Omics Science and Personalized Approaches in Bladder Cancer

Urothelial carcinoma, tumors originating from the multilayered covering tissue (transitional epithelium) of the renal pelvis or the ureter, also known as transitional cell carcinoma, is a cancer that originates from the cells lining the urinary system, including the bladder, ureters, and renal pelvis. It is a significant global health issue, with an estimated 430,000 new cases and 165,000 deaths in 2020 alone. In the US, around 83,000 new cases of bladder cancer are diagnosed each year, resulting in over 17,000 deaths. The disease is more common in men, and the risk increases with age.

Urothelial carcinoma

Urothelial carcinoma is a complex and varied disease that can be either non-invasive or invasive, with different clinical and molecular characteristics. Non-invasive urothelial carcinoma, also known as papillary urothelial neoplasms of low malignant potential (PUNLMP) or non-invasive papillary urothelial carcinoma (NIPUC), accounts for about 70% of bladder cancers. This form is usually slow-growing and has a good prognosis, with a low risk of becoming invasive. In contrast, invasive urothelial carcinoma can spread to other organs and tissues, leading to metastasis and a poor prognosis.

Prognosis and Treatments

Despite progress in diagnosis and treatment, urothelial carcinoma often has a poor prognosis, particularly in advanced stages. Current treatment options include surgery, chemotherapy, radiation therapy, and immunotherapy. However, the effectiveness of these treatments varies depending on the stage and molecular profile of the tumor. There is an urgent need to identify new biomarkers and therapeutic targets specific to this type of cancer to improve patient outcomes, especially given the disease's heterogeneity and the range of molecular alterations seen in different patients.

Role of Omics

Omics sciences, including genomics, proteomics, metabolomics, and microbiomics, have significantly improved our understanding of cancer biology.

• These approaches involve a comprehensive analysis of molecular data, including DNA, RNA, proteins, metabolites, and their interactions with the environment and microbiome.

• Studies have identified recurring genetic alterations that drive urothelial carcinoma growth and survival.

• Understanding these altered metabolic pathways in cancer cells allows researchers to develop targeted therapies to disrupt these pathways and inhibit tumor progression.

• The role of the microbiome in cancer development and treatment response is also increasingly recognized, with specific microbial compositions associated with urothelial carcinoma.

Review: Omics in Bladder Cancer

In their recently published review, a group of scientists discuss the use of omics sciences in diagnosing and treating urothelial carcinoma, focusing on genomics, proteomics, metabolomics, and microbiomics. They propose future directions, including integrating multi-omics data, developing new therapeutic strategies, and implementing personalized approaches to cancer management. While omics sciences offer potential in identifying biomarkers, therapeutic targets, and advancing our knowledge of cancer biology in urothelial carcinoma, it's important to validate their clinical utility and overcome challenges for widespread adoption through standardized assays, biomarker validation, and large-scale studies in clinical practice. 

Let's take a look at the researchers' findings!

Understanding the Genetic Basis of Cancer

Cancer is a genetic disease that originates from the accumulation of genetic alterations in cells, disrupting normal cell functions such as cell proliferation, differentiation, and apoptosis. While germline mutations, like those in the BRCA1/2 genes, have been extensively studied in breast and ovarian cancer, their role in urothelial carcinoma is less understood. 

Role of Somatic Mutations in Urothelial Carcinoma

Somatic mutations in oncogenes and tumor suppressor genes play a vital role in the development and progression of urothelial carcinoma, contributing to the dysregulation of key signaling pathways involved in cell growth, survival, and proliferation. 

The Impact of FGFR3 Mutations

One of the most frequently mutated genes in urothelial carcinoma is fibroblast growth factor receptor 3 (FGFR3). These mutations are mainly seen in low-grade non-invasive urothelial carcinomas, such as papillary urothelial neoplasms of low malignant potential (PUNLMP) and non-invasive papillary urothelial carcinoma (NIPUC). These mutations lead to the consistent activation of the FGFR3 signaling pathway, promoting cell proliferation and inhibiting differentiation. As a result, targeting FGFR3 signaling has emerged as a potential therapeutic strategy for urothelial carcinoma, with FGFR inhibitors currently being tested in clinical trials.

TP53 Mutations and Their Implications

Another commonly mutated gene in urothelial carcinoma is TP53, which encodes the p53 tumor suppressor protein. These mutations are often seen in high-grade invasive urothelial carcinomas. The loss or dysfunction of p53 results in impaired DNA damage response and cell cycle control, leading to genomic instability and increased tumor aggressiveness. In urothelial carcinoma, TP53 mutations are associated with poor prognosis and resistance to chemotherapy. Therefore, targeting mutant p53 or restoring wild-type p53 function is a potential therapeutic approach.

Other Gene Mutations in Urothelial Carcinoma

Other genes frequently implicated in urothelial carcinoma include ERBB2 (HER2), PIK3CA, and KDM6A. ERBB2 amplifications and overexpression have been observed in a subset of urothelial carcinomas, particularly in muscle-invasive and metastatic cases. Targeting ERBB2 with anti-HER2 therapies has shown promise in selected patients with ERBB2-positive urothelial carcinoma. PIK3CA mutations are present in a subset of urothelial carcinomas and may predict response to targeted therapies. KDM6A is an X-linked histone demethylase frequently mutated or deleted in urothelial carcinoma, and its loss is associated with a more aggressive phenotype.

In conclusion, somatic mutations in oncogenes and tumor suppressor genes such as FGFR3, TP53, ERBB2, PIK3CA, and KDM6A contribute to the development of urothelial carcinoma by driving abnormal cell growth, survival, and invasion. These genetic alterations can serve as potential diagnostic and prognostic biomarkers, as well as therapeutic targets for precision medicine approaches in urothelial carcinoma treatment.

Genetic variations of carcinoma

Tumor genomics is critical in understanding the genetic variations of urothelial carcinoma. These variations can include somatic mutations, copy number changes, and chromosomal rearrangements. The use of next-generation sequencing (NGS) technologies has revolutionized this field by allowing a comprehensive examination of the tumor genome and transcriptome, leading to the discovery of new driver mutations and potential therapeutic targets.

#1 Targeting FGFR

In urothelial carcinoma, the discovery of actionable mutations has become one of the most promising applications of tumor genomics. These actionable mutations are specific genetic changes that can be targeted by drugs designed to inhibit or modulate the activity of the genes or pathways affected. One example is the FGFR inhibitor erdafitinib, which has been approved for treating advanced urothelial carcinoma with FGFR alterations. Clinical trials have demonstrated the efficacy of erdafitinib in patients with FGFR-altered urothelial carcinoma, underlining the importance of genomic profiling in guiding targeted therapy selection

#2 Use of PARP

Another promising therapeutic approach is the use of poly(ADP-ribose) polymerase (PARP) inhibitors in urothelial carcinoma. These inhibitors take advantage of synthetic lethality, where cancer cells with defects in DNA repair pathways become highly reliant on PARP-mediated DNA repair mechanisms. The PARP inhibitor olaparib has shown promising results in clinical trials for urothelial carcinoma patients with DNA repair gene mutations.

#3 Analyzing ctDNA

Analyzing circulating tumor DNA (ctDNA) has also emerged as a promising method for monitoring tumor burden and treatment response in urothelial carcinoma. ctDNA consists of small fragments of DNA released into the bloodstream by tumor cells. By analyzing ctDNA, real-time information on the genetic changes present in the tumor can be obtained non-invasively. Several studies have demonstrated the potential of ctDNA analysis in predicting treatment response, monitoring disease progression, and detecting minimal residual disease in urothelial carcinoma patients

Urine markers, genomic profiling and optimized treatment strategies

Recent research has focused on the use of urine markers and cytology for the surveillance of patients with urothelial carcinoma. The Cxbladder Monitor test was found to have superior sensitivity and negative predictive value compared to cytology, NMP22 ELISA, and NMP22 BladderChek tests. Other studies have detected chromosomal aberrations in urothelial carcinoma using whole-genome sequencing technology, demonstrating the high performance of customized bioinformatics workflows in identifying chromosomal aberrations.

Genomic profiling, including ctDNA analysis, offers the potential to improve patient outcomes and optimize treatment strategies in urothelial carcinoma when integrated into routine clinical practice. Numerous clinical trials, prospective studies, and retrospective studies have highlighted the efficacy of targeted therapies such as erdafitinib and olaparib, the potential of ctDNA as a biomarker, and the prognostic implications of genetic alterations in urothelial carcinoma. Future research will continue to uncover the complex genetic landscape of urothelial carcinoma, paving the way for personalized treatment strategies.

Biological therapies and proteomic biomarkers

Immunotherapy for Urothelial Carcinoma

Immunotherapy, a treatment method that stimulates the immune system to target cancer cells, has shown promise in treating Urothelial Carcinoma (UC). A revolutionary type of immunotherapy, immune checkpoint inhibitors (ICIs), has been approved for UC treatment. ICIs enhance the immune system's response against cancer cells by blocking proteins that limit the immune system's ability to attack these cells. Studies show that ICIs like pembrolizumab and atezolizumab improve survival rates and have fewer side effects compared to chemotherapy.

Monoclonal Antibodies in UC Treatment

Monoclonal antibodies (mAbs) are targeted drugs designed to bind to specific proteins on the surface of cancer cells. This binding either destroys the cells or hinders their growth and spread. Atezolizumab, a mAb approved for UC treatment, targets a protein called PD-L1 expressed on some cancer cells, activating the immune system to attack these cells. Other mAbs, like enfortumab vedotin, target proteins such as Nectin-4, which is often overexpressed in UC cases.

Biomarker-Driven Strategies

Biomarker-driven strategies leverage biomarkers like genetic mutations or protein expression levels to identify patients likely to benefit from specific treatments. For example, FGFR3 mutations, which are present in about 20% of UC cases, are associated with a more favorable response to FGFR inhibitors. Similarly, PD-L1 expression may indicate a higher likelihood of response to ICIs.

Proteomic Biomarkers

Proteomics, a field that aims to identify and quantify all the proteins expressed by a cell, tissue, or organism, is rapidly evolving. Proteomic biomarkers can provide valuable insights into the molecular mechanisms underlying UC development and progression. Promising proteomic biomarkers in UC include fibroblast growth factor receptor 3 (FGFR3) and aquaporin-1 (AQP1). FGFR3 mutations are present in up to 80% of low-grade non-invasive UC cases and are associated with a favorable prognosis. AQP1 overexpression has been observed in high-grade invasive UC and is associated with poor survival outcomes. Furthermore, AQP1 has been shown to enhance the sensitivity of UC cells to cisplatin, a commonly used chemotherapy drug. Therefore, AQP1 may serve as a predictive biomarker for chemotherapy response in UC patients.

Researchers have also identified plasma protein biomarkers for early diagnosis of bladder carcinoma. These findings emphasize the need for further validation and investigation. Table 3 describes the role of protein biomarkers, metabolites, and microbes in urothelial cancers.

Metabolomic Prognostic Indicators

Metabolomic profiling, specifically of urine samples, has shown potential in predicting the prognosis of urothelial carcinoma. Several studies have aimed to identify metabolites in urine samples from urothelial carcinoma patients that correlate with disease progression and patient outcomes. 

An example includes a study by Issaq et al, which used a high-performance liquid chromatography-mass spectrometry approach to analyze urine samples from 48 healthy individuals and 41 patients with transitional cell carcinoma (bladder cancer). The statistical analysis accurately predicted the status of all samples, demonstrating a sensitivity and specificity of 100% for bladder cancer detection. Another study by Pasikanti et al. identified alterations in metabolites associated with amino acid metabolism, lipid metabolism, and energy metabolism in urine samples from urothelial carcinoma patients. They found specific metabolites, including:

• Creatinine

• Taurine

• Citrate

These metabolites exhibited significant associations with patient prognosis, suggesting their potential as prognostic biomarkers. 

Microbiomic Prognostic Indicators

In addition to metabolomics, microbiomic analysis shows promise as a prognostic indicator in urothelial carcinoma. Several studies have explored the link between microbial communities and clinical outcomes in urothelial carcinoma patients. 

For instance, a study by Xu et al. compared the urine microbiota of healthy individuals and that of bladder cancer patients, and observed an enrichment of Streptococcus in the urine of patients with urothelial carcinoma. Another study revealed Firmicutes as the most abundant phylum in both groups, followed by Actinobacteria, Bacteroidetes, and Proteobacteria.

Conclusion

The advent of omics sciences has significantly improved our understanding of urothelial carcinoma. It has opened opportunities for advancements in diagnosis, prognosis, and treatment. Comprehensive research into tumor genomics, pharmacogenomics, biological therapies, proteomic biomarkers, and metabolomic and microbiomic prognostic indicators have paved the way towards refined strategies for managing urothelial carcinoma. Future research should focus on creating personalized approaches to urothelial carcinoma by integrating multi-omics data with clinical parameters, identifying novel therapeutic targets, and creating strategies to overcome resistance mechanisms.