The history of oncology is marked by numerous clinical trials that have inexplicably failed. The most puzzling of these are trials with identical designs conducted in different countries that have yielded contradictory results. Despite advancements in clinical genomics, this enigma has persisted, producing more questions than answers.
At BioCorteX, we decided it was time to solve this mystery.
Drug-Bacteria Interactions: An Overlooked Factor
It has long been understood that the microbiome – the community of bacteria, viruses and fungi that co-exist within each of us – differs between populations, a concept that aligns intuitively with the cultural variations in diet and dietary habits worldwide. These differences range from soy vs. dairy, to plant vs. meat-based diets, and traditional vs. processed foods. Such variations influence microbiome composition, as established by research from our team and others in the field. At BioCorteX, we seek to translate these observations into credible, patient-centred insights that drive forward drug development and clinical care. In this case, we focused on Japan and the USA, two countries with well-documented differences in stool microbiomes and parallel histories of differential trial outcomes.
A Tale of Two Trials
In 2002, Noda et al reported in the New England Journal of Medicine striking results from a Japanese Phase III clinical trial. Irinotecan, a topoisomerase 1 (TOP-1) inhibitor chemotherapy, had been found to be superior to etoposide, a topoisomerase 2 (TOP-2) inhibitor and longstanding standard of care, for advanced lung cancer. The trial was so successful that it was stopped early, as the magnitude of the benefit of irinotecan meant that it was felt to be unethical for patients to continue to receive the older treatment. In short course, irinotecan was licensed as the first-line treatment for this cancer in Japan.
However, when Lara et al attempted to replicate this trial in North America in 2009, the results were profoundly disappointing. Irinotecan was found to be no better than etoposide, and consequently, it did not receive licensing approval for extensive-stage small-cell lung cancer in the USA.
For over a decade, the reason for this discrepancy remained unexplained. Pharmacogenomic studies – exploring the influence of genetic variation on drug metabolism – failed to find a link with efficacy. Even when associations with toxicity were found, the variants involved were rare. The question of what was causing this difference was consigned to history.
The Hidden Answer: Drug-bacteria interactions
What differs persistently between Japanese and US populations aside from genetics? At BioCorteX, we believe this to be drug-bacteria interactions.
Using our 15 billion node knowledge graph, Carbon Knowledge™, we compared thousands of microbiome samples from Japanese and US populations. The differences were clear and persistent, allowing us to independently cluster the two groups based on microbiome composition. Though fascinating in and of itself, at BioCorteX, we strive for more than mere associations.
We take a unified biology approach to science, attempting to map all our discoveries to biologically plausible mechanisms that cross-cut cancer genomics, immunity and metabolism. This approach underpins our most significant technology, our foundational emulator, Carbon Mirror™. Using Carbon Mirror, our analysis revealed that the Japanese microbiome harboured bacteria producing a protein similar to human TOP-1. These bacterial homologs sequester active irinotecan, reducing its availability to act on the cancer target site. TOP-1 unwinds DNA in preparation for cell division, a key step in normal cell proliferation that spirals out of control in cancer. TOP-1 inhibitors disrupt this process, leading to lethal breaks in the DNA as cells attempt to replicate, causing cancer cell death. By reducing the effective amount of irinotecan that acts on the cancer DNA, these bacteria were blunting the capacity of the treatment to kill the cancer. As a result, irinotecan’s efficacy was diminished in patients from the USA, where these bacteria were more prevalent, explaining the trial outcome differences. After 20 years with no answers, the mystery of the two trials had finally been solved.
Recognition and Future Directions
Our discovery has been celebrated within the oncology and scientific communities. We were honoured to receive a Conquer Cancer Award from the prestigious American Society of Clinical Oncologists (ASCO), which hosts the largest annual congress of oncologists and cancer care providers, with over 40,000 delegates. It was a fantastic opportunity to present our work, which received a huge amount of interest from clinicians, scientists and industry stakeholders from around the world, fostering new collaborations and exciting partnerships.
This breakthrough is a significant step toward solving the problem of cancer drug development. However, many mysteries remain, and the shadow of unmet need looms large for patients with cancer. BioCorteX is committed to delivering the right drug, for the right patient, at the right time. Each step we take, with our technology and our science, moves us forward in achieving our vision.
