CCR5 and CCL5 in metastatic colorectal cancer

The CCR/L5 axis is known for its role in immune regulation in a variety of settings and has been shown to have dichotomous functions in cancer, influencing both tumor progression and immune responses. Battaglin et al investigated its role using genomic and transcriptomic data from several datasets of patients with advanced colorectal cancer (CRC), including patients treated on CALGB/SWOG 80405, a trial of chemotherapy plus cetuximab versus bevacizumab, as well as a larger population of patients whose CRCs underwent commercially available Caris NGS and CODEai assays. These authors showed that CCR/L5 expression was both prognostic and predictive. They reported that low expression of the CCR/L5 axis was correlated with improved survival broadly, with particular benefit in patients treated with chemotherapy plus cetuximab. They demonstrated that high expression of CCR/L5 was associated with infiltration by negatively prognostic Tregs, M1 and M2 macrophages, myeloid-derived suppressor cells, and cancer-associated fibroblasts. They also showed that increased expression was correlated a wide variety of immune suppressive proteins, including PD-1, PD-L1, PD-L2, CTLA4, CD80, CD86, TIM3, IDO1, LAG3, and IFN-γ. This suggests mechanisms by which CRC resists anti-cancer immune responses. This study enhances our understanding of the role of the CCR/L5 axis in advanced CRC.</p

Genes and Race in Colon Cancer

 Colon cancer is the second leading cause of cancer deaths in the United  States and on track to be the leading cause of death in adults younger  than 50 years by 2030.1  First-line therapy for metastatic colorectal cancer generally includes a  fluoropyrimidine backbone with the addition of oxaliplatin, irinotecan,  or both and a monoclonal antibody directed against the vascular  endothelial growth factor receptor or the epidermal growth factor  receptor (EGFR).2  The Cancer and Leukemia Group B (CALGB)/Southwest Oncology Group (SWOG)  80405 trial investigated first-line palliative infusional fluorouracil,  leucovorin, and oxaliplatin or fluorouracil, leucovorin, and irinotecan  with either bevacizumab or cetuximab and serves as a seminal study  supporting this approach. Key findings of CALGB/SWOG 80405 were that  there was no difference in overall survival (OS) between the regimens in  KRAS wild-type tumors.3  In addition, tumors arising from the left colon had better outcomes  than those arising from the right, with a median OS of 36.0 versus 16.7  months (hazard ratio, 1.87 [95% CI, 1.48 to 2.32]; P < .0001)...</p

Baricitinib: the first immunomodulatory treatment to reduce COVID-19 mortality in a placebo-controlled trial

Antibacterial, antifungal, antiviral, and antiparasitic treatments developed in the past century have improved survival outcomes, even in high-mortality conditions such as sepsis, a condition that is mostly caused by bacteria but can also be due to other infections. In the 21st century, of all therapies that have improved the outcomes of patients with sepsis, the appropriate and early administration of antibiotics has been shown to be the most effective therapy to save lives.1 However, despite highly effective antibiotics that can kill microorganisms causing sepsis, and cultures showing eradication of these organisms, overall mortality from the condition remains high. In part, this high mortality might be explained by dysregulated immune responses arising from redundant pathways in the human immune system, which have developed—along with the array of defensive mechanisms involving the innate and adaptive responses, inflammation, and coagulation—as a result of the selective pressure of thousands of years of exposure to infections, zoonoses, and resulting epidemics and pandemics. This dysregulated immune response can be as harmful as, or more harmful than, the pathogens themselves.2 Accordingly, two original studies showed significant reduction in mortality due to sepsis among solid organ transplant recipients compared with patients without transplants.3, 4 This finding suggests that immunosuppressive drugs, required lifelong to avoid transplant graft rejection, might have been protective by decreasing dysfunctional responses to sepsis. These lessons learned from bacterial sepsis are highly relevant in the context of COVID-19...</p

Polo-like Kinase 1 Inhibition in <i>KRAS</i>-Mutated Metastatic Colorectal Cancer

Summary: Inhibition of Polo-like kinase 1 (Plk1) is a promising new target and therapeutic strategy in metastatic colorectal cancer, especially those with KRAS mutations. New data support further development of onvansertib, and highlights the role of circulating tumor DNA in phase I clinical trials. See related article by Ahn et al., p. 2039</p

The Emergence of Baricitinib: A Story of Tortoises Versus Hares

Baricitinib is a once daily orally administered JAK1/2 inhibitor, which inhibits the signaling of many cytokines and has been approved for the treatment of moderate to severe rheumatoid arthritis (RA) based on long-term randomized dosing against both placebo and standard of care [1], notably tumor necrosis factor (TNF)-alpha blockade. Its use for the treatment of coronavirus disease 2019 (COVID-19) was originally suggested after a search of the extensive BenevolentAI knowledge graph for approved drugs that could be used in this pandemic [2]. An advantage of approved drugs is that they have a known safety profile and can therefore be rapidly approved in fast moving pandemics. The artificial intelligence algorithms predicted that baricitinib would inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of cells [2], (an effect later confirmed in human liver spheroids) [3], combined with its better-known anti-inflammatory properties. The doses required were predicted to be the same as used for the treatment of RA. At these doses, interleukin 6 (IL-6) levels were reduced both in COVID19 patients as well as dose dependently in RA patients in a previous phase 2b randomized RA trial, the first time this was shown in humans [4]. What was more intriguing was its inhibition of members of the numb associated kinase family, thought in turn to translate to reduced AP-2 mediated viral propagation early in the infectious cycle, suggesting antiviral activity; this was shown in liver spheroid models, which express detectable albeit low levels of the ACE2 receptor...</p

COVID-19: combining antiviral and anti-inflammatory treatments

Both coronavirus disease 2019 (COVID-19) and severe acute respiratory syndrome (SARS) are characterised by an overexuberant inflammatory response and, for SARS, viral load is not correlated with the worsening of symptoms. In our previous Correspondence to The Lancet, we described how BenevolentAI's proprietary artificial intelligence (AI)-derived knowledge graph, queried by a suite of algorithms, enabled identification of a target and a potential therapeutic against SARS coronavirus 2 (SARS-CoV-2; the causative organism in COVID-19). We identified a group of approved drugs that could inhibit clathrin-mediated endocytosis and thereby inhibit viral infection of cells (appendix). The drug targets are members of the numb-associated kinase (NAK) family—including AAK1 and GAK—the inhibition of which has been shown to reduce viral infection in vitro. Baricitinib was identified as a NAK inhibitor, with a particularly high affinity for AAK1, a pivotal regulator of clathrin-mediated endocytosis. We suggested that this drug could be of use in countering SARS-CoV-2 infections, subject to appropriate clinical testing. To take this work further in a short timescale, a necessity when dealing with a new human pathogen, we re-examined the affinity and selectivity of all the approved drugs in our knowledge graph to identify those with both antiviral and anti-inflammatory properties. Such drugs are predicted to be of particular importance in the treatment of severe cases of COVID-19, when the host inflammatory response becomes a major cause of lung damage and subsequent mortality. Comparison of the properties of the three best candidates are shown in the table. Baricitinib, fedratinib, and ruxolitinib are potent and selective JAK inhibitors approved for indications such as rheumatoid arthritis and myelofibrosis. All three are powerful anti-inflammatories that, as JAK–STAT signalling inhibitors, are likely to be effective against the consequences of the elevated levels of cytokines (including interferon-γ) typically observed in people with COVID-19·2 Although the three candidates have similar JAK inhibitor potencies, a high affinity for AAK1 suggests baricitinib is the best of the group, especially given its once-daily oral dosing and acceptable side-effect profile.The most significant side-effect seen over 4214 patient-years in the clinical trial programmes used for European Medicines Agency registration was a small increase in upper respiratory tract infections (similar to that observed with methotrexate), but the incidence of serious infections (eg, herpes zoster) over 52 weeks' dosing was small (3·2 per 100 patient-years), and similar to placebo.7 Use of this agent in patients with COVID-19 over 7–14 days, for example, suggests side-effects would be trivial.</p

Absolute numbers of previously described and putative drivers identified in this study in different tumor types.

<p>Inset: color coding reflecting tumor types. Abbreviations: TNBC (Triple Negative Breast Cancer), HER2+BC (Her2-enriched Breast Cancers), ER+BC (ER-positive Breast Cancer), CRC (Colorectal Cancer), LUAD (Lung Adenocarcinoma), LUSC (Lung Squamous Cell Carcinoma), SCC (Squamous Cell Carcinoma), SRC (Soft Tissue Sarcoma), NET (Neuroendocrine Tumor), TC (Thymic Carcinoma), GC (Gastric Cancer), SIGRCA/KRUK (Signet Ring Adenocarcinoma/Krukenberg Cell Tumor), CUPO (Carcinoma of Unknown Primary Origin).</p

Previously described and putative drivers identified in this study grouped by functional classes or biological pathways.

<p>Pathway or functional class assignment was based on Gene Ontology supplemented by individual PathCards searches (<a href="http://pathcards.genecards.org/" target="_blank">http://pathcards.genecards.org/</a>) for each gene. Inset: color coding reflecting tumor types. Abbreviations: TNBC (Triple Negative Breast Cancer), HER2+BC (Her2-enriched Breast Cancers), ER+BC (ER-positive Breast Cancer), CRC (Colorectal Cancer), LUAD (Lung Adenocarcinoma), LUSC (Lung Squamous Cell Carcinoma), SCC (Squamous Cell Carcinoma), SRC (Soft Tissue Sarcoma), NET (Neuroendocrine Tumor), TC (Thymic Carcinoma), GC (Gastric Cancer), SIGRCA/KRUK (Signet Ring Adenocarcinoma/Krukenberg Cell Tumor), CUPO (Carcinoma of Unknown Primary Origin).</p

Left Panel: variants obtained from exome sequencing of tumor samples from Colorectal Cancer (CRC) patients.

<p>Right Panel: Variants identified as potential drivers. Color codes are as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0194790#pone.0194790.g001" target="_blank">Fig 1</a>.</p

Novel putative drivers revealed by targeted exome sequencing of advanced solid tumors - Fig 2

<p><b>A</b>) Left Panel: variants obtained from exome sequencing of tumor samples from Her2-enriched Breast Cancer (HER2+ BRC) patients. Right Panel: Variants identified as potential drivers. <b>B)</b> Left Panel: variants obtained from exome sequencing of tumor samples from ER positive Breast Cancer (ER+ BRC) patients. Right Panel: Variants identified as potential drivers. Color codes are as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0194790#pone.0194790.g001" target="_blank">Fig 1</a>.</p