Advances in Biomarker Discovery: From Disease Detection to Cure
Biomarkers can reveal a drug’s mechanism of action, early signs of toxicity and which patients are most likely to benefit from treatment.
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Biomarkers – measurable biological indicators found in blood, bodily fluids or tissues – reflect changes from normal biological processes to pathogenic ones that cause disease. They are also used to assess responses to medical treatment. Thus, biomarkers are crucial for early diagnosis, drug target identification, monitoring drug response and predicting patient prognosis.
In recent years, biomarkers have become increasingly important in drug discovery and development as they can reveal a drug’s mechanism of action, early signs of toxicity and which patients are most likely to benefit from treatment.
This article examines some of the latest advances in biomarker discovery in the fields of cancer and neurodegenerative and infectious diseases and the technologies that are driving these discoveries.
Translating cancer biomarker research into the clinic
Because of the heightened focus on personalized cancer medicine, biomarkers are taking center stage, helping to customize treatment approaches for individual patients based on their distinct tumor profiles.
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Researchers, including Cho, are also turning their attention to microRNAs and long non-coding RNAs, which regulate gene expression and may serve as potential drug targets. His team recently identified the small, non-coding RNA miR-145 as a promising biomarker for non-small cell lung cancer.1
Cho anticipates important developments in the field as researchers adopt multiomic approaches that integrate genomics, proteomics and metabolomics data, leading to a more comprehensive understanding of cancer biology, and the identification of new biomarkers and therapeutic targets.2
However, several challenges need to be overcome for biomarkers to be used more widely in the diagnosis and management of patients with cancer. “Establishing standardized protocols for biomarker discovery and thorough clinical validation is essential to guarantee consistency and reliability across research studies,” Cho noted. He also underscores the need for clear guidelines to navigate the regulatory frameworks for biomarker-based tests and streamline approval processes, and the importance of integrating biomarker testing into regular clinical workflows.
Cho is optimistic that the use of artificial intelligence and machine learning to pinpoint and validate biomarkers from complex datasets will expedite the translation of biomarker research into clinical application. Additionally, advances in liquid biopsy methodologies will allow for non-invasive and cost-effective monitoring of tumor dynamics and treatment responses.
Biomarkers and the early detection of neurodegeneration
Neurodegenerative diseases affect over 50 million people worldwide. Alzheimer’s disease is the most common one and accounts for up to 70% of all dementia cases.3 Despite recent advances in the development of disease-modifying treatments, the drugs available to most patients today only relieve the symptoms; they do not address the underlying cause of disease or halt progression.
Yet, in the case of Alzheimer’s disease, pathological features such as amyloid-beta aggregates and neurofibrillary tangles, can start to form 10-30 years before the onset of dementia, highlighting the opportunity for early detection and treatment.4
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As Dr. Marc Suárez-Calvet, neurologist and scientist at BarcelonaBeta Brain Research Center (BBRC) and Hospital del Mar in Spain explains, there are three main types of biomarkers of neurodegenerative disease that are used in specialist centers, clinical trials and observational studies. Those found in the cerebrospinal fluid (CSF) or blood, those detected by neuroimaging techniques such as MRI or PET scans and cognitive digital biomarkers — data collected from digital devices that can provide information about patients’ cognitive abilities over time.
Suárez-Calvet spent five years in Munich working on TREM2 (Triggering receptor expressed on myeloid cells 2), a protein that is elevated in the CSF of patients with early-stage Alzheimer’s disease.5 “A few years ago, I was skeptical about the possibility of blood biomarkers for Alzheimer’s disease,” he admitted. “But now, we actually have very effective blood biomarkers for detecting the disease.”
Improvements in the specificity and sensitivity of detection methods that rely on antibodies or mass spectrometry allow the detection of biomarker proteins, such as phosphorylated tau and amyloid-beta, found in much lower concentrations in the blood than in CSF.
“Automated, ultra-sensitive immunoassays that are scalable, robust and reproducible, are crucial for the routine clinical use of blood biomarkers,” Suárez-Calvet said.
Suárez-Calvet also highlights the role of proximity extension assays and aptamer-based technologies in accelerating biomarker discovery. These technologies overcome some of the limitations of antibodies and enable the unbiased detection of hundreds of proteins in complex biological samples at the same time. “Because neurodegenerative diseases are highly heterogeneous, using a combination of biomarkers could uncover disease subtypes and help predict progression, which is instrumental for patients,” he added.
While current biomarkers can accurately detect Alzheimer’s disease and can be used to assess the effect of new treatments on pathology in clinical trials, more work is required to determine if changes in these biomarkers predict a clinical benefit.
Progress in other neurodegenerative diseases has been somewhat slower. Although real-time quaking-induced conversion can detect α-synuclein aggregates in the CSF and peripheral tissues of patients with early Parkinson’s disease with high sensitivity, and measuring TDP-43 in blood extracellular vesicles has shown promise for detecting frontotemporal dementia, there is still a lot of work to be done.6,7
Suárez-Calvet has recently been appointed head of the Biomarkers Group in Fluids and Translational Neurology at the BBRC and is particularly interested in the prevention and early diagnosis of Alzheimer’s disease. Drug trials have shown that the earlier the treatment is given, the greater the benefit. Moreover, there is evidence that it may be possible to prevent or delay the development of dementia in a proportion of the population by modifying exposure to common risk factors such as hypertension, smoking and obesity.8
He is currently carrying out an observational study on people who are cognitively normal but who have a parent with sporadic Alzheimer’s disease. “We are exploring how CSF and blood biomarkers change over the continuum of disease in a cohort enriched for risk factors for Alzheimer’s disease to better understand the preclinical stage of the disease,” he explained.
His team is also exploring the effects of various nonpharmacological and pharmacological interventions to prevent Alzheimer’s disease. Suárez-Calvet is cautiously optimistic as the trials are starting to show modest effects.
“The field is at a very interesting point; we know we need to identify and treat patients as early as possible and that new, better drugs are in the pipeline,” he said. Biomarkers will be key to test early interventions and monitor their effects.
Biomarkers of prognosis and potential therapeutic targets in infectious disease
Many different molecular biomarkers are commonly used to monitor the progression of infectious diseases. They can indicate the level of infection, the body’s response to it and the effectiveness of treatments.
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In 2020, as the COVID-19 pandemic unfolded, it became imperative not just to identify patients infected with the SARS-CoV-2 virus but also to identify those at high risk of progressing to a severe stage of disease, requiring hospitalization and oxygen treatment. Among the many biomarkers of disease severity and mortality are C-reactive protein, fibrin-D-dimer, pro- and anti-inflammatory cytokines (IL-6 and IL-10), liver enzymes (aspartate aminotransferase and alanine aminotransferase) and high-sensitivity cardiac troponin I.9 The contribution of each of these biomarkers to disease progression is still the subject of intense investigation as it could provide insights into the mechanisms of disease and lead to new drug targets or treatment approaches.
While most people recover fully from COVID-19, over 40% of survivors might suffer from a variety of persistent symptoms for months after SARS-CoV-2 infection.10 They are referred to as long COVID patients. Professor Katerina Akassoglou, director of the Center for Neurovascular Brain Immunology at the University of California San Francisco (UCSF), has been researching the role of fibrin, an insoluble protein formed during blood clotting, in COVID-19 pathogenesis.
“We were intrigued by the mounting clinical evidence reporting the abundant presence of fibrin in the lungs, brains and blood of COVID-19 patients,” she said, “and in particular, the strong associations of leaks of blood in the brain with brain fog in long COVID patients.”
Previous studies have shown that fibrinogen, the soluble precursor of fibrin, is a predictive biomarker for post-COVID-19 cognitive deficits. In an article published in Nature, Akassoglou and colleagues showed that fibrin binds to the SARS-CoV-2 spike protein to activate an innate immune response in the brain and lungs.11
“Our study shows that the fibrinogen/fibrin pathway is not only associated with the disease but is a key culprit of toxic inflammation in COVID-19 pathogenesis,” explained Akassoglou.
By using genetic and pharmacological tools to inhibit the toxic effects of fibrin in mice, as well as unbiased proteomic and transcriptomic technologies to examine the effects of fibrin on immune cells, her team was able to reduce the severity of COVID-19 and improve viral clearance. These findings suggest that fibrin could not only be a useful biomarker for monitoring the course of COVID-19 pathogenesis but also a potential therapeutic target.
“Inhibiting fibrin genetically or pharmacologically protects animal models of multiple sclerosis, Alzheimer’s disease, traumatic brain injury, rheumatoid arthritis, periodontitis and, as shown in our study, COVID-19,” Akassoglou noted.
Akassoglou’s lab has developed a first-in-class therapeutic monoclonal antibody that specifically targets fibrin’s inflammatory properties without affecting its essential role in blood coagulation. She will be keeping a close eye on how the drug progresses through Phase 1 safety and tolerability clinical trials as it could transform the treatment of a wide range of inflammatory diseases affecting the central nervous system.
Outlook for biomarker discovery
Regardless of the type of disease, biomarkers are vital for spotting and treating diseases at the earliest stage. Improvements in the sensitivity and throughput of omic technologies, as well as in data analysis techniques, including artificial intelligence, are making biomarker discovery more precise and actionable.
As the field evolves, there is an expectation that biomarkers will be used more frequently in routine clinical practice, not just to aid in the early detection of disease but also to guide personalized treatment, ultimately leading to better patient outcomes.
References:
1. Cho WC, Wong CF, Li KP, Fong AH, et al. miR-145 as a potential biomarker and therapeutic target in patients with non-small cell lung cancer. Int J Mol Sci. 2023;24(12):10022. doi: 10.3390/ijms241210022
2. Huang HH, Li J, Cho WC. Editorial: Integrative analysis for complex disease biomarker discovery. Front Bioeng Biotechnol. 2023;11:1273084. doi: 10.3389/fbioe.2023.1273084
3. Dementia. World Health Organisation. https://www.who.int/news-room/fact-sheets/detail/dementia. Published 2023. Accessed November 15, 2024
4. Jansen WJ, Ossenkoppele R, Knol DL, et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA. 2015;313(19):1924-1938. doi: 10.1001/jama.2015.4668
5. Morenas-Rodríguez E, Li Y, Nuscher B, et al. Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer's disease: a longitudinal observational study. Lancet Neurol. 2022;21(4):329-341. doi: 10.1016/S1474-4422(22)00027-8
6. Bargar C, Wang W, Gunzler SA, et al. Streamlined alpha-synuclein RT-QuIC assay for various biospecimens in Parkinson’s disease and dementia with Lewy bodies. acta neuropathol commun. 2021;9(1):62. doi: 10.1186/s40478-021-01175-w
7. Chatterjee M, Özdemir S, Fritz C, et al. Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS. Nat Med. 2024;30:1771-1783. doi: 10.1038/s41591-024-02937-4
8. Rasmussen J, Langerman H. Alzheimer's Disease - Why we need early diagnosis. Degener Neurol Neuromuscul Dis. 2019;9:123-130. doi: 10.2147/DNND.S228939
9. Gallo Marin B, Aghagoli G, Lavine K, et al. Predictors of COVID-19 severity: A literature review. Rev Med Virol. 2021;31(1):1-10. doi: 10.1002/rmv.2146
10. Domingo FR, Waddell LA, Cheung AM, et al. Prevalence of long-term effects in individuals diagnosed with COVID-19: an updated living systematic review. medRxiv. 2021:2021.06.03.21258317. doi: 10.1101/2021.06.03.21258317
11. Ryu JK, Yan Z, Montano M, et al. Fibrin drives thromboinflammation and neuropathology in COVID-19. Nature. 2024;633(8031):905-913. doi: 10.1038/s41586-024-07873-4
