Malignant melanoma is the most aggressive type of skin cancer with invasive growth patterns. In 2021, 106,110 patients are projected to be diagnosed with melanoma, out of which 7180 are expected to die. Traditional methods like surgery, radiation therapy, and chemotherapy are not effective in the treatment of metastatic and advanced melanoma. Recent approaches to treat melanoma have focused on biomarkers that play significant roles in cell growth, proliferation, migration, and survival. Several FDA-approved molecular targeted therapies such as tyrosine kinase inhibitors (TKIs) have been developed against genetic biomarkers whose overexpression is implicated in tumorigenesis. The use of targeted therapies as an alternative or supplement to immunotherapy has revolutionized the management of metastatic melanoma. Although this treatment strategy is more efficacious and less toxic in comparison to traditional therapies, targeted therapies are less effective after prolonged treatment due to acquired resistance caused by mutations and activation of alternative mechanisms in melanoma tumors. Recent studies focus on understanding the mechanisms of acquired resistance to these current therapies. Further research is needed for the development of better approaches to improve prognosis in melanoma patients. In this article, various melanoma biomarkers including BRAF, MEK, RAS, c-KIT, VEGFR, c-MET and PI3K are described, and their potential mechanisms for drug resistance are discussed.

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.

Telomeres function as protective caps at the terminal portion of chromosomes, containing non-coding nucleotide sequence repeats. As part of their protective function, telomeres preserve genomic integrity and minimize chromosomal exposure, thus limiting DNA damage responses. With continued mitotic divisions in normal cells, telomeres progressively shorten until they reach a threshold at a point where they activate senescence or cell death pathways. However, the presence of the enzyme telomerase can provide functional immortality to the cells that have reached or progressed past senescence. In senescent cells that amass several oncogenic mutations, cancer formation can occur due to genomic instability and the induction of telomerase activity. Telomerase has been found to be expressed in over 85% of human tumors and is labeled as a near-universal marker for cancer. Due to this feature being present in a majority of tumors but absent in most somatic cells, telomerase and telomeres have become promising targets for the development of new and effective anticancer therapeutics. In this review, we evaluate novel anticancer targets in development which aim to alter telomerase or telomere function. Additionally, we analyze the progress that has been made, including preclinical studies and clinical trials, with therapeutics directed at telomere-related targets. Furthermore, we review the potential telomere-related therapeutics that are used in combination therapy with more traditional cancer treatments. Throughout the review, topics related to medicinal chemistry are discussed, including drug bioavailability and delivery, chemical structure-activity relationships of select therapies, and the development of a unique telomere assay to analyze compounds affecting telomere elongation.