Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma.

In pancreatic ductal adenocarcinoma (PDAC), glutamine is a critical nutrient that drives a wide array of metabolic and biosynthetic processes that support tumor growth. Here, we elucidate how 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist that broadly inhibits glutamine metabolism, blocks PDAC tumor growth and metastasis. We find that DON significantly reduces asparagine production by inhibiting asparagine synthetase (ASNS), and that the effects of DON are rescued by asparagine. As a metabolic adaptation, PDAC cells upregulate ASNS expression in response to DON, and we show that ASNS levels are inversely correlated with DON efficacy. We also show that L-asparaginase (ASNase) synergizes with DON to affect the viability of PDAC cells, and that DON and ASNase combination therapy has a significant impact on metastasis. These results shed light on the mechanisms that drive the effects of glutamine mimicry and point to the utility of cotargeting adaptive responses to control PDAC progression.

VAX014, an Oncolytic Therapy, Reduces Adenomas and Modifies Colon Microenvironment in Mouse Model of CRC.

Colorectal cancer (CRC) remains the third most common form of cancer and, despite its reduced mortality, results in over 50,000 deaths annually, highlighting the need for novel therapeutic approaches. VAX014 is a novel clinical-stage, oncolytic bacterial minicell-based therapy shown to elicit protective antitumor immune responses in cancer, but it has not been fully evaluated in CRC. Here, VAX014 was demonstrated to induce oncolysis in CRC cell lines in vitro and was evaluated in vivo, both as a prophylactic (before spontaneous development of adenomatous polyps) and as a neoadjuvant treatment using the Fabp-CreXApcfl468 preclinical animal model of colon cancer. As a prophylactic, VAX014 significantly reduced the size and number of adenomas without inducing long term changes in the gene expression of inflammatory, T helper 1 antitumor, and immunosuppression markers. In the presence of adenomas, a neoadjuvant VAX014 treatment reduced the number of tumors, induced the gene expression of antitumor TH1 immune markers in adenomas, and promoted the expansion of the probiotic bacterium Akkermansia muciniphila. The neoadjuvant VAX014 treatment was associated with decreased Ki67 proliferation in vivo, suggesting that VAX014 inhibits adenoma development through both oncolytic and immunotherapeutic effects. Combined, these data support the potential of VAX014 treatment in CRC and "at risk" polyp-bearing or early adenocarcinoma populations.

The Viral Janus: Viruses as Aetiological Agents and Treatment Options in Colorectal Cancer.

In recent years, our understanding of the importance of microorganisms on and within our bodies has been revolutionized by the ability to characterize entire microbial communities. No more so is this true than in cases of disease. Community studies have revealed strong associations between microbial populations and disease states where such concomitance was previously absent from aetiology: including in cancers. The study of viruses, in particular, has benefited from the development of new community profiling techniques and we are now realising that their prominence within our physiology is nearly as broad as the diversity of the organisms themselves. Here, we examine the relationship between viruses and colorectal cancer (CRC), the leading cause of gastrointestinal cancer-related death worldwide. In CRC, viruses have been suggested to be involved in oncogenesis both directly, through infection of our cells, and indirectly, through modulating the composition of bacterial communities. Interestingly though, these characteristics have also led to their examination from another perspective-as options for treatment. Advances in our understanding of molecular and viral biology have caused many to look at viruses as potential modular biotherapeutics, where deleterious characteristics can be tamed and desirable characteristics exploited. In this article, we will explore both of these perspectives, covering how viral infections and involvement in microbiome dynamics may contribute to CRC, and examine ways in which viruses themselves could be harnessed to treat the very condition their contemporaries may have had a hand in creating.