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Relevant frequencies and locations of FGFR3 mutations in urothelial carcinomas. Frequencies are the proportion of all FGFR3 mutations characterized to date. IgI, IgII, IgIII, immunoglobulin-like domains; TK-1, TK-2, split tyrosine kinase domain (1).
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Background: Bladder cancer is the most frequent malignancy that affects the urinary tract. Studies have shown different types of FGFR3 and HRAS genes mutations in human bladder cancer, with a comprehensive range of mutation number in various populations. This study aimed to determine the specific point mutations of these 2 genes among Iranian patie...
Context in source publication
Context 1
... a Phase II study has examined the efficacy of an FGFR3 inhibitor in patients with MIBC. Most common somatic FGFR3 mutations in bladder malignancies occurred in exons 7, 10, and 15 (12, 13), and it frequently has been shown in low stage and grade tumors (14,15). Some common mutations of FGFR3 gene that are involved in bladder cancer are shown in (Fig. 1) (16). Some studies have shown that an integration of HRAS and FGFR3 tests could identify many of primary tumors (17). The connections between these genes allowed managing this project with the goal of determining the frequency of mutations of these 2 genes in bladder tumors in Iran. When noninvasive papillary urothelial carcinoma (pTa) ...
Citations
... A mutation in exons of the FGFR3 gene upstream of RAS genes activates the RAS-MAPK pathway, producing more cell growth signals, and is often present in 70% of early tumors [259]. 13-27% of bladder tumors were found to have somatic mutations in the PIK3CA oncogene, which codes for the catalytic subunit p110α of class-IA PI3-kinase [260]. RAS oncogenes also showed mutations in about 13% of the cancers [261]. ...
Gene therapy involves either the direct introduction of genetic material (DNA or RNA) into the host cell (or organ), known as in vivo gene therapy, the re-introduction of the modified target cells taken out of the host, or ex vivo gene therapy. Cancer is mainly caused by the non-functioning of genes required for normal cell proliferation, and it has emerged as the leading cause of death globally due to the absence of efficient and safe therapies as well as early diagnostic modalities. Therapeutic trials using gene therapy have shown that they considerably increase the survival rate and life expectancy of patients with cancer. There are many potential strategies for the treatment of cancer using gene therapy currently being used, including (a) expressing a gene to induce apoptosis or increase tumor sensitivity to conventional drug/radiation therapy; (b) inserting a wild-type tumor suppressor gene to compensate for its loss/deregulation; (c) blocking the expression of an oncogene using an antisense (RNA/DNA) approach; and (d) enhancing tumor immunogenicity to stimulate immune cell reactivity. Gene therapy can employ many different genes, including anti-angiogenesis, any suicidal gene, immunotherapeutic gene, siRNA gene, pro-apoptotic gene, oncolytic gene, and gene-directed enzyme prodrug. Moreover, with advancements in gene transfer technologies, various kinds of new treatment strategies have been developed that complement conventional therapies used to treat cancer that are used to modify the DNA directly, such as zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9), etc. Even though there has been a lot of progress in pre-clinical research in both better targeting and expression in a tumor-selective way, there are still a lot of problems that need to be fixed before it can be used in humans. These problems include non-specific expression, low-efficiency delivery, and biosafety. This review will highlight gene therapy's current challenges and future opportunities in cancer treatment.
Simple Summary
Urothelial cell carcinoma (UCC) is the ninth most common cancer worldwide and in the US the fourth most common cancer, with ~82,000 new cases (~62,000 men) diagnosed annually leading to ~17,000 deaths/year (~12,000 men). While early-stage cases exhibit more favorable outcomes, the emergence of drug resistance and distant metastasis reduces median overall survival (OS) to 12–15 months. The development of modern genetic and molecular assays to detect high-risk mutations has improved the detection of high-risk disease. Recently, immune therapies have been developed; these demonstrate markedly improved OS rates compared to treatment with chemotherapy alone. However, challenges persist and there remains an urgent, unmet need to develop and advance novel molecular and therapeutic strategies that prevent or overcome drug resistance, to improve patient outcome. Here, we provide an overview of the etiology, diagnostic approach and emerging therapeutic strategies for improving UCC patient quality of life and OS.
Abstract
Urothelial cell carcinoma (UCC, bladder cancer, BC) remains a difficult-to-treat malignancy with a rising incidence worldwide. In the U.S., UCC is the sixth most incident neoplasm and ~90% of diagnoses are made in those >55 years of age; it is ~four times more commonly observed in men than women. The most important risk factor for developing BC is tobacco smoking, which accounts for ~50% of cases, followed by occupational exposure to aromatic amines and ionizing radiation. The standard of care for advanced UCC includes platinum-based chemotherapy and programmed cell death (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors, administered as frontline, second-line, or maintenance therapy. UCC remains generally incurable and is associated with intrinsic and acquired drug and immune resistance. UCC is lethal in the metastatic state and characterized by genomic instability, high PD-L1 expression, DNA damage-response mutations, and a high tumor mutational burden. Although immune checkpoint inhibitors (ICIs) achieve long-term durable responses in other cancers, their ability to achieve similar results with metastatic UCC (mUCC) is not as well-defined. Here, we discuss therapies to improve UCC management and how comprehensive tumor profiling can identify actionable biomarkers and eventually fulfill the promise of precision medicine for UCC patients.
