Unlocking Liquid Biopsy’s Full Potential

Precede Biosciences is embracing comprehensive epigenomics to help drive personalized medicine.

 

The more researchers dive into the genome, the more they understand the limitations of DNA sequencing alone. In this complex world, genes are not solely governed by their sequences; regulatory elements dictate which genes and pathways are switched on and off.

These are critically important mechanisms. The human body contains neurons, liver, pancreatic, immune, and other cells—and they all have the same DNA. How their genomes are modulated dictates their cellular identities and functions. This regulatory apparatus, called epigenomics, is where diagnostics developer Precede Bio is putting its energy.

“Genomic sequencing does not explain the vast majority of diseases physicians see in the clinic,” said Wouter Meuleman, Partner at Illumina Ventures. “Precede Bio’s minimally invasive epigenomics platform offers the opportunity to survey the activation status of druggable targets and pathways, creating a unique opportunity to inform drug development and enable precision medicine.”

 

A Broader Lens on Disease

Precede Bio’s technology originated with Matthew Freedman, M.D., who is a professor of medicine at Harvard and has a lab at the Dana-Farber Cancer Institute. Freedman had long focused on cancer genetics before becoming increasingly interested in the epigenome’s influences on cancer development.

If the genome is like computer hardware, the epigenome is the software that controls it, switching genes, or even entire genomic regions, on and off. Freedman partnered with Sylvan Baca, M.D., Ph.D., a member of his lab at the time and now an assistant professor at Harvard Medical School, and Toni Choueiri, M.D., a professor of medicine who directs the Lank Center for GU Oncology at Dana-Farber. Together, they developed a comprehensive epigenomic platform that could be deployed as a simple blood test. Later, they joined forces with Rehan Verjee, a biopharmaceutical executive, and co-founded Precede Biosciences.

“Epigenomics can offer a powerfully informative lens on the drivers of disease,” said Verjee, Precede Bio’s CEO. “Matt Freedman showed me an example of this power when we first met in patients with advanced prostate cancer, and he really captured my attention. Through epigenomics—specifically the gene enhancers—thousands of highly conserved regulatory changes were evident across the patients, changes that pointed to clear common biological programs. In contrast, mutational profiling in prostate cancer reveals mutations with little to no conservation across the majority of patients.”

This all circles back to DNA’s structure. If we stretched out the DNA from a single nucleus, it would extend for almost two meters, requiring compact packaging. To make that happen, cells wrap DNA around histone proteins, and these proteins have a profound impact on gene expression.

Using only a single milliliter of blood plasma, Precede Bio’s technology interrogates circulating tumor DNA, genome-wide, for histone modifications associated with active gene enhancers and gene promoters, as well as DNA methylation.

“Our platform accesses an incredibly rich set of dynamic epigenomic features across the genome,” said Verjee. “As a result, we can see if specific genes and pathways are active in individual patients and see how their status changes in response to treatment, all from a simple blood test.”

 

Leveraging Epigenomics to Understand Therapeutic Efficacy

Understanding whether specific genes are switched on or off can help determine which patients respond to a specific drug and assess how effectively drugs modulate their targets. If a target is not activated in a specific patient’s cancer, it’s unlikely that drug will work. Genomics alone cannot provide that information; however, the Precede Bio team believes epigenomics can.

The team is focused on developing novel epigenomic biomarkers associated with breast, lung, prostate, and colorectal cancers. These biomarkers can inform how specific therapies will be developed. Emerging approaches, such as antibody-drug conjugates (ADCs), could benefit from this epigenomic information.

ADCs are intricate treatments and Precede Bio’s platform could show how each tumor’s unique complexities affect its performance. These drugs are like drones that deliver chemotherapeutic payloads directly to cancer cells. However, the molecular linker must be detached from the warhead, or the system does not work. Even if the warhead is released properly, some patients may be resistant due to previous chemotherapy treatments.

“We can look at target biology, linker-cleavage biology, and sensitivity to the warhead and put all this information into a single predictor for a given antibody drug conjugate,” said Verjee. “This should give drug developers the ability to more precisely predict the patient populations that are likely to benefit, increasing the drug’s chances of approval and making clinical decisions biology-based versus trial-and-error-based.”

Precede Bio is actively working with drug developers to leverage the platform’s capabilities. And, while cancer therapies are the initial focus, its liquid biopsy platform could be applied to other conditions.

“Epigenomic dysregulation is a hallmark of disease, so we have a unique opportunity to interrogate actionable disease biology across many conditions,” said Verjee. “Autoimmune conditions would be one area we can have an impact, and we have some tantalizing early data in that area.”