Small molecule biomarkers to align patients, disease, and therapy

22 September 2022

FiercePharma

While parallel sequencing has been instrumental in advancing genomics-based medicine, DNA biomarkers are largely static measures set from early life. It is clear that human internal exposures — how host organs interact with one another — as well as external exposures, including host interactions with diet, lifestyle, physical activity, toxicants, environment, microbes, and other exposures over the course of lifespan, have profound influence on human health, development of disease, and therapeutic response.

Metabolomics seeks to identify small molecule biomarkers that capture these dynamic influences of the world around us, and is a critical next step towards advancing personalized medicine and most closely aligning an individual patient, with a specific disease, and a given therapeutic. Explore the new biological insights that small molecule biomarkers can deliver, and see how next-generation mass spectrometry is revolutionizing their discovery.

Small molecule biomarkers: transforming patient selection and disease diagnosis

Dynamic organ physiology, inter-organ communication, host-disease interactions, and host-environment exposures are encoded in small molecule biomarkers. They have the potential to provide an unprecedented view into host and disease factors that modulate health status, disease pathobiology, and drug responses across individuals. Modern, high resolution analytical tools have revealed that there are tens of thousands of these small molecule factors present in human circulation.

As is the case with more traditional genetic or protein biomarkers, small molecule biomarkers are produced intracellularly in target or diseased tissues. Given their physico-chemical properties, however, small molecules are readily released across cellular membranes and biological barriers into the central circulation, where they can be non-invasively captured in blood samples and measured, providing a deep view into tissue-level physiology.

Moreover, given their dynamic nature, small molecule biomarkers provide a real-time readout of biological processes, enabling detection of disease years before clinical symptoms may be apparent, early response to specific therapy, or even overall health status of an individual. Small molecule biomarkers are present in the simplest, most ancient organisms to the most complex hosts, and their conserved nature allows for cross integration of data and rapid translation from cellular systems, to preclinical models, to human biology. When integrated with genetic markers, small molecule biomarkers can provide further insights into mechanisms underlying genetic disease risk, measures of target engagement, and even the inference of causal relationships between biomarkers and disease pathobiology.

Next-gen mass spectrometry: for a new era of discovery

To date, the great challenge has been the lack of tools that enable rapid capture and measure of the thousands of small molecule biomarkers that exist in humans. Next-generation mass spectrometry developed and powered by Sapient now overcomes this challenge by enabling ultra high throughput, nontargeted small molecule biomarker discovery – measuring tens of thousands of circulating factors across tens of thousands of individuals at a time. These technical systems are embedded in a discovery pipeline that includes:  

  1. Next generation, rapid mass spectrometry-liquid chromatography (rLC-MS), able to measure >11,000 small molecule biomarkers per biosample in <1 minute analytical cycle time. The method captures broad chemistries in a single run, with 4D chemical characterization of known and unknown molecules.
  2. Bicomputational integration to handle, process, and extract insight from the massive mass spectral datasets generated, using statistical and machine learning tools to identify singular biomarkers of interest and/or signatures of disease. These approaches include integration of other high dimensional data, including genomics, proteomics, metagenomics, digital biomarkers, and clinical outcome measures.
  3. An expansive Human Biology Database curated by Sapient to amplify discovery. This database is comprised of data from greater than 100,000 human biosamples already assayed via Sapient’s rLC-MS, from individuals around the world who have been deeply phenotyped and longitudinally followed for decades, and may be leveraged to cross validate a new biomarker discovery across broad, diverse populations – achieving specificity at scale.

The ability to rapidly generate comprehensive nontargeted data on small molecule biomarkers, combined with approaches that elucidate biomarker robustness on a population level, makes Sapient a leading partner to accelerate biomarker-guided drug development and advance personalized medicine.

Accelerated biomarker discovery: the key to unlock the underpinnings of human health and disease

As growing data has now made clear, all disease is not identical. Even among individuals that fall into a singular diagnosis, whether it be for a ‘common disease’ such as diabetes, atherosclerosis, NASH, or Alzheimer’s or for a rare genetic disorder, there exists tremendous heterogeneity in mechanisms that promote disease, clinical manifestations, long-term prognosis, and ultimately, drug response.

By providing a detailed view of tissue physiology and disease pathobiology, small molecule biomarkers can now identify subgroups of individuals that share a common disease risk, disease pathway, and/or treatment response. They can differentiate those with slow- vs. fast-progressing forms of a disease; elucidate exposures that can contribute to or improve a condition; and identify patients who will be responders vs. those who will not benefit from a drug, among other applications. Specific therapies can thereby be aligned with the right patient based on their unique biology and disease mechanisms.

Partnering with leading biopharma, academic labs, and research institutes alike, Sapient’s work has already validated new early diagnostic biomarkers of disease and discovered companion diagnostics that denote individuals that respond to specific therapies. Its next-generation mass spectrometry based technologies are enabling an entirely new scale of small molecule biomarker discovery, equipping sponsors with actionable insights to better personalize disease prediction, diagnostics, and therapies.

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