40-41 - In sickness and in health

In recent years, the idea of the microbiome has gone from being an esoteric term used in scientific circles, to a mainstream concept employed in adverts to sell ‘microbiome-boosting’ health drinks and supplements. The increase in public interest has been fed by a series of headline-grabbing research breakthroughs, and the fact that the microbiome has a key role to play in the development of precision medicine.

The trillions of microbes contained in the human body are a key element of a personalised approach to treatment; the microbiome influences endocrinology, physiology and even neurology, and has a crucial role in disease progression. The growing awareness of the various ways in which microbiota affects each of us individually in sickness and in health is also leading to an increase in research. An area in which this interest is growing particularly quickly is oncology.

Multiple publications implicate microbiota in the onset and progression of cancers, as well as toxicity and the response rate of cancer treatments. An analysis of 12 million full-text publications, 29 million abstracts and 521,000 grant applications for semantic relations between cancers and microbiota is shown in Figure 1. The data shows a considerable increase in the number of articles linking cancers to microbiota for five cancer types with the highest number of reports overall.

With overall cancer rates set to increase worldwide, the current interest in the microbiome and its role in precision medicine is likely to continue because it offers new hope of treatments. Evidence suggests the importance of looking for predictors of therapeutic response beyond the tumour by focusing on host factors, such as microbiota and host genomics. Importantly, microbiota is a modifiable factor, and potentially can become not just a predictive marker but also a potential target in order to improve outcomes for patients.

To further investigate the link between the microbiome and cancer, Elsevier undertook an in-depth analysis of the current landscape of melanoma research. Melanoma was selected because cases are rising – with the rate of new melanoma cases worldwide estimated to be almost 300,000 yearly – underlining the importance of further investigation to form a fuller understanding of the disease and potential treatments.

Melanoma was also chosen for further study because there is an emerging link between melanoma and the microbiome demonstrated by the literature that warrants further exploration. Recent findings show that response to immune checkpoint inhibitors, a new class of drugs effective in melanoma treatment, correlates with the composition, diversity and functional differences in patients’ microbiomes.
The connection between the microbiome and melanoma was first shown in animal models, and then further confirmed in human studies. The findings of our analysis show that in 2018, two of the three most cited research papers (based on Elsevier’s Scopus data) mentioning melanoma in the title, abstract or keywords explore the influence of the microbiome in response to melanoma patients, with over 700 citations.

Progress is also being made in clinical trials looking at the microbiome and melanoma. Since 2018, four clinical trials that aim to study and modulate gut microbiome’s impact on response to immunotherapy of melanoma have been registered at clinicaltrials.gov. Dr Marc Hurlbert, chief science officer for the Melanoma Research Alliance, commented on the findings, “As noted in the report, there has been an explosion of knowledge about melanoma with an ever-increasing list of protein targets. Also noted, the role of the microbiome in melanoma and in response to immunotherapy is of increasing interest in the field.”

Our study also found that within the small molecules and targets pipeline there is an increased focus on targeted therapeutics towards patients with specific melanoma gene mutations, echoing the industry trend towards the development of precision medicines. In total, 23 genes are linked to hereditary melanoma, of which 12 genes have 177 genetic variants linked to melanoma. The remaining 11 genes that are genetically linked currently have no known genetic variants associated with melanoma.

To further develop targeted precision therapies, further research is now required. Firstly, to map genetic variants; secondly, to determine which variant is clinically significant; thirdly, to understand the impact of variant on gene function, and whether variation activates or inhibits the gene. This is particularly important for increased understanding of specific, precision medicine and to enhance therapeutic efficacy.

For non-hereditary (sporadic) melanoma, the analysis showed that there are 752 genes genetically linked to sporadic melanomas and its subtypes, and 449 genetic variants genetically linked to sporadic melanoma and its subtypes. Out of the 449 genetic variants, 395 are from 78 genes that are genetically linked to melanoma. The remaining missing 54 variants are not currently genetically linked in the platform to any known melanoma gene; this could therefore be a potential area for further research.

Understanding whether specific genetic variants exist and/or contribute to melanoma’s severity and prevalence in populations will help the R&D industry to develop more effective and profitable therapeutics. These types of data will provide the R&D community with a greater depth of understanding and of the increased likelihood of hitting the target. Through our analysis we found an increased incidence of drugs targeting genetic mutations over the last decade, particularly targeting protein kinases and growth factor receptors.

The analysis of melanoma research is instructive for all cancer research. Having a greater understanding of the influence of the microbiome on both disease progression and therapeutic efficacy, as well as drug safety, will have a pronounced influence on the success of therapeutics. There is a complex interplay between the host-immune response and microbiome, resulting in an intricate balance of symbiosis and pathogenesis.

It is an attractive future research avenue to recognise how a patient’s microorganisms’ genome, both symbiotic and pathogenic, can dramatically affect treatment plans and outcomes. Positively influencing the microbiome in patients needs further study that could lead to exciting opportunities for patients and for drug discovery. For the therapeutic pipeline it would be beneficial to understand these host-microbiota interactions and ways to positively tip the balance towards improving treatment outcomes.

One other interesting future consideration during drug development for all cancers is the influence of the microbiome on treatment-induced adverse events, and whether clinical and post-clinical adverse events are related to a patient’s microbial composition. It adds a level of complexity as to the efficacy of therapeutics that may not readily be considered, and potentially may be something to consider during future clinical trials.

As this analysis of the melanoma research landscape shows, data science is essential in arming the R&D industry with a greater depth of information to help battle diseases and industry problems. Conducting deep research by integrating, harmonising, and analysing data across the pharma life-cycle helps to identify the gaps in our knowledge, as well as show areas with the greatest potential for future research. Data-driven decision-making will accelerate science and enable researchers to find preventative and therapeutic interventions quicker.

Moreover, in the current COVID-19 era, in-person and patient interactions are reduced and many research labs are still unable to operate at full capacity. The ability to conduct research, take samples, and study real patients is limited at present, so looking at detailed existing literature and data is a vital avenue to support R&D. It will keep R&D functions going and help them to direct efforts to the areas of greatest potential. 2021 will be a year of reduced R&D budgets globally – this type of data insight will be vital to empowering future R&D.