scholarly journals Oligonucleotides and microRNAs Targeting Telomerase Subunits in Cancer Therapy

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2337
Author(s):  
Adam Eckburg ◽  
Joshua Dein ◽  
Joseph Berei ◽  
Zachary Schrank ◽  
Neelu Puri
Keyword(s):  
Cancer Therapeutics ◽  
Telomerase Activity ◽  
Cancer Therapies ◽  
Human Telomerase Reverse Transcriptase ◽  
Conceptual Foundation ◽  
Telomerase Inhibitors ◽  
Current State ◽  
Anti Cancer ◽  
Cancer Types ◽  
Human Telomerase

Telomerase provides cancer cells with replicative immortality, and its overexpression serves as a near-universal marker of cancer. Anti-cancer therapeutics targeting telomerase have garnered interest as possible alternatives to chemotherapy and radiotherapy. Oligonucleotide-based therapies that inhibit telomerase through direct or indirect modulation of its subunits, human telomerase reverse transcriptase (hTERT) and human telomerase RNA gene (hTERC), are a unique and diverse subclass of telomerase inhibitors which hold clinical promise. MicroRNAs that play a role in the upregulation or downregulation of hTERT and respective progression or attenuation of cancer development have been effectively targeted to reduce telomerase activity in various cancer types. Tumor suppressor miRNAs, such as miRNA-512-5p, miRNA-138, and miRNA-128, and oncogenic miRNAs, such as miRNA-19b, miRNA-346, and miRNA-21, have displayed preclinical promise as potential hTERT-based therapeutic targets. Antisense oligonucleotides like GRN163L and T-oligos have also been shown to uniquely target the telomerase subunits and have become popular in the design of novel cancer therapies. Finally, studies suggest that G-quadruplex stabilizers, such as Telomestatin, preserve telomeric oligonucleotide architecture, thus inhibiting hTERC binding to the telomere. This review aims to provide an adept understanding of the conceptual foundation and current state of therapeutics utilizing oligonucleotides to target the telomerase subunits, including the advantages and drawbacks of each of these approaches.

scholarly journals Physical connectivity mapping by circular permutation of human telomerase RNA reveals new regions critical for activity and processivity

2015 ◽  
pp. MCB.00794-15 ◽  
Author(s):  
Melissa A. Mefford ◽  
David C. Zappulla
Keyword(s):  
Cancer Therapeutics ◽  
Telomerase Activity ◽  
Circular Permutation ◽  
Telomerase Rna ◽  
Recognition Element ◽  
Circular Permutations ◽  
Anti Cancer ◽  
Human Telomerase ◽  
First Time

Telomerase is a specialized ribonucleoprotein complex that extends the 3’ ends of chromosomes to counteract telomere shortening. However, increased telomerase activity is associated with ∼90% of human cancers. The telomerase enzyme minimally requires an RNA (hTR) and a specialized reverse transcriptase protein (TERT) for activityin vitro. Understanding the structure-function relationships within hTR has important implications for human disease. For the first time, we have tested the physical-connectivity requirements in the 451-nucleotide hTR RNA using circular permutations, which reposition the 5’ and 3’ ends. Our extensivein vitroanalysis identified three classes of hTR circular permutants with altered function. First, circularly permuting 3’ of the template causes specific defects in repeat-addition processivity, revealing that the template-recognition element found in ciliates is conserved in human telomerase RNA. Second, seven circular permutations residing within the catalytically important core and CR4/5 domains completely abolish telomerase activity, unveiling mechanistically critical portions of these domains. Third, several circular permutations between the core and CR4/5 significantly increase telomerase activity. Our extensive circular permutation results provide insights into the architecture and coordination of human hTR and highlight where the RNA could be targeted for the development of anti-aging and anti-cancer therapeutics.

scholarly journals Telomerase-Targeted Cancer Immunotherapy

2019 ◽  
Vol 20 (8) ◽  
pp. 1823 ◽  
Author(s):  
Eishiro Mizukoshi ◽  
Shuichi Kaneko
Keyword(s):  
Cancer Cells ◽  
Anticancer Drugs ◽  
Viral Vectors ◽  
Cancer Therapeutics ◽  
Current Evidence ◽  
Telomerase Reverse Transcriptase ◽  
Future Perspectives ◽  
Human Telomerase Reverse Transcriptase ◽  
Telomerase Inhibitors ◽  
Human Telomerase

Telomerase, an enzyme responsible for the synthesis of telomeres, is activated in many cancer cells and is involved in the maintenance of telomeres. The activity of telomerase allows cancer cells to replicate and proliferate in an uncontrolled manner, to infiltrate tissue, and to metastasize to distant organs. Studies to date have examined the mechanisms involved in the survival of cancer cells as targets for cancer therapeutics. These efforts led to the development of telomerase inhibitors as anticancer drugs, drugs targeting telomere DNA, viral vectors carrying a promoter for human telomerase reverse transcriptase (hTERT) genome, and immunotherapy targeting hTERT. Among these novel therapeutics, this review focuses on immunotherapy targeting hTERT and discusses the current evidence and future perspectives.

scholarly journals Telomerase Activity Reconstitutedin Vitrowith Purified Human Telomerase Reverse Transcriptase and Human Telomerase RNA Component

2000 ◽  
Vol 275 (29) ◽  
pp. 22568-22573 ◽  
Author(s):  
Kenkichi Masutomi ◽  
Shuichi Kaneko ◽  
Naoyuki Hayashi ◽  
Tatsuya Yamashita ◽  
Yukihiro Shirota ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Telomerase Activity ◽  
Telomerase Reverse Transcriptase ◽  
Telomerase Rna ◽  
Human Telomerase Reverse Transcriptase ◽  
Human Telomerase

Breast Cancer Therapeutics Based on Fusarochromanone and EGFR Inhibitors

2021 ◽  
Author(s):  
Natalie Carroll ◽  
Alena Smith ◽  
Brian A. Salvatore ◽  
Elahe Mahdavian
Keyword(s):  
Breast Cancer ◽  
Mode Of Action ◽  
Cancer Therapeutics ◽  
Egfr Inhibitors ◽  
Cancer Therapies ◽  
Racemic Form ◽  
Combination Treatments ◽  
Anti Cancer ◽  
Cancer Agent ◽  
Cancer Activity

Abstract Background: Fusarochromanone (FC101) is a small molecule with potent anti-cancer activity. It was originally derived from the fungal plant pathogen, Fusarium equiseti, and it has also been synthesized in non-racemic form in our lab. Numerous studies reveal the promising biological activity of FC101, including potent anti-angiogenic and anti-cancer activity. While FC101 is potent as a single drug treatment across many cancer cell lines, current cancer therapies often incorporate a combination of drugs in order to increase efficacy and decrease the development of drug resistance. In this study, we leverage drug combinations and cellular phenotypic screens to address important questions about FC101’s mode of action and its potential synergies as an anti-cancer therapeutic agent in triple negative breast cancer (TNBC).Method: We hypothesized that FC101’s activity against TNBC is similar to the known mTOR inhibitor, everolimus, because FC101 reduces the phosphorylation of two key mTOR substrates, S6K and S6. Since everolimus synergistically enhances the anti-cancer activities of known EGFR inhibitors (erlotinib or lapatinib) in TNBC, we performed analogous studies with FC101. Phenotypic cellular assays helped assess whether FC101 (in both single and combination treatments) acts similarly to everolimus.Results: FC101 outperformed all other single treatments in both cell proliferation and viability assays. Unlike everolimus, however, FC101 brought about a sustained decrease in cell viability in drug washout studies. None of the other drugs were able to maintain comparable effects upon removal of the treatment agents. Although we observed slightly additive effects when the TNBC cells were treated with FC101 and either EGFR inhibitor, those effects were not truly synergistic in the manner displayed with everolimus. Conclusion: Our results rule out direct inhibition of mTOR by FC101 and suggest that FC101 acts through a different mechanism than everolimus. This lays the foundation for the refinement of our hypothesis in order to better understand FC101’s mode of action as a novel anti-cancer agent.

The Complex Cancer Care Coverage Environment — What is the Role of Legislation?

2020 ◽  
Vol 48 (3) ◽  
pp. 538-551 ◽  
Author(s):  
Christine Leopold ◽  
Rebecca L. Haffajee ◽  
Christine Y. Lu ◽  
Anita K. Wagner
Keyword(s):  
Cancer Care ◽  
Insurance Coverage ◽  
Cancer Therapeutics ◽  
Health Insurance Coverage ◽  
Cancer Therapies ◽  
Cancer Treatments ◽  
Difficult Situation ◽  
Cell Therapies ◽  
State Laws ◽  
Anti Cancer

Over the past decades, anti-cancer treatments have evolved rapidly from cytotoxic chemotherapies to targeted therapies including oral targeted medications and injectable immunooncology and cell therapies. New anti-cancer medications come to markets at increasingly high prices, and health insurance coverage is crucial for patient access to these therapies. State laws are intended to facilitate insurance coverage of anti-cancer therapies.Using Massachusetts as a case study, we identified five current cancer coverage state laws and interviewed experts on their perceptions of the relevance of the laws and how well they meet the current needs of cancer care given rapid changes in therapies. Interviewees emphasized that cancer therapies, as compared to many other therapeutic areas, are unique because insurance legislation targets their coverage. They identified the oral chemotherapy parity law as contributing to increasing treatment costs in commercial insurance. For commercial insurers, coverage mandates combined with the realities of new cancer medications — including high prices and often limited evidence of efficacy at approval — compound a difficult situation. Respondents recommended policy approaches to address this challenging coverage environment, including the implementation of closed formularies, the use of cost-effectiveness studies to guide coverage decisions, and the application of value-based pricing concepts. Given the evolution of cancer therapeutics, it may be time to evaluate the benefits and challenges of cancer coverage mandates.

scholarly journals CDK7 inhibitors as anticancer drugs

2020 ◽  
Vol 39 (3) ◽  
pp. 805-823 ◽  
Author(s):  
Georgina P. Sava ◽  
Hailing Fan ◽  
R. Charles Coombes ◽  
Lakjaya Buluwela ◽  
Simak Ali
Keyword(s):  
Cell Cycle ◽  
Rna Polymerase Ii ◽  
Cancer Therapeutics ◽  
Model Systems ◽  
Current Status ◽  
Cancer Therapies ◽  
Gene Promoters ◽  
Normal Tissues ◽  
Bet Inhibitors ◽  
Cancer Types

Abstract Cyclin-dependent kinase 7 (CDK7), along with cyclin H and MAT1, forms the CDK-activating complex (CAK), which directs progression through the cell cycle via T-loop phosphorylation of cell cycle CDKs. CAK is also a component of the general transcription factor, TFIIH. CDK7-mediated phosphorylation of RNA polymerase II (Pol II) at active gene promoters permits transcription. Cell cycle dysregulation is an established hallmark of cancer, and aberrant control of transcriptional processes, through diverse mechanisms, is also common in many cancers. Furthermore, CDK7 levels are elevated in a number of cancer types and are associated with clinical outcomes, suggestive of greater dependence on CDK7 activity, compared with normal tissues. These findings identify CDK7 as a cancer therapeutic target, and several recent publications report selective CDK7 inhibitors (CDK7i) with activity against diverse cancer types. Preclinical studies have shown that CDK7i cause cell cycle arrest, apoptosis and repression of transcription, particularly of super-enhancer-associated genes in cancer, and have demonstrated their potential for overcoming resistance to cancer treatments. Moreover, combinations of CDK7i with other targeted cancer therapies, including BET inhibitors, BCL2 inhibitors and hormone therapies, have shown efficacy in model systems. Four CDK7i, ICEC0942 (CT7001), SY-1365, SY-5609 and LY3405105, have now progressed to Phase I/II clinical trials. Here we describe the work that has led to the development of selective CDK7i, the current status of the most advanced clinical candidates, and discuss their potential importance as cancer therapeutics, both as monotherapies and in combination settings. ClinicalTrials.gov Identifiers: NCT03363893; NCT03134638; NCT04247126; NCT03770494.

Sign in / Sign up

Export Citation Format

Share Document