Emerging drug targets for colon cancer: A preclinical assessment

Crutcher, Madison; Baybutt, Trevor R.; Kopenhaver, Jessica; Snook, Adam E.

doi:10.1080/14728222.2022.2039119

Cited by 6 publications

(3 citation statements)

References 80 publications

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“…Historically, RAS was considered “undruggable” due to its picomolar affinity for GTP/GDP, the absence of identified allosteric regulatory sites, and the necessity of wild type RAS in normal biologic functions. However, small molecules that specifically inhibit the G12C variant have been identified, making RAS a potential therapeutic target ( 37 ).…”

Section: Mapk Pathway (Ras-raf-mek-erk)mentioning

confidence: 99%

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Biomarkers in the development of individualized treatment regimens for colorectal cancer

Crutcher

2022

Front. Med.

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IntroductionColorectal cancer (CRC) is the third most common and second most deadly malignancy in the world with an estimated 1. 9 million cases and 0.9 million deaths in 2020. The 5-year overall survival for stage I disease is 92% compared to a dismal 11% in stage IV disease. At initial presentation, up to 35% of patients have metastatic colorectal cancer (mCRC), and 20–50% of stage II and III patients eventually progress to mCRC. These statistics imply both that there is a proportion of early stage patients who are not receiving adequate treatment and that we are not adequately treating mCRC patients.BodyTargeted therapies directed at CRC biomarkers are now commonly used in select mCRC patients. In addition to acting as direct targets, these biomarkers also could help stratify which patients receive adjuvant therapies and what types. This review discusses the role of RAS, microsatellite instability, HER2, consensus molecular subtypes and ctDNA/CTC in targeted therapy and adjuvant chemotherapy.DiscussionGiven the relatively high recurrence rate in early stage CRC patients as well as the continued poor survival in mCRC patients, additional work needs to be done beyond surgical management to limit recurrence and improve survival. Biomarkers offer both a potential target and a predictive method of stratifying patients to determine those who could benefit from adjuvant treatment.

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Section: Mapk Pathway (Ras-raf-mek-erk)mentioning

confidence: 99%

“…Created with BioRender.com . Adapted from Crutcher et al ( 37 ) Overview of predictive and prognostic biomarkers and their importance in developing a clinical pharmacology treatment plan in colorectal cancer patients, Expert Review of Clinical Pharmacology.…”

Section: Her2mentioning

confidence: 99%

Biomarkers in the development of individualized treatment regimens for colorectal cancer

Crutcher

2022

Front. Med.

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“…Colon cancer is a common form of cancer with a multifactorial etiology affected by both genetic and environmental factors ( 1 ). While comprehensive surgical treatment is emphasized for colon cancer, treatment options for patients with advanced stages are very limited ( 2 ) and outcomes remain poor ( 3 ). The prognosis of colon cancer is poor, with low postoperative survival and high recurrence rates ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

Comprehensive analysis of the correlation between GSTM1 and tumor immunity in colon cancer

Luo¹,

Tang²,

Ling³

et al. 2022

J Gastrointest Oncol

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Background: Glutathione S-transferase mu 1 (GSTM1) is one of the major glutathione conjugation enzymes. Its expression and activity have been suggested to correlate with the occurrence of colon cancer; however, the role of GSTM1 in tumor immunity remains unclear.Methods: Relevant data downloaded from The Cancer Genome Atlas (TGGA), Clinical Proteomic Tumor Analysis Consortium (CPTAC), and Human Protein Atlas (HPA) was used to perform a multi-dimensional expression analysis of GSTM1 in colon adenocarcinoma (COAD). The correlation between GSTM1 and tumor immunity was analyzed with multiple online tools. Then protein-protein interaction (PPI) network and functional enrichment analyses of GSTM1-associated immunomodulators were performed. Further, we developed the Cox regression model based on the GSTM1-related immunomodulators. Finally, a GSTM1based clinical nomogram and a calibration curve was established to predict the probability and accuracy of long-term survival.Result: GSTM1 was significantly downregulated in COAD versus normal tissues. Infiltration levels of B cells, CD8 + T cells, and dendritic cells were closely correlated to GSTM1 gene copy number deletion, and GSTM1 expression levels in COAD positively correlated with dendritic cell, B cell, neutrophil, and macrophage infiltration. Functional enrichment analysis indicated 36 GSTM1-related immunomodulators are involved in immune-related pathways of regulating T cell activation and lymphocytic activation. A 2-gene prognostic risk signature based on the 36 GSTM1-related immunomodulators was built using the Cox regression model, and the risk signature in combination with stage had an area under the curve (AUC) value of 0.747 by the receiver operating characteristic method. patients with higher risk scores-calculated based on 2 gene prognostic risk characteristics and further identified as an independent prognostic factorwere associated with worse survival using the Kaplan-Meier analysis. Together, the clinical nomogram and calibration curve based on GSTM1 suggested a good prediction accuracy for long-term survival probability.Conclusions: Our study provided evidence supporting the significant role of GSTM1 in COAD immunity and suggests GSTM1 as a potential novel target for COAD immunotherapy.

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