Exploring the Relationship Between the Microbiome, Precision Drugs and Most cancers

In recent years, the idea of ​​the “microbiome” has evolved from an esoteric term used in scientific circles to a popular concept used in advertisements for the sale of “microbiome-enhancing” health drinks and nutritional supplements. The growing public interest has been fueled by a number of groundbreaking research breakthroughs and the fact that the microbiome plays a key role in the development of precision medicine.

The trillions of microbes in the human body are a key element of a personalized approach to treatment. The microbiome affects endocrinology, physiology, and even neurology, and plays a critical role in disease progression. The growing awareness of the different ways in which microbiota affects each of us individually in disease and health is also leading to an increase in research. One area where this interest is growing particularly rapidly is oncology.

Several publications imply microbiota in the incidence and progression of cancer, as well as the toxicity and response rate of cancer treatments. An analysis of 12 million full-text publications, 29 million abstracts, and 521,000 grant applications for semantic relationships between cancer and microbiota is shown in Figure 1. The data shows a sizeable increase in the number of articles associating cancer with microbiota for five cancers with the highest number of reports overall.

Figure 1. Trend in reports linking cancer to microbiota 2008-2019. Credit: Diagram made with Elsevier Text Mining and Scopus.

With cancer rates rising around the world, current interest in the microbiome and its role in precision medicine is likely to continue as it opens up new hopes for treatments. There is evidence of the importance of looking for predictors of therapeutic response beyond the tumor by focusing on host factors such as the microbiota and host genomics.1 What is important is that the microbiota is a modifiable factor, and possibly not just one predictive marker, but also a potential target can be used to improve outcomes for patients.

Exploring the link via melanoma research

To further explore the link between the microbiome and cancer, Elsevier conducted an in-depth analysis of the current landscape of melanoma research. Melanoma was chosen because the number of cases is increasing – the number of new melanoma cases worldwide is estimated at close to 300,000 per year – which underscores the importance of further research to gain a better understanding of the disease and possible treatments

Melanoma was also selected for further investigations, as the literature shows a relationship between melanoma and the microbiome that warrants further investigation. Recent results show that response to immune checkpoint inhibitors, a new class of drugs effective in treating melanoma, correlates with the composition, diversity, and functional differences in the patient’s microbiome

The relationship between the microbiome and melanoma was first shown in animal models and then further confirmed in human studies. The results of our analysis show that in 2018, two of the top three most cited research papers (based on Elsevier’s Scopus data) that mentions melanoma in the title, abstract, or keywords examined the impact of the microbiome in response to melanoma patients with over 700 examine quotes.

Progress is also being made in clinical studies of the microbiome and melanoma. Since 2018, four clinical studies have been registered with clinicaltrials.gov that aim to investigate and modulate the influence of the gut microbiome on the response to immunotherapy for melanoma. Dr. Commenting on the findings, Marc Hurlbert, Chief Science Officer of the Melanoma Research Alliance, “As noted in the report, there has been an explosion of knowledge about melanoma with an ever-growing list of protein targets. In addition, the role of the microbiome in melanoma and in response to immunotherapy is of increasing interest in this area. “

Precision therapies require further investigation

Our study also found that there is an increased focus on targeted therapeutics for patients with specific melanoma gene mutations within the small molecule and targets pipeline, reflecting the industry trend towards precision drug development. A total of 23 genes are linked to hereditary melanoma, of which 12 genes have 177 genetic variants that are linked to melanoma. The remaining 11 genes that are genetically linked do not currently have any known genetic variants associated with melanoma.

Further research is now required to further develop targeted precision therapies. First, to map genetic variants; second, to determine which variant is clinically significant; third, to understand the influence of the variant on gene function and whether variation activates or inhibits the gene. This is especially important in order to improve understanding of specific precision medicine and improve therapeutic effectiveness.

For non-hereditary (sporadic) melanoma, the analysis showed that 752 genes are genetically linked to sporadic melanoma and its subtypes and 449 genetic variants are genetically linked to sporadic melanoma and its subtypes. Of the 449 genetic variants, 395 come from 78 genes that are genetically linked to melanoma. The remaining 54 missing variants are currently not genetically linked to a known melanoma gene on the platform. This could therefore be a potential area for further research.

Understanding whether certain genetic variants exist and / or contribute to the severity and prevalence of melanoma in populations will help the research and development industry develop more effective and profitable therapeutics. This type of data provides the R&D community with a deeper understanding and an increased likelihood of achieving the goal. Through our analysis, we have found an increased incidence of drugs that target genetic mutations, particularly protein kinases and growth factor receptors, over the past decade.

Implications for all cancer research

The analysis of melanoma research is revealing for all cancer research. A better understanding of the influence of the microbiome on disease progression and therapeutic efficacy as well as drug safety will have a significant impact on the success of therapeutics. There is a complex interplay between the host’s immune response and the microbiome, creating a complicated balance between symbiosis and pathogenesis.

It is an attractive future avenue of research to understand how the symbiotic and pathogenic genome of a patient’s microorganism can dramatically affect treatment plans and outcomes. Affecting the microbiome in patients requires further research that could lead to exciting patient opportunities and drug discovery. It would be beneficial for the therapeutic pipeline to understand these host-microbiota interactions and find ways to positively influence the balance to improve treatment outcomes.

Another interesting future consideration during drug development for all cancers is the impact of the microbiome on treatment-related adverse events and whether clinical and post-clinical adverse events are related to a patient’s microbial makeup. It adds complexity to the efficacy of therapeutics that may not be readily considered and may need to be considered in future clinical trials.

The role of data science in future breakthroughs

As this analysis of the melanoma research landscape shows, data science is critical to empowering the R&D industry with greater depth of information to combat disease and industrial problems. Through thorough research through integration, harmonization and analysis of data across the entire pharmaceutical life cycle, we can identify the knowledge gaps and point out areas with the greatest potential for future research. Data-driven decisions will accelerate science and allow researchers to find preventive and therapeutic interventions faster.

Furthermore, in the current COVID-19 era, human-patient interactions are being reduced and many research laboratories are still unable to operate at full capacity. The ability to conduct research, take samples, and examine real patients is currently limited. Therefore, looking at detailed existing literature and data is a critical way to support R&D. It will keep the R&D functions going and help them focus their efforts on the areas of greatest potential. 2021 will be a year of reduced R&D budgets around the world – this type of data insight will be vital to empowering future R&D.

References

Tom is the Life Sciences Group Manager for Project Management, Knowledge Manager and Research Scientist. He has extensive experience as an academic researcher in the fields of neurodegeneration and Alzheimer’s disease. He is also trained in biophysical chemistry, dementia, and biochemistry. He is the author of numerous publications in the field of protein-membrane interactions, protein misfolding and Alzheimer’s disease. At Elsevier he delivers and implements information solutions for customers.

Tom reviews the study and the unmet needs in melanoma research and development in detail here, along with Marc Hurlbert, Ph.D. Chief Science Officer of the Melanoma Research Alliance.