bims-pimaco 2023-01-22 papers

Antioxidants (Basel). 2022 Dec 28. pii: 67. [Epub ahead of print]12(1):

Role of Phosphoinositide 3-Kinase in Regulation of NOX-Derived Reactive Oxygen Species in Cancer.

Activation of NADPH oxidases (NOX) and the ensuing formation of reactive oxygen species (ROS) is a vital aspect of antimicrobial defense but may also promote tumorigenesis. Enhanced NOX activity has been associated with aberrant activation of oncogenic cascades such as the phosphoinositide 3-kinase (PI3K) signaling pathway, which is upregulated in several malignancies. In this review, we examine the role of PI3K on the regulation of NOX-induced ROS formation in cancer.

Keywords: NOX; PI3K pathway; cancer; reactive oxygen species

DOI: https://doi.org/10.3390/antiox12010067

Stem Cell Reports. 2022 Dec 29. pii: S2213-6711(22)00605-1. [Epub ahead of print]

USP7 inactivation suppresses APC-mutant intestinal hyperproliferation and tumor development.

Laura Novellasdemunt, Anna Kucharska, Anna Baulies, Colin Hutton, Georgios Vlachogiannis, Dimitra Repana, Andrew Rowan, A Suárez-Bonnet, Francesca Ciccarelli, Nicola Valeri, Vivian S W Li.

Adenomatous polyposis coli (APC) mutation is the hallmark of colorectal cancer (CRC), resulting in constitutive WNT activation. Despite decades of research, targeting WNT signaling in cancer remains challenging due to its on-target toxicity. We have previously shown that the deubiquitinating enzyme USP7 is a tumor-specific WNT activator in APC-truncated cells by deubiquitinating and stabilizing β-catenin, but its role in gut tumorigenesis is unknown. Here, we show in vivo that deletion of Usp7 in Apc-truncated mice inhibits crypt hyperproliferation and intestinal tumor development. Loss of Usp7 prolongs the survival of the sporadic intestinal tumor model. Genetic deletion, but not pharmacological inhibition, of Usp7 in Apc+/- intestine induces colitis and enteritis. USP7 inhibitor treatment suppresses growth of patient-derived cancer organoids carrying APC truncations in vitro and in xenografts. Our findings provide direct evidence that USP7 inhibition may offer a safe and efficacious tumor-specific therapy for both sporadic and germline APC-mutated CRC.

Keywords: APC; LGR5 stem cell; USP7; Wnt signaling; colorectal cancer

DOI: https://doi.org/10.1016/j.stemcr.2022.12.013

JAMA Netw Open. 2023 Jan 03. 6(1): e2250030

Receipt of Targeted Therapy and Survival Outcomes in Patients With Metastatic Colorectal Cancer.

Siran M Koroukian, Benjamin D Booker, Long Vu, Fredrick R Schumacher, Johnie Rose, Gregory S Cooper, J Eva Selfridge, Sarah C Markt.

Importance: Professional society guidelines recommend treating patients with metastatic colorectal cancer with targeted therapies, including epithelial growth factor receptor (EGFR) inhibitors and vascular endothelial growth factor (VEGF) inhibitors, depending on the presence or absence of certain mutations. Since most studies of first-line targeted therapies have been limited by sample size, there is a need for larger studies using data from routine clinical care.
Objectives: To identify factors associated with receipt of first-line targeted therapies among patients with metastatic colorectal cancer for whom RAS or BRAF mutation data in the tumor were available and investigate whether targeted therapy is associated with survival.
Design, Setting, and Participants: This cohort study used deidentified data from an electronic health record-derived database to include patients from 800 sites of patient care across the US who were diagnosed with de novo metastatic colorectal cancer between January 1, 2013, and March 31, 2020 (n = 9134).
Main Outcomes and Measures: Receipt of first-line targeted therapy, categorized as ever having received EGFR inhibitors, VEGF inhibitors, or neither. The secondary outcome was overall survival.
Results: The study population included 9134 patients. The median age at diagnosis was 62 years (IQR, 53-71 years), 5019 (54.9%) were male, and 5692 (62.3%) were White. The median follow-up period was 15 months. Overall, 713 patients (7.8%) received EGFR inhibitors and 5081 patients (55.6%) received VEGF inhibitors as part of their first-line treatment. Among patients with RAS wild-type (RAS-WT) tumors, 625 patients (15.5%) received EGFR inhibitors and 2053 patients (50.9%) received VEGF inhibitors. In patients with RAS mutant (RAS-Mut) tumors, 50 patients (1.1%) received EGFR inhibitors and 2682 patients (59.7%) received VEGF inhibitors; among those with BRAF-mutant (BRAF-Mut) tumors, 38 patients (6.3%) received EGFR inhibitors and 346 patients (57.2%) received VEGF inhibitors. More than one-third of the patients (36.6%) received neither EGFR inhibitors nor VEGF inhibitors. Compared with patients younger than age 40 years, those aged 80 years or older had significantly lower odds to receive targeted therapies (EGFR or VEGF inhibitors in patients with RAS-WT tumors: adjusted odds ratio [aOR], 0.53; 95% CI, 0.36-0.79; and VEGF inhibitors in patients with RAS-Mut tumors: aOR, 0.62; 95% CI, 0.42-0.90). Improved survival was associated with EGFR inhibitor therapy in patients with RAS-WT tumors (adjusted hazard ratio [aHR], 0.85; 95% CI, 0.74-0.98). Unlike in clinical trials, however, no survival benefit was noted with use of VEGF inhibitors among patients with RAS-WT (aHR, 1.00; 95% CI, 0.91-1.11) or RAS-Mut (aHR, 1.01; 95% CI, 0.93-1.10) tumors.
Conclusions and Relevance: The findings of this study showed mixed results on survival benefits associated with targeted therapy. In addition, given that some of the results differed from those of randomized clinical trials, this study highlights the importance of using data originating from routine clinical care.

DOI: https://doi.org/10.1001/jamanetworkopen.2022.50030