One of the most promising developments in cancer research originates with the microbiome
If there is one area of cancer research that is causing a lot of excitement, it’s the link between the disease and the microbiome, and with good reason: it presents an opportunity to improve all stages of cancer care, from diagnosis to treatment. Microbiome-aware cancer diagnostics may also enable earlier detection of the disease, which is key to improving patient quality of life and survival rates. If cancers could be detected earlier, it could also potentially prevent up to four million annual deaths worldwide.
Scientists all over the world are working hard to create better cancer diagnostics, to hopefully make widespread, early-detection screening available to high-risk populations for various types of cancers. Leading the charge is the team at Micronoma, the first and only cancer diagnostic company using the circulating microbiome to detect early-stage cancer. Co-founded by the threesome of Sandrine Miller-Montgomery, PharmD-PhD, Greg Poore, MD-PhD candidate, and Rob Knight, PhD, Micronoma is dedicated to the prompt commercialization of their discovery published in Nature in 2020.
Understanding the cancer microbiome link
The link between cancer and microbes existed as early as 1550 BCE, when writings in the Ebers Papyrus suggested a crude treatment for tumors involving application of a poultice followed by an incision, which would invariably cause an infection. Fast-forwarding to the 19th and 20th centuries, several clinicians in Germany and the United States documented associations between patient infections and spontaneous regressions of their tumors, leading some to treat their patients’ tumors with cocktails of bacteria. Although crude and sometimes dangerous, this ended up being the first successful demonstration of immunotherapy. Nonetheless, these observations led many scientists to erroneously hypothesize a universal microbial cause of cancer. While that working theory has since been dismissed, several types of cancer were linked to pathogenic viruses or bacteria during the research that followed (e.g., hepatitis C virus and liver cancer or Helicobacter pylori and stomach cancer).
After decades of research focused on characterizing the host-centric aspects of cancer, the field came full circle, once again looking at the role that microbes—including non-pathogenic ones—can play in cancer development. Widespread within every human body and more numerous than human cells, microbes have essential jobs that assist with many of the body’s metabolic and immune functions.
Until recently, it was a common assumption that tumors were sterile entities, so attempting to diagnose or treat a cancer based on its microbial constituents seemed inconceivable, let alone using blood samples from these same patients to detect the disease. This sterility assumption was made despite observations in the clinic as early as 1977 that showed links between bacteria in patient blood and subsequent diagnoses of colorectal cancer. Only recently, scientists have shown with substantial evidence that the tissues and blood of cancer patients indeed have a microbiome with specific characteristics, whether healthy or diseased, and that this information can be useful in making cancer diagnoses.
These studies revealed a surprising finding that each cancer type appears to harbor a distinct microbiome. So, lung cancer tissue will harbor one set of microbial markers while breast cancer will harbor another, for instance. Since non-microbial cells and molecules from tumors are known to leak into blood, it is fitting that microbial cells and molecules also seem to be leaked. In this manner, it can be possible to detect the presence and kind of cancer through detecting small amounts of microbial DNA in the blood of patients.
This is an important finding in the world of diagnostics. Currently, cancer diagnostics that rely on detecting human markers have several limitations, including limited sensitivity (since detection is often related to the size of the tumor) and the possibility of false positives (since cancer-specific changes and aging-related changes are similar). Instead, the microbiome presents an independent picture from the human markers that can still diagnose the presence and type of cancer without being affected by these limitations.
Micronoma’s team is a spinoff of a UC San Diego team which analyzed data for 33 cancer types, derived from a database of more than 18,000 samples. Using machine learning, they were able to drill down in the 3% or so of the sequencing data which are non-human—bacterial, archaeal or viral in nature. Analyzing the data further, the team revealed that the microbial information could distinguish which samples belonged to which cancer types.
As the Micronoma team works hard to analyze even more samples, the hope is to detect these markers long before cancer has advanced to a less treatable, late-stage disease. This is especially important with certain types of cancer that often escape detection until it is too late, causing poor survival for most patients. Lung cancer and pancreatic cancer are two such examples and having early diagnostics for them could make a world of difference.
The science at work
The Micronoma team has successfully identified these unique microbial (nucleic acid) codes in the blood and tissues of cancer patients, leading to its Oncobiota™ platform to diagnose cancers in their earliest stages. On a patient level, the process is simple, requiring only a blood draw, the basis of a liquid biopsy. Behind the scenes, however, the identification process is complex, combining the use of artificial intelligence and bioinformatics tools that complement the microbiome science.
The Oncobiota™ platform first isolates, amplifies, and sequences a vast number of circulating microbial nucleic acids. It then looks for patterns in the data that match those known to associate with the presence and type of cancer. These markers can show up before traditional methods of detection become positive, potentially improving patient treatment options and outcomes. Notably, these circulating microbial nucleic acids represent material from “dead” microbes shed into the blood, likely from the tumor and potentially other parts of the body.
While microbiome-aware liquid biopsies have the potential to diagnose many cancer types, Micronoma is first turning its attention to the detection of lung cancer. There are several reasons for this choice. Firstly, it’s the most frequently occurring type of cancer in the world. In 2020 alone, there were ~228,000 new cases. Secondly, it is a cancer type that doesn’t have good screening methods and is generally not detected until late stages (III and IV). In fact, a full 75 percent of lung cancer cases fall into this category, and the associated five-year survival rate is only 15 percent for these later stages.
A third reason lung cancer is an ideal choice for liquid biopsy diagnosis is that it has a well-defined at-risk population: heavy smokers. While non-smokers can develop lung cancer, smoking dramatically increases the likelihood of developing or dying from lung cancer by 15 to 30 times. This provides a well-defined target population for blood biopsy screening if they turn up to their physicians with cancer-related concerns.
Next up for Micronoma could be pancreatic cancer, which is on track to be the number two cancer killer in the United States within the next decade and a type of cancer that usually only reveals itself in late stages. Identifying a particular population at high risk for the disease isn’t as clear cut as lung cancer, but age is one of the leading risk factors, and about two-thirds of this patient population is over the age of 65. In addition, more is becoming understood about other potential risk factors, such as late-onset diabetes. If proven effective at early detection, a microbiome-aware liquid biopsy might one day become a routine screening test for those in this age group and these associated risk factors.
Micronoma is taking a one-cancer-at-a-time approach to develop microbiome-aware liquid biopsy assays for early-stage cancers. They want to ensure that their method is validated using the proper controls for each cancer type to reduce the risk of false positives that hinders the current standard of care. Building on years of research into the microbiome and its relationship to cancer, microbiome-aware liquid biopsies stand uniquely poised to have a significant impact on early-stage cancer detection, and along with it, patients’ lives.