Cancer survival has dramatically increased in the past half century, driven by a deeper understanding of cancer biology, improved surgical outcomes and increasingly efficacious multimodal chemotherapy and radiotherapy regimens. Cytotoxic drugs continue to be the mainstay of medical treatment for most patients with advanced disease, yet they have an unpredictable treatment response and considerable treatment-related morbidity and mortality. The next generation of personalised cancer therapies are now emerging, which exploit advances in molecular and phenotypic heterogeneity, tumour evolution, immunotherapy and vaccination. However, even targeted therapies, which have revolutionised outcomes in cancers such as malignant melanoma, suffer from novel problems including acquired resistance, idiosyncratic adverse effects and high costs.
A major contribution of systems biology to modern medicine has been the rediscovery of the importance of the gut microbiota to almost all aspects of human health. The major focus of 'oncomicrobiome' research to date has been on the microbiome's role in the aetiology of cancer and cancer risk. However, the gut microbiota also have a major role in defining the efficacy and toxicity of a broad range of drugs. Advances in high-throughput sequencing and other '‑omics' platforms have led to the concept of 'pharmacomicrobiomics', and the importance of the gut microbiota for chemotherapeutic drug modulation and drug discovery is now increasingly recognised.
Pancreatic ductal adenocarcinoma (PDAC) accounts for 85-95% of pancreatic cancers, which represents the fourth lethal malignancy, with less than 5% of patients reaching 5-year survival. Chemotherapy is the first‑line approach in the treatment of the advanced and metastatic disease and gemcitabine the standard of care is used as a single agent or in combination with other drugs to improve efficacy. However, gemcitabine‑based therapies provide only a modest improvement in prognosis, mainly because of both intrinsic and acquired drug resistance phenomena.
It has become evident that inflammation plays a central role in both the onset and in the progression of PDAC, not only as a risk factor but also as a consequence of cancer itself; the persistence of an inflammatory state hinders the curability of the disease.
A recent study performed by Panebianco et al used a xenograft model of PDAC to evaluate gemcitabine treatment efficacy, but more importantly the influence of chemotherapy treatment on gut microbiota and serum metabolomics.
BxPC‑3‑luc cells were implanted subcutaneously on the right flank of female Nu/Nu nude mice. When tumours reached 100mm3, mice were randomised to receive weekly intraperitoneal injections of gemcitabine 25mg/kg or saline for 3 consecutive weeks. Faecal samples were collected from both groups and the microbiota composition was analysed using NGS. Liquid chromatography/mass spectrometry was used to analyse serum metabolites.
Panebianco et al demonstrated that:
Gemcitabine treatment resulted in a 35% reduction in tumour volume and a lower mean body weight compared to the control group at the end of therapy.
Gemcitabine considerably decreased the proportion of Gram‑positive Firmicutes (from about 39 to 17%) and the Gram‑negative Bacteroidetes (from 38 to 17%) which are the two dominant phyla in the gut of tumour‑bearing control mice.
In addition, a concomitant overall increase in inflammation-associated bacteria was observed upon gemcitabine treatment.
Consistently, an activation of the NF‑kB canonical pathway was found in cancer tissues from gemcitabine-treated mice.
Serum metabolomics revealed a significant decrease of the purine compounds inosine and xanthine and a decreasing trend for their metabolically-related molecule hypoxanthine in the gemcitabine group as compared to the control group.
This study showed that gemcitabine treatment only had limited effect, but caused substantial modifications of the intestinal microbiota in mice bearing PDAC, many of which may be detrimental for its own efficacy. The normal phyla was replaced by bacteria known to be related to intestinal inflammation, which increases the intestinal permeability thus allowing bacteria to enter the circulation and move to distant organs. In addition, the activation of the NF‑kB canonical pathway and the decreased serum levels of inosine were likely correlated to the observed dysbiosis.
Taken together, these results have yielded new insights of the impact of gemcitabine therapy on the microbiota profile in PDAC. More research focusing on understanding the side effects of chemotherapy may help to set up new strategies to improve the efficacy of therapy.