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

The role of tumor angiogenesis as a therapeutic target in colorectal cancer

<p><b>Introduction</b>: Angiogenesis is a complex process regulated by several pro- and anti-angiogenic factors, thus the loss of its fine equilibrium plays a key role in colorectal cancer (CRC) development and progression. Therapeutic agents targeting VEGF/VEGFR signaling, the main regulator of this process, proved to be effective across different treatment lines in metastatic CRC (mCRC) and contributed greatly to improve patients’ survival in recent years.</p> <p><b>Areas covered</b>: This review aimed to summarize the actual body of knowledge available on the VEGF pathway in CRC, including currently available anti-angiogenic drugs and treatment challenges, mechanisms of resistance, promising predictive biomarkers and future perspectives.</p> <p><b>Expert commentary</b>: Angiogenesis inhibition in subsequent lines of treatment is a valid strategy in the continuum of care of mCRC patients. In this scenario, the availability of multiple agents warrants to tailor therapy to an individualized approach. However, the validation of predictive biomarkers to aid therapeutic decisions remains an issue. Intrinsic and adaptive resistance to anti-angiogenic agents comprises distinct and intertwined processes, eventually leading to treatment failure and disease progression. The expanding knowledge on the mechanisms underlying the angiogenesis pathway, different potential treatment targets and mechanisms of tumor resistance, may lead to promising new perspectives in this field.</p

A revised nomenclature for the lemur family of protein kinases

The lemur family of protein kinases has gained much interest in recent years as they are involved in a variety of cellular processes including regulation of axonal transport and endosomal trafficking, modulation of synaptic functions, memory and learning, and they are centrally placed in several intracellular signalling pathways. Numerous studies have also implicated role of the lemur kinases in the development and progression of a wide range of cancers, cystic fibrosis, and neurodegenerative diseases. However, parallel discoveries and inaccurate prediction of their kinase activity have resulted in a confusing and misleading nomenclature of these proteins. Herein, a group of international scientists with expertise in lemur family of protein kinases set forth a novel nomenclature to rectify this problem and ultimately help the scientific community by providing consistent information about these molecules.</p

Aryl hydrocarbon receptor nuclear translocator-like (ARNTL/BMAL1) is associated with bevacizumab resistance in colorectal cancer via regulation of vascular endothelial growth factor A.

BACKGROUND: The identification of new biomarkers and the development of novel, targetable contexts of vulnerability are of urgent clinical need in drug-resistant metastatic colorectal cancer (mCRC). Aryl-Hydrocarbon-Receptor-Nuclear-Translocator-Like (ARNTL/BMAL1) is a circadian clock-regulated transcription factor promoting expression of genes involved in angiogenesis and tumour progression. We hypothesised that BMAL1 increases expression of the vascular endothelial growth factor A VEGFA gene and, thereby, confers resistance to anti-angiogenic therapy with bevacizumab (Beva), a clinically used antibody for neutralization of VEGFA. METHODS: PCR and immunohistochemistry were employed to assess BMAL1 expression in mice (C57BL/6 J FINDINGS: In murine CRCs, high BMAL1 expression correlated with poor preclinical response to Beva treatment. In CRC patients' tumours (n = 74), high BMAL1 expression was associated with clinical non-response to combination chemotherapy with Beva (*p = .0061) and reduced progression-free survival (PFS) [*p = .0223, Hazard Ratio (HR) = 1.69]. BMAL1 SNPs also correlated with shorter PFS (rs7396943, rs7938307, rs2279287) and overall survival (OS) [rs11022780, *p = .014, HR = 1.61]. Mechanistically, Nuclear-Receptor-Subfamily-1-Group-D-Member-1 (NR1D1/REVERBA) bound a - 672 bp Retinoic-Acid-Receptor-Related-Orphan-Receptor-Alpha-responsive-element (RORE) adjacent to a BMAL1 DNA-binding motif (E-box) in the VEGFA gene promoter, resulting in increased VEGFA synthesis and proliferation of human CRC cell lines. INTERPRETATION: BMAL1 was associated with Beva resistance in CRC. Inhibition of REVERBA-BMAL1 signalling may prevent resistance to anti-angiogenic therapy. FUND: This work was in part supported by the European Commission Seventh Framework Programme (Contract No. 278981 [ANGIOPREDICT]).</p

Prospective Validation of Candidate SNPs of <i>VEGF/VEGFR</i> Pathway in Metastatic Colorectal Cancer Patients Treated with First-Line FOLFIRI Plus Bevacizumab

<div><p>Purpose</p><p>The potential impact of different SNPs of <i>VEGF/VEGFR</i> pathway on the clinical outcome of mCRC patients receiving bev-containing regimens has been investigated in retrospective experiences with contrasting results. We previously reported the association of <i>VEGFA</i> rs833061 C/T variants with PFS in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab. The primary objective of this work was to prospectively validate that retrospective finding. A confirmatory analysis of other SNPs of <i>VEGF/VEGFR</i> pathway genes was included.</p><p>Experimental design</p><p>To detect a HR for PFS of 1.7 for <i>VEGFA</i> rs833061 T/T compared to C- variants in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab, setting two-sided α = 0.05 and β = 0.20, 199 events were required. <i>VEGFA</i> rs699946 A/G, rs699947 A/C, <i>VEGFR1</i> rs9582036 A/C and rs7993418 A/G, <i>VEGFR2</i> rs11133360 C/T, rs12505758 C/T and rs2305948 C/T and <i>EPAS1</i> rs4145836 A/G were also tested. Germ-line DNA was extracted from peripheral blood. SNPs were analyzed by PCR and sequencing.</p><p>Results</p><p>Four-hundred-twenty-four pts were included. At the univariate analysis, no differences according to <i>VEGFA</i> rs833061 C/T variants were observed in PFS (p = 0.38) or OS (p = 0.95). Among analyzed SNPs, only <i>VEGFR2</i> rs12505758 C- variants, compared to T/T, were associated to shorter PFS (HR: 1.36 [1.05–1.75], p = 0.015, dominant genetic model) and OS, with a trend toward significance (HR: 1.34 [0.95–1.88], p = 0.088). In the multivariate model, this association retained significance (HR: 1.405 [1.082–1.825], p = 0.012) in PFS, that was lost by applying multiple testing correction (p = 0.14).</p><p>Conclusion</p><p>This prospective experience failed to validate the hypothesized predictive impact of <i>VEGFA</i> rs833061 variants. Retrospective findings on different candidate SNPs were not confirmed. Only <i>VEGFR2</i> rs12505758 variants, whose prognostic and not predictive impact was previously reported, correlated with PFS. Given the complexity of angiogenesis, it is rather unlike that a single germ-line SNP might be a good predictor of benefit from bevacizumab.</p></div

<i>VEGFA 833061</i> C/T allelic variants and PFS.

<p><i>VEGFA 833061</i> C/T allelic variants and PFS.</p

Baseline characteristics and survival outcomes.

*<p><i>P</i> value was based on Cochran-Mantel-Haenszel test for response and log-rank test for PFS and OS.</p

Investigated SNPs: current evidences from literature.

<p>Investigated SNPs: current evidences from literature.</p

Other candidate <i>VEGFA</i>, <i>VEGFR1</i>, <i>VEGFR2</i> and <i>EPAS1</i> SNPs allelic variants and survival outcomes.

*<p><i>P</i> value was based on Cochran-Mantel-Haenszel test for response and log-rank test for PFS and OS.</p>†<p>Dominant model.</p

Baseline characteristics and RECIST response.

*<p><i>P</i> value was based on Cochran-Mantel-Haenszel test for response and log-rank test for PFS and OS.</p