forefront of cancer therapies. FUNDING No external funding received. CONFLICTS OF INTEREST The author declares no conflict of intrest
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Acute Myeloid Leukemia (AML). Blood 2010; doi: https://doi.org/10.1182/blood.V116.21.2190.2190
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