(Image credit: Microsoft Copilot generated image)
You could say that startup SentryDx did not originate in a research laboratory, but in a living room conversation. Several years ago, Dr. Matt Nelson, PhD, was shaken by the news of a close friend's triple-negative breast cancer diagnosis. This young woman, a mother with a young daughter, faced an uncertain future. The emotional toll was immense, compounded by the limitations of current diagnostic tools.
After rounds of treatment, Nelson's friend appeared to be in remission. Unfortunately, blood tests resulted in two cancer positive results. A month later, the results were determined to be false positives. In the meantime, this friend was riding the roller coaster of uncertainty. In the end, Nelson's friend was fortunate and there was no recurrence. However, they both knew that many others are not so lucky.
This diagnostic uncertainty got Nelson thinking—how could we improve the way we detect cancer? That personal connection led him to launch his startup SentryDx. The company's focus is on creating a highly sensitive, standardized liquid biopsy that could transform how oncologists detect and monitor cancer.
The Birth of an Idea and the Journey of a Startup
Nelson’s journey into the cancer detection world wasn’t a traditional path of oncology research. In fact, his background was in plant and microbial biology. However, this background gave Nelson extensive experience in functional genomics and polymerase chain reaction (PCR) techniques. From his grad school days at the University of Minnesota, he knew how to tackle molecular biology problems, including those related to cancer.
After his friend's cancer scare, Nelson began thinking and reading deeply about how to detect cancer. In particular, he wanted to understand how you could measure the presence of a single cancer cell amid the noise of a whole body full of cells. After working through some ideas on nucleic acid amplification, Nelson was ready to start testing his hypothesis. Thus, SentryDx was formed.
SentryDx began with a scrappy start. Seed funding came from family members and friends. Even his initial lab space began with assistance from the company MNPharm. They let him use their lab space in the un-used night hours, and Nelson took a turn in the lab from 9pm to 2am for many days. He also began working with molecular geneticist Paul Atkins to tackle some of the thorny genetics questions.
Ultimately, Nelson's and Atkins' work began to pay off with promising results. Not long ago, SentryDx was able to secure seed fund money from the National Science Foundation (NSF), based on preliminary results of their liquid biopsy technology.
Redefining Cancer Detection with the Liquid Biopsy
Traditional biopsies involve removing cancerous tissue from a known tumor site. The removed cells are then analyzed with a variety of techniques including treating/preparing the cells followed by visual examination by a trained pathologist. Genetic molecular tests may also be performed.
Traditional biopsy analysis is crucial in appropriate cancer diagnosis, but it relies on the skill and training of the pathologist, the accuracy of the lab tests being performed, and the correct acquisition of representative tumor cells. This last part—the acquisition of tumor cells—can be challenging for tumors in inaccessible locations. It can also be challenging after a tumor has been removed and the biopsy is looking for a few remaining tumor cells.
A liquid biopsy, on the other hand, is done by a simple blood draw. This is possible because cancer cells shed portions of their DNA into the bloodstream. As a result, it is possible to identify this circulating tumor DNA, also known as ctDNA, using molecular genetic analysis techniques. Thus, rather than attempting to take a representative tissue sample near the tumor site, a liquid biopsy enables an oncologist to use blood as the cancer detecting sample.
This offers the benefit to the patient by enabling the test to be done with a simple blood draw rather than an invasive removal of tissue. Additionally, because blood permeates the entire body, a blood sample offers a sample representative of the entire body rather than relying on sampling luck with a localized tissue biopsy.
Several companies have products to look at ctDNA for cancer detection or monitoring. The challenge with existing assays, however, is two-fold. Some assays use highly standardized techniques that apply generally to most patients and samples, but they lack the sensitivity to accurately identify ctDNA amid the other DNA from healthy cells circulating in the bloodstream. Other tests have improved sensitivity, but they require a personalized approach to detection, and thus are difficult to generalize for the entire patient population.
SentryDx's approach aims to gain the high sensitivity needed to detect minor mutations in DNA and do it with the sensitivity that will enable it to detect a single strand of errant ctDNA. This will all be done with standard molecular genetics techniques to make the process generalizable to a large population of patients and samples.
Answers via Amplifying and Blocking
The key to SentryDx's sensitive and standardized approach resides in the amplification process. Nelson's key insight into the detection process came from thinking about detection in a different way.
One of the main problems with detection of ctDNA is obtaining the high sensitivity amid the other circulating DNA. Usual detection involves PCR amplification of DNA species. Normally this is done by selecting primers that bind to the mutated sections of the ctDNA. However, these primers can also bind with some mild affinity to the normal DNA. Because the normal DNA vastly outnumbers the rare ctDNA, normal DNA can still swamp out the ctDNA in the amplification process.
However, if a blocker oligonucleotide sequence is added to the mix, it will bind to the normal DNA with high specificity and drastically minimize the normal DNA amplification. As a result, the mutated ctDNA gets amplified to levels that far exceed the normal DNA.
Thus far, the SentryDx method shows impressive results, including 93% sensitivity for detecting 0.1% ctDNA with 100% specificity for certain cancer mutations, like the KRAS G13D mutation. This is an important breakthrough, as KRAS mutations are found in several cancers, including colorectal and pancreatic cancer.
SentryDx has also made other modifications to enable a clear negative response in samples that have no mutant DNA. This is an important aspect for a clinical test to verify that negative samples have been run correctly.
The figure below also showcases some of the data SentryDx has generated. In this experiment, the team looked at analyzing seven different cancer mutations. For each mutation, they spiked 0.01% DNA into a matrix with 99.99% normal DNA. At the concentrations used for analysis, it's expected by Poisson distribution statistics to have 0, 1, 2, or 3 copies of mutated DNA.
Dots in the figure show the results for each analysis of amplified samples. The percentage of DNA with the mutation is determined by Sanger sequencing of the amplified samples. Control samples (blue) show a low percentage, as expected. This is clearly separable from the orange samples that have the 0.01% spike of mutated DNA. Among the samples with 0.01% spiked mutated DNA, there are some samples that give a response like the control sample (green). These are the samples expected to have 0 DNA copies based on Poisson distribution statistics.
Overall, this data suggests that the mutation below can be detected with just one to three copies of DNA amid many other copies of normal DNA!
(image credit: SentryDx)
Next Steps and Future for SentryDx
With funding and data in hand, SentryDx is now focused on refining its tests and preparing for clinical trials with biobanks of colorectal cancer samples. In addition, SentryDx will be looking to have their results independently validated. Nelson recognizes the need to ensure their diagnostic test can be rigorously performed in multiple labs by a variety of scientists.
In all these steps, SentryDx is searching for partners to accelerate their scientific progress. Nelson recognizes that achieving FDA approval and clinical uptake will be a large challenge. Making inroads into the cancer diagnostics world in the face of established techniques and practices will be another barrier. Finding the right partners at the right steps in the journey will be a key to the success of this new technique.
Despite the obstacles, Nelson remains optimistic about the future. Although he started this quest in response to a friend's plight, his vision has expanded to see the broader impact. As he stated, "If we succeed, if we're right, we're going to save a lot of lives. Not just through better treatment and earlier treatment, but we're going to change screening."
To learn more about SentryDx visit https://sentrydx.com/home.
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