Journal articles on the topic 'Novel CRC therapies'
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1
Krauss, John, and Christine Veenstra. "Emerging Systemic Therapies for Colorectal Cancer." Clinics in Colon and Rectal Surgery 31, no. 03 (April 1, 2018): 179–91. http://dx.doi.org/10.1055/s-0037-1602238.
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AbstractDespite advances over the past 20 years in colorectal cancer (CRC) screening, diagnosis, and treatment, survival outcomes remain suboptimal. Five-year survival for patients with locally advanced CRC is 69%; 5-year survival drops to 12% for patients with metastatic disease. Novel, effective systemic therapies are needed to improve long-term outcomes. In this review, we describe currently available systemic therapies for the treatment of locally advanced and metastatic CRC and discuss emerging therapies, including encouraging advances in identifying novel targeted agents and exciting responses to immunotherapeutic agents.
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Torres Adorno, Angie M., Julie Fong, Jeff Grein, Wendy Blumenschein, Danye Cheng, Katherine Porth, Peng Yang, Jennifer Yearley, Amy Beebe, and Barbara Joyce-Shaikh. "Development of a Humanized 3D Tumor Spheroid Models and Discovery of Effective Immunotherapy Strategies Against Resistant Microsatellite Stable Colorectal Cancers." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 241.9. http://dx.doi.org/10.4049/jimmunol.204.supp.241.9.
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Abstract Despite the current success of immunotherapies, only microsatellite instable (MSI) Colorectal Cancer (CRC) typically respond to T cell-driven immunotherapies while microsatellite stable (MSS) CRC displays poor response. Our goal is to identify resistance mechanisms in MSS-CRC to uncover novel therapeutic targets. Current syngeneic CRC models are largely immunogenic and lack complex structure. Therefore, we developed novel 3D humanized CRC mouse models which form complex human-like tumors which are typically absent in syngeneic systems. We investigated molecular profiles of human MSI-versus MSS-CRC tumor xenografts following Keytruda immunotherapy and identified an immunosuppressive profile in MSS models that was not observed in MSI-CRC. We evaluated the therapeutic potential of blocking inflammation in combination with other immuno-modulatory therapies in both cold and hot CRC models and identified a significant regression of tumor burden in MSS-CRC mice. Our studies provide a novel CRC in vivo model and a unique opportunity to better define how immune cells interact in human MSS- and MSI-CRC microenvironments, to enable clinical therapeutic implementation.
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Bitar, Lynn, Joseph Zouein, Fady Gh Haddad, Roland Eid, and Hampig R. Kourie. "HER2 in metastatic colorectal cancer: a new to target to remember." Biomarkers in Medicine 15, no. 2 (February 2021): 135–38. http://dx.doi.org/10.2217/bmm-2020-0491.
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Metastatic colorectal cancer is the second most common cause of cancer death. Standard chemotherapy in combination with targeted therapies represent the backbone for the treatment of advanced disease. However, options are limited for patients progressing on these regimens. Genetic testing can offer patients the opportunity to benefit from novel therapies, namely immune checkpoint inhibitors in microsatellite instability-positive tumors. HER2 overexpression has recently emerged as a potentially targetable tumor marker in colorectal cancer (CRC). Despite the absence of approvals for anti-HER2 therapies in CRC, many agents such as trastuzumab and pertuzumab were tested and demonstrated significant antitumor activity, even in heavily pretreated patients. Early trials are also evaluating lapatinib, T-DM1, tucatinib and other anti-HER2 agents in patients with metastatic CRC, with promising results.
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Perillo, Federica, Chiara Amoroso, Francesco Strati, Maria Rita Giuffrè, Angélica Díaz-Basabe, Georgia Lattanzi, and Federica Facciotti. "Gut Microbiota Manipulation as a Tool for Colorectal Cancer Management: Recent Advances in Its Use for Therapeutic Purposes." International Journal of Molecular Sciences 21, no. 15 (July 29, 2020): 5389. http://dx.doi.org/10.3390/ijms21155389.
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Colorectal cancer (CRC) is a multifaceted disease influenced by both environmental and genetic factors. A large body of literature has demonstrated the role of gut microbes in promoting inflammatory responses, creating a suitable microenvironment for the development of skewed interactions between the host and the gut microbiota and cancer initiation. Even if surgery is the primary therapeutic strategy, patients with advanced disease or cancer recurrence after surgery remain difficult to cure. Therefore, the gut microbiota has been proposed as a novel therapeutic target in light of recent promising data in which it seems to modulate the response to cancer immunotherapy. The use of microbe-targeted therapies, including antibiotics, prebiotics, live biotherapeutics, and fecal microbiota transplantation, is therefore considered to support current therapies in CRC management. In this review, we will discuss the importance of host−microbe interactions in CRC and how promoting homeostatic immune responses through microbe-targeted therapies may be useful in preventing/treating CRC development.
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Medin, Caroline, Michael K. Turgeon, Jessica M. Keilson, Bhakti Dwivedi, Cameron Herting, Shishir K. Maithel, and Gregory B. Lesinski. "High-risk gene expression in colorectal liver metastasis: Potential for novel therapies." Journal of Clinical Oncology 40, no. 4_suppl (February 1, 2022): 147. http://dx.doi.org/10.1200/jco.2022.40.4_suppl.147.
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147 Background: Over half of patients with colorectal cancer (CRC) develop liver metastases. While immunotherapy is an emerging treatment of solid tumors, its use among CRC patients is limited. Furthermore, gene expression patterns of liver-specific CRC metastases remain unclear. The purpose of this study was to identify a high-risk gene expression profile for patients with colorectal liver metastasis (CRLM) to better inform prognosis and development of novel targeted therapies. Methods: Fifty-three FFPE CRLM samples from patients who underwent complete metastatectomy from 2009-2017 were examined. Expression profiling of extracted RNA was performed using NanoString Immuno-Oncology (IO360) 750-gene panel. Statistical analyses using cutoffs of absolute log 2-fold change≥1.5 and p-value≤0.05 were performed. Patients were analyzed by extremes of outcomes: survival time in the lowest quartile compared to those still alive at last follow-up. Results: Eight differentially expressed genes were associated with poor survival. Overexpressed genes included IL6R, CXCL2, C7, MGMT, PCK2, CSF1 and LILRB4 (Table). PLA2G2A was under-expressed. Conclusions: This study demonstrates differential gene expression associated with poor survival among patients with CRLM. Specific genes of interest include IL6R, MGMT, CSF1 and LILRB4. IL6R is a known effector in tumor proliferation via IL-6 signaling from tumor-associated macrophages, myeloid-derived suppressor cells (MDSCs) and T-cells. MGMT repairs alkylating DNA damage and is implicated in carcinogenesis and response to chemotherapy. CSF1 promotes macrophage differentiation to M2 phenotype, suppressing inflammation and anti-tumor defense mechanisms. LILRB4 activation via MDSCs leads to T-cell inhibition. These overall suggest a myeloid-dominant tumor immune microenvironment and represent important potential therapeutic targets. Next steps include performing immunohistochemistry to validate findings at the protein level and investigate the tumor intrinsic role using human cell lines.[Table: see text]
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De Pauw, Ines, Filip Lardon, Jolien Van den Bossche, Hasan Baysal, Patrick Pauwels, Marc Peeters, Jan Baptist Vermorken, and An Wouters. "Overcoming Intrinsic and Acquired Cetuximab Resistance in RAS Wild-Type Colorectal Cancer: An In Vitro Study on the Expression of HER Receptors and the Potential of Afatinib." Cancers 11, no. 1 (January 15, 2019): 98. http://dx.doi.org/10.3390/cancers11010098.
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The epidermal growth factor receptor (EGFR) is an important therapeutic target in colorectal cancer (CRC). After the initial promising results of EGFR-targeted therapies such as cetuximab, therapeutic resistance poses a challenging problem and limits the success of effective anti-EGFR cancer therapies in the clinic. In order to overcome resistance to these EGFR-targeted therapies, new treatment options are necessary. The objective of this study was to investigate the expression of human epidermal growth factor (HER) receptors and the efficacy of afatinib, a second-generation irreversible EGFR-tyrosine kinase inhibitor, in RAS wild-type CRC cell lines with different cetuximab sensitivities. CRC cell lines with different sensitivities to cetuximab showed rather low EGFR expression but high HER2 and HER3 expression. These results were in line with the The Cancer Genome Atlas (TCGA) data from CRC patients, where higher mRNA levels of HER2 and HER3 were also detected compared to EGFR. Therefore, the targets of afatinib were indeed expressed on the CRC cell lines used in this study and in CRC patients. Furthermore, cetuximab resistance had no significant influence on the expression levels of HER receptors in CRC cell lines (p ≥ 0.652). This study also demonstrated that afatinib was able to induce a concentration-dependent cytotoxic effect in RAS wild-type CRC cell lines with different cetuximab sensitivities. Neither cetuximab resistance (p = 0.233) nor hypoxia (p = 0.157) significantly influenced afatinib’s cytotoxic effect. In conclusion, our preclinical data support the hypothesis that treatment with afatinib might be a promising novel therapeutic strategy for CRC patients experiencing intrinsic and acquired cetuximab resistance.
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Vekic, Jelena, Aleksandra Zeljkovic, Aleksandra Stefanovic, Rosaria Vincenza Giglio, Marcello Ciaccio, and Manfredi Rizzo. "Diabetes and Colorectal Cancer Risk: A New Look at Molecular Mechanisms and Potential Role of Novel Antidiabetic Agents." International Journal of Molecular Sciences 22, no. 22 (November 17, 2021): 12409. http://dx.doi.org/10.3390/ijms222212409.
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Epidemiological data have demonstrated a significant association between the presence of type 2 diabetes mellitus (T2DM) and the development of colorectal cancer (CRC). Chronic hyperglycemia, insulin resistance, oxidative stress, and inflammation, the processes inherent to T2DM, also play active roles in the onset and progression of CRC. Recently, small dense low-density lipoprotein (LDL) particles, a typical characteristic of diabetic dyslipidemia, emerged as another possible underlying link between T2DM and CRC. Growing evidence suggests that antidiabetic medications may have beneficial effects in CRC prevention. According to findings from a limited number of preclinical and clinical studies, glucagon-like peptide-1 receptor agonists (GLP-1RAs) could be a promising strategy in reducing the incidence of CRC in patients with diabetes. However, available findings are inconclusive, and further studies are required. In this review, novel evidence on molecular mechanisms linking T2DM with CRC development, progression, and survival will be discussed. In addition, the potential role of GLP-1RAs therapies in CRC prevention will also be evaluated.
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Hu, Bangli, Yixin Yin, Siqi Li, and Xianwen Guo. "Insights on Ferroptosis and Colorectal Cancer: Progress and Updates." Molecules 28, no. 1 (December 28, 2022): 243. http://dx.doi.org/10.3390/molecules28010243.
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Patients with advanced-stage or treatment-resistant colorectal cancer (CRC) benefit less from traditional therapies; hence, new therapeutic strategies may help improve the treatment response and prognosis of these patients. Ferroptosis is an iron-dependent type of regulated cell death characterized by the accumulation of lipid reactive oxygen species (ROS), distinct from other types of regulated cell death. CRC cells, especially those with drug-resistant properties, are characterized by high iron levels and ROS. This indicates that the induction of ferroptosis in these cells may become a new therapeutic approach for CRC, particularly for eradicating CRC resistant to traditional therapies. Recent studies have demonstrated the mechanisms and pathways that trigger or inhibit ferroptosis in CRC, and many regulatory molecules and pathways have been identified. Here, we review the current research progress on the mechanism of ferroptosis, new molecules that mediate ferroptosis, including coding and non-coding RNA; novel inducers and inhibitors of ferroptosis, which are mainly small-molecule compounds; and newly designed nanoparticles that increase the sensitivity of cells to ferroptosis. Finally, the gene signatures and clusters that have predictive value on CRC are summarized.
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Naydenov, Nayden, Susana Lechuga, Emina Huang, and Andrei Ivanov. "Myosin Motors: Novel Regulators and Therapeutic Targets in Colorectal Cancer." Cancers 13, no. 4 (February 11, 2021): 741. http://dx.doi.org/10.3390/cancers13040741.
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Colorectal cancer (CRC) remains the third most common cause of cancer and the second most common cause of cancer deaths worldwide. Clinicians are largely faced with advanced and metastatic disease for which few interventions are available. One poorly understood aspect of CRC involves altered organization of the actin cytoskeleton, especially at the metastatic stage of the disease. Myosin motors are crucial regulators of actin cytoskeletal architecture and remodeling. They act as mechanosensors of the tumor environments and control key cellular processes linked to oncogenesis, including cell division, extracellular matrix adhesion and tissue invasion. Different myosins play either oncogenic or tumor suppressor roles in breast, lung and prostate cancer; however, little is known about their functions in CRC. This review focuses on the functional roles of myosins in colon cancer development. We discuss the most studied class of myosins, class II (conventional) myosins, as well as several classes (I, V, VI, X and XVIII) of unconventional myosins that have been linked to CRC development. Altered expression and mutations of these motors in clinical tumor samples and their roles in CRC growth and metastasis are described. We also evaluate the potential of using small molecular modulators of myosin activity to develop novel anticancer therapies.
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Kang, Bo, Xiaobing Zhang, Weibing Wang, Shiqi She, Wenjie Chen, Cheng Chen, Yisha Wang, Xiaoyun Pan, Ouyuan Xu, and Yingjie Wang. "The Novel IGF-1R Inhibitor PB-020 Acts Synergistically with Anti-PD-1 and Mebendazole against Colorectal Cancer." Cancers 14, no. 23 (November 23, 2022): 5747. http://dx.doi.org/10.3390/cancers14235747.
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CRC is one of the leading causes of cancer mortality worldwide. Chemotherapy is widely used for the treatment of CRC, but its efficacy remains unsatisfactory, mainly due to drug resistance. Therefore, it is urgent to develop new strategies to overcome drug resistance. Combination therapy that aims to achieve additive or synergistic therapeutic effects is an effective approach to tackle the development of drug resistance. Given its established roles in tumor development, progression and metastasis, IGF-1R is a promising drug target for combination therapy against CRC. In this study, we revealed that the novel IGF-1R inhibitor PB-020 can act synergistically with mebendazole (MBZ) to reduce the viability of CRC cells and block xenograft CRC progression. Moreover, the PB-020/anti-PD-1 combination synergistically blocked CRC propagation in the MC38 murine colon carcinoma model. Both combination therapies potently suppressed the PI3K/AKT signaling pathway genes in CRC that may be associated with the development of drug resistance. Our findings establish a preclinical proof-of-concept for combating CRC using combined multi-target treatment with PB-020 and clinical anticancer drugs, which may provide useful clues for clinical trials to evaluate the efficacy and safety of these drug combinations in CRC patients.
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Oh, Hyung-Hoon, and Young-Eun Joo. "Novel biomarkers for the diagnosis and prognosis of colorectal cancer." Intestinal Research 18, no. 2 (April 30, 2020): 168–83. http://dx.doi.org/10.5217/ir.2019.00080.
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Colorectal cancer (CRC) is among the most common malignancies and remains a major cause of cancer-related death worldwide. Despite recent advances in surgical and multimodal therapies, the overall survival of advanced CRC patients remains very low. Cancer progression, including invasion and metastasis, is a major cause of death among CRC patients. The underlying mechanisms of action resulting in cancer progression are beginning to unravel. The reported molecular and biochemical mechanisms that might contribute to the phenotypic changes in favor of carcinogenesis include apoptosis inhibition, enhanced tumor cell proliferation, increased invasiveness, cell adhesion perturbations, angiogenesis promotion, and immune surveillance inhibition. These events may contribute to the development and progression of cancer. A biomarker is a molecule that can be detected in tissue, blood, or stool samples to allow the identification of pathological conditions such as cancer. Thus, it would be beneficial to identify reliable and practical molecular biomarkers that aid in the diagnostic and therapeutic processes of CRC. Recent research has targeted the development of biomarkers that aid in the early diagnosis and prognostic stratification of CRC. Despite that, the identification of diagnostic, prognostic, and/or predictive biomarkers remains challenging, and previously identified biomarkers might be insufficient to be clinically applicable or offer high patient acceptability. Here, we discuss recent advances in the development of molecular biomarkers for their potential usefulness in early and less-invasive diagnosis, treatment, and follow-up of CRC.
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Huang, Jiuhong, Juanli Wang, Guiting Song, Chunsheng Hu, Zhigang Xu, Zhongzhu Chen, Chuan Xu, and Donglin Yang. "Antiproliferative Evaluation of Novel 4-Imidazolidinone Derivatives as Anticancer Agent Which Triggers ROS-Dependent Apoptosis in Colorectal Cancer Cell." Molecules 27, no. 24 (December 13, 2022): 8844. http://dx.doi.org/10.3390/molecules27248844.
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Colorectal cancer (CRC) is one of the most common causes of cancer-related death worldwide, and more therapies are needed to treat CRC. To discover novel CRC chemotherapeutic molecules, we used a series of previously synthesized novel imidazolidin-4-one derivatives to study their anticancer role in several cancer cell lines. Among these compounds, compound 9r exhibited the best anticancer activity in CRC cell lines HCT116 and SW620. We further investigated the anticancer molecular mechanism of compound 9r. We found that compound 9r induced mitochondrial pathway apoptosis in HCT116 and SW620 cells by inducing reactive oxygen species (ROS) production. Moreover, the elevated ROS generation activated the c-Jun N-terminal kinase (JNK) pathway, which further accelerated apoptosis. N-acetylcysteine (NAC), an antioxidant reagent, suppressed compound 9r-induced ROS production, JNK pathway activation, and apoptosis. Collectively, this research synthesized a series of imidazolidin-4-one derivatives, evaluated their anticancer activity, and explored the molecular mechanism of compound 9r-induced apoptosis in CRC cells. The present results suggest that compound 9r has a potential therapeutic role in CRC. Hence, it deserves further exploration as a lead compound for CRC treatment.
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Zhao, Lan, and Yi Pan. "SSCS: A Stage Supervised Subtyping System for Colorectal Cancer." Biomedicines 9, no. 12 (December 2, 2021): 1815. http://dx.doi.org/10.3390/biomedicines9121815.
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Colorectal cancer (CRC) is heterogeneous and deadly, and the exact cause of the disease is unknown. Recent progress indicated that CRC is not a single disease, but a group of diseases with significant heterogeneity. Three previous CRC subtyping systems: microsatellite instability (MSI), consensus molecular subtypes (CMS), and tumor-node-metastases (TNM) stage were evaluated for their molecular and clinical implications. Results suggested that the MSI and CMS systems are prognostic and predictive mostly in early-stage CRC. As the stage remains an influential factor for CRC subtype analysis, we developed a new subtyping system named stage supervised CRC subtypes (SSCS), in order to better stratify CRC biologically and clinically. Our subtyping system can be used to classify CRC patients into five subtypes (SSCS1-5). SSCS1 was found to have the highest frequency of MSI-H cases compared to the remaining four subtypes. SSCS2 had the most favorable prognosis, whereas the worst prognosis was seen in SSCS4. SSCS3 had cell cycle and metabolism-related gene sets upregulation, and SSCS5 subtype was enriched with amplicon-associated gene sets. Moreover, tumor-infiltrating fibroblast was found to be predictive for poor disease-free survival (DFS) only within the SSCS4 subtype. Conventional dendritic cells (cDC), on the contrary, were associated with favorable DFS in the SSCS3 subtype. Our study provides a new subtyping system SSCS, which can be used for better stratify CRC patients compared to current standards. Further exploration of the subtype-specific cell types has the potential to be novel therapies for CRC.
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Xiao, Boduan, Leilei Zhang, Huihui Liu, Huiling Fang, Chunming Wang, Biao Huang, Xinyuan Liu, Xiumei Zhou, and Yigang Wang. "Oncolytic Adenovirus CD55-Smad4 Suppresses Cell Proliferation, Metastasis, and Tumor Stemness in Colorectal Cancer by Regulating Wnt/β-Catenin Signaling Pathway." Biomedicines 8, no. 12 (December 11, 2020): 593. http://dx.doi.org/10.3390/biomedicines8120593.
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During the past few decades, colorectal cancer (CRC) incidence and mortality have significantly increased, and CRC has become the leading cause of cancer-related death worldwide. Thus, exploring novel effective therapies for CRC is imperative. In this study, we investigated the effect of oncolytic adenovirus CD55-Smad4 on CRC cell growth. Cell viability assay, animal experiments, flow cytometric analysis, cell migration, and invasion assays, and Western blotting were used to detect the proliferation, apoptosis, migration, and invasion of CRC cells. The oncolytic adenovirus CD55-Smad4 was successfully constructed and effectively suppressed CRC cell proliferation in vivo and in vitro. Notably, CD55-Smad4 activated the caspase signaling pathway, inducing the apoptosis of CRC cells. Additionally, the generated oncolytic adenovirus significantly suppressed migration and invasion of CRC cells by overexpressing Smad4 and inhibiting Wnt/β-catenin/epithelial-mesenchymal transition (EMT) signaling pathway. Moreover, CRC cells treated with CD55-Smad4 formed less and smaller spheroid colonies in serum-free culture than cells in control groups, suggesting that CD55-Smad4 suppressed the stemness of CRC cells by inhibiting the Wnt/β-catenin pathway. Together, the results of this study provide valuable information for the development of a novel strategy for cancer-targeting gene-virotherapy and provide a deeper understanding of the critical significance of Smad4 in gene therapy of CRC.
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Loong, Herbert H., Brigette B. Ma, and Anthony T. C. Chan. "Update in Antiepidermal Growth Factor Receptor Therapy in the Management of Metastatic Colorectal Cancer." Journal of Oncology 2009 (2009): 1–6. http://dx.doi.org/10.1155/2009/967920.
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The approval of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in the treatment of metastatic colorectal cancer (CRC) has expanded the armamentarium against this disease. This paper will review the historical progress and recent clinical developments of anti-EGFR therapies in the treatment of metastatic CRC. Novel strategies of targeting the EGFR pathway to improve efficacy as well as ongoing research in identifying specific molecular predictors of response will be discussed.
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Jansen, Lina, Daniel Boakye, Elizabeth Alwers, Prudence R. Carr, Christoph Reissfelder, Martin Schneider, Uwe M. Martens, Jenny Chang-Claude, Michael Hoffmeister, and Hermann Brenner. "Uptake Rates of Novel Therapies and Survival Among Privately Insured Versus Publicly Insured Patients With Colorectal Cancer in Germany." Journal of the National Comprehensive Cancer Network 19, no. 4 (April 2021): 411–20. http://dx.doi.org/10.6004/jnccn.2020.7636.
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Background: In the era of personalized medicine, cancer care is subject to major changes and innovations. It is unclear, however, to what extent implementation of such innovations and their impact on patient outcomes differ by health insurance type. This study compared provision of treatment and survival outcomes among patients with colorectal cancer (CRC) who had statutory health insurance (SHI) versus private health insurance (PHI) in Germany. Methods: We analyzed patterns of CRC treatment (surgery, chemotherapy/radiotherapy, and targeted therapy) and survival in a large cohort of patients who were diagnosed with CRC in 2003 through 2014 and were observed for an average of 6 years. Associations of type of health insurance with treatment administration and with overall, CRC-specific, and recurrence-free survival were investigated using multivariable logistic and Cox proportional hazards models, respectively. Results: Of 3,977 patients with CRC, 427 (11%) had PHI. Although type of health insurance was not associated with treatment administration in patients with stage I–III disease, those with stage IV disease with PHI more often received targeted therapy (65% vs 40%; odds ratio, 2.43; 95% CI, 1.20–4.91), with differences decreasing over time because of catch-up of uptake rates in patients with SHI. Median overall survival was longer in patients with PHI than in those with SHI (137.0 vs 114.9 months; P=.010), but survival advantages were explained to a large extent by differences in sociodemographic factors. In patients with stage IV disease, survival advantages of PHI were nonsignificant and were restricted to the early years after diagnosis. Conclusions: We observed major differences in uptake of targeted therapy between patients with PHI and those with SHI but no differences in patient survival after adjusting for relevant sociodemographic, clinical, and tumor characteristics. Further studies are needed on factors associated with the uptake of therapeutic innovations and their impact on patient survival by health insurance type.
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Loupakis, Fotios, Kenneth Joel Bloom, Wendy Allen, Enya Scanlon, Isabel Stacey, Derry Mae Keeling, Nital Patel, and Jordan Clark. "Drugging the undruggable: A market readiness analysis for KRAS-G12C." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15667-e15667. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15667.
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e15667 Background: KRAS G12C is a distinctively aggressive, poor survival, tumor genotype conferring resistance to anti-EGFR therapies in lung, colorectal (CRC) and pancreatic cancers. Prospective therapies targeting G12C have demonstrated promising activity in Phase I trials. In the advent of potentially transformative novel inhibitor therapies, we assess the need for earlier and repeated tumor profiling between treatments to accurately guide further therapeutics and assess market readiness for specified testing. Methods: Treatment-naïve patients and cell-lines were assessed for genomic change by consensus molecular classification in CRC pre/post treatment with standard chemotherapy. Assessing mutation occurrence, prevalence and testing rates, we aimed to identify areas of translational potential for testing within common cancers. A laboratory and prescriber mapping of the US across lung, CRC and pancreatic cancer types, was carried out using Diaceutics’ proprietary Global Diagnostics Index (GDI), a real-world data diagnostic database, to determine market readiness for companion diagnostic (CDx) and follow-on testing in the dawn of transformative therapies. Potential barriers to test adoption were explored including reimbursement analysis. Results: Genomic analysis shows CRC tumors change after treatment with first-line therapies rendering the primary tumor profile result less reliable. This highlights a distinct need for repeated testing post-treatment for continued efficacy in therapeutics. Patients with pancreatic cancer would benefit the most from increased testing for G12C particularly earlier testing as KRAS mutants occur before neoplastic transformation. Although the market appears ready, reimbursement for KRAS G12C remains a challenge for pancreatic cancer compared to either lung or CRC. Conclusions: This study provides genomic evidence of the necessity for more frequent tumor testing post-treatment with chemotherapy, and earlier testing in pancreatic cancer to enhance efficacy of targeted therapies. The market is ready for increased testing volumes, yet problems surrounding reimbursement and stage of testing remain. Earlier testing may increase survival and decrease cost of patient care, suggesting more frequent testing is imperative across cancer types.
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Catalano, Fabio, Roberto Borea, Silvia Puglisi, Andrea Boutros, Annalice Gandini, Malvina Cremante, Valentino Martelli, Stefania Sciallero, and Alberto Puccini. "Targeting the DNA Damage Response Pathway as a Novel Therapeutic Strategy in Colorectal Cancer." Cancers 14, no. 6 (March 9, 2022): 1388. http://dx.doi.org/10.3390/cancers14061388.
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Major advances have been made in CRC treatment in recent years, especially in molecularly driven therapies and immunotherapy. Despite this, a large number of advanced colorectal cancer patients do not benefit from these treatments and their prognosis remains poor. The landscape of DNA damage response (DDR) alterations is emerging as a novel target for treatment in different cancer types. PARP inhibitors have been approved for the treatment of ovarian, breast, pancreatic, and prostate cancers carrying deleterious BRCA1/2 pathogenic variants or homologous recombination repair (HRR) deficiency (HRD). Recent research reported on the emerging role of HRD in CRC and showed that alterations in these genes, either germline or somatic, are carried by up to 15–20% of CRCs. However, the role of HRD is still widely unknown, and few data about their clinical impact are available, especially in CRC patients. In this review, we report preclinical and clinical data currently available on DDR inhibitors in CRC. We also emphasize the predictive role of DDR mutations in response to platinum-based chemotherapy and the potential clinical role of DDR inhibitors. More preclinical and clinical trials are required to better understand the impact of DDR alterations in CRC patients and the therapeutic opportunities with novel DDR inhibitors.
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Salman Roghani, Roham, Ali Sanjari moghaddam, Gabrielle Rupprecht, Erdem Altunel, So Young Kim, Shannon McCall, Beatrice Thomas, Katie Ware, Jason Somarelli, and David S. Hsu. "A precision medicine drug discovery pipeline to identify dual CDK2/9 inhibition as a novel treatment for colorectal cancer." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e16056-e16056. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16056.
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e16056 Background: Colorectal cancer (CRC) is the 3rdmost common form of cancer in the US, responsible for over 50,000 death each year. Therapeutic options for advanced colorectal cancer are limited, and there remains an unmet clinical need to identify new therapies to treat this deadly disease. To address this need, we have developed a precision medicine pipeline that integrates high throughput chemical screens with matched patient-derived cell lines and patient-derived xenografts (PDXs) to identify new treatments for CRC. Methods: We used high-throughput chemical screens of 2,100 compounds across five low-passage, patient-derived CRC cell lines. These results were validated using dose-response IC50curves for CDK1, CDK2, CDK9 or CDK1/2/9 inhibitors and by siRNA-mediated knockdown of CDK9 with or without CDK2 inhibition. Cell cycle arrest analysis was performed by flow cytometry and anaphase catastrophe was analyzed by immunofluorescence staining. For in vivo studies, matched PDXs were treated with either CDK2, CDK9 or dual CDK2/9 inhibitors. Results: We identified the CDK inhibitor drug class as among the most effective cytotoxic compounds across all five CRC lines. Further analysis of the CDK inhibitor class revealed that combined targeting of CDK1, 2, and 9 was the most effective, with IC50 in the range of 110 nM to 1.2 μM. We further validated the efficacy of combined CDK2/9 inhibition using siRNA-mediated knockdown of CDK9 in the presence of a CDK2 inhibitor(CVT-313), and showed that CDK9 knockdown acted synergistically with CDK2 inhibition. Dual CDK2/9 inhibition led to significant G2/M cell cycle arrest and anaphase catastrophe. Finally, combined CDK2/9 inhibition in vivo synergistically inhibited PDX tumor growth as compared to single-agent CDK inhibitors. Conclusions: Our precision medicine pipeline revealed CDK2/9 dual inhibition as a combinatorial therapy to treat CRC and can also be used to identify new and novel therapies
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Kim, Dae Dong, and Cathy Eng. "The Current State of Targeted Agents in Rectal Cancer." International Journal of Surgical Oncology 2012 (2012): 1–14. http://dx.doi.org/10.1155/2012/406830.
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Targeted biologic agents have an established role in treating metastatic colorectal cancer (CRC), and the integration of targeted therapies into the treatment of CRC has resulted in significant improvements in outcomes. Rapidly growing insight into the molecular biology of CRC, as well as recent developments in gene sequencing and molecular diagnostics, has led to high expectations for the identification of molecular markers to be used in personalized treatment regimens. The mechanisms of action and toxicities of targeted therapies differ from those of traditional cytotoxic chemotherapy. Targeted therapy has raised new insight about the possibility of tailoring treatment to an individual’s disease, the assessment of drug effectiveness and toxicity, and the economics of cancer care. This paper covers the last decade of clinical trials that have explored the toxicity and efficacy of targeted agents in locally advanced and metastatic CRC and how their role may benefit patients with rectal cancer. Future efforts should include prospective studies of these agents in biomarker-defined subpopulations, as well as studies of novel agents that target angiogenesis, tumor-stromal interaction, and the cell signaling pathways implicated in rectal cancer.
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Leonard, Niamh A., Eileen Reidy, Kerry Thompson, Emma McDermott, Eleonora Peerani, Elena Tomas Bort, Frances R. Balkwill, Daniela Loessner, and Aideen E. Ryan. "Stromal Cells Promote Matrix Deposition, Remodelling and an Immunosuppressive Tumour Microenvironment in a 3D Model of Colon Cancer." Cancers 13, no. 23 (November 29, 2021): 5998. http://dx.doi.org/10.3390/cancers13235998.
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Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. CRC develops in a complex tumour microenvironment (TME) with both mesenchymal stromal cells (MSCs) and immune infiltrate, shown to alter disease progression and treatment response. We hypothesised that an accessible, affordable model of CRC that combines multiple cell types will improve research translation to the clinic and enable the identification of novel therapeutic targets. A viable gelatine-methacrloyl-based hydrogel culture system that incorporates CRC cells with MSCs and a monocyte cell line was developed. Gels were analysed on day 10 by PCR, cytokine array, microscopy and flow cytometry. The addition of stromal cells increased transcription of matrix remodelling proteins FN1 and MMP9, induced release of tumour-promoting immune molecules MIF, Serpin E1, CXCL1, IL-8 and CXCL12 and altered cancer cell expression of immunotherapeutic targets EGFR, CD47 and PD-L1. Treatment with PD153035, an EGFR inhibitor, revealed altered CRC expression of PD-L1 but only in gels lacking MSCs. We established a viable 3D model of CRC that combined cancer cells, MSCs and monocytic cells that can be used to research the role the stroma plays in the TME, identify novel therapeutic targets and improve the transitional efficacy of therapies.
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Grizzle, William E., Upender Manne, Nirag C. Jhala, and Heidi L. Weiss. "Molecular Characterization of Colorectal Neoplasia in Translational Research." Archives of Pathology & Laboratory Medicine 125, no. 1 (January 1, 2001): 91–98. http://dx.doi.org/10.5858/2001-125-0091-mcocni.
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Abstract Objective.—To present recent advances in the use of molecular markers in diagnosis, in prognosis, in early detection, in novel therapies, and in understanding the molecular pathogenesis of colorectal neoplasia. Data and Literature Sources.—A review of studies of molecular markers in colorectal neoplasia, published in English and available on MEDLINE and BioMednet, indicates that molecular markers are being increasingly studied to predict clinical outcomes in patients with colorectal adenocarcinoma (CRC). We have used this resource, together with our published and unpublished observations at the University of Alabama at Birmingham, to provide an overview of translational research related to molecular markers in colorectal neoplasia. Conclusions.—Currently, the prognosis of patients with CRC is predicted primarily on the basis of clinicopathologic staging; however, pathologists and oncology surgeons have recently begun to investigate the use of molecular markers to diagnose and/or understand the progression of CRC. In recent years, much has been learned about the molecular events responsible for the development of CRC. Also, several studies have reported the implication of some molecular markers in metastasis and tumor aggression and their usefulness in predicting clinical outcome. In this article, we discuss the use of specific molecular markers, including tumor-associated glycoprotein 72 (TAG-72), carcinoembryonic antigen (CEA), and oncofetal tumor antigens (Lewis X and Y) in diagnosis and as targets for novel therapies, as well as the phenotypic expression of bcl-2, mucin antigens (MUC1 and MUC2), and nuclear accumulation of p53 in predicting the clinical outcome of patients with CRC. We also review the ways in which molecular markers may aid the early detection of colorectal neoplasia and promote our understanding of the earliest changes in colorectal neoplasia.
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Yu, Guan-Hua, Shuo-Feng Li, Ran Wei, and Zheng Jiang. "Diabetes and Colorectal Cancer Risk: Clinical and Therapeutic Implications." Journal of Diabetes Research 2022 (March 7, 2022): 1–16. http://dx.doi.org/10.1155/2022/1747326.
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Several epidemiological studies have identified diabetes as a risk factor for colorectal cancer (CRC). The potential pathophysiological mechanisms of this association include hyperinsulinemia, insulin-like growth factor (IGF) axis, hyperglycemia, inflammation induced by adipose tissue dysfunction, gastrointestinal motility disorder, and impaired immunological surveillance. Several studies have shown that underlying diabetes adversely affects the prognosis of patients with CRC. This review explores the novel anticancer agents targeting IGF-1R and receptor for advanced glycation end products (RAGE), both of which play a vital role in diabetes-induced colorectal tumorigenesis. Inhibitors of IGF-1R and RAGE are expected to become promising therapeutic choices, particularly for CRC patients with diabetes. Furthermore, hypoglycemic therapy is associated with the incidence of CRC. Selection of appropriate hypoglycemic agents, which can reduce the risk of CRC in diabetic patients, is an unmet issue. Therefore, this review mainly summarizes the current studies concerning the connections among diabetes, hypoglycemic therapy, and CRC as well as provides a synthesis of the underlying pathophysiological mechanisms. Our synthesis provides a theoretical basis for rational use of hypoglycemic therapies and early diagnosis and treatment of diabetes-related CRC.
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Lee, Hey Min, Stefania Napolitano, Alexy Sorokin, Melanie N. Woods, Saikat Chowdhury, Jumanah Y. Alshenaifi, Anand K. Singh, et al. "Abstract 3275: Bromodomain and extraterminal (BET) protein inhibition sensitize BRAFV600E colorectal cancer to standard targeted therapies." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3275. http://dx.doi.org/10.1158/1538-7445.am2022-3275.
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Abstract Background: Standard treatment in BRAFV600E colorectal cancer (CRC) patients has demonstrated an extremely poor prognosis with only little benefits. Interestingly, BRAFV600E CRC has been identified as a subgroup highly epigenetically regulated in its tumorigenesis and maintenance. Our preliminary data demonstrated loss of BET family genes sensitizes BRAFV600E CRC cells to targeted therapies. However, the activity of BET inhibition is unknown in the context of BRAF mutation. Therefore, we investigated the efficacy of BETi combined with standard treatments in BRAFV600E CRC. Methods: CRISPR-based synthetic lethality screen was conducted using RKO, BRAFV600E CRC cell line. Library containing 355 epigenetic genes was introduced and cells were treated with either DMSO, BRAFi (vemurafenib), or BRAFi/EGFRi (cetuximab). Clonal dropouts under control versus BRAFi or BRAFi/EGFRi lead to identifying top candidate genes potentially synthetic lethal with standard treatments. We further compared the response to targeted therapies between individual BET family (BRD2/3/4) knockout and control BRAFV600E CRC cell lines by XTT or clonogenic assays. Furthermore, BRAFV600E CRC PDX models were treated with vehicle, BETi (iBET151), MEKi (binimetinib), or BETi/MEKi doublet. The efficacy of BETi (zen3694) and BRAFi/EGFRi triplet combination is under investigation. Also, we tested a combination of BETi/MEKi or BETi/BRAFi/EGFRi in the BRAFV600E CRC model with acquired resistance to BRAFi/EGFRi. We assessed treatment response by measuring tumors volume changes for 21 days. For BETi/MEKi combination, RNA-seq and RPPA were performed at 7 days to understand the pharmacodynamics of the combination. Results: Our negative selection screen confirmed loss of BRD2, one of the BET family members, sensitizes cells to both targeted treatments (p < 0.05). BRD2 or BRD4 KO CRC cell lines have shown growth inhibition with BRAFi or BRAFi/EGFRi treatments compared to control (p <0.05). Intriguingly, the efficacy study showed selective tumor regression under the combination of BETi/MEKi (-39% volume change in best responding model) while the effect of individual treatment was limited. We also identified potential adaptive resistance mechanisms to BETi treatment, associated with upregulation of key oncogenic signaling and cell cycle regulators, such as MAPK signaling, MYC, or E2F targets; which were significantly inhibited when combined with MEKi. Lastly, we found stabilized tumor growth induced by both combinations of BETi/MEKi and BETi/BRAFi/EGFRi in the resistant PDX model compared to targeted treatment alone (p <0.05). Conclusion: Our data showed combination of BET inhibition improved sensitivity or overcame resistance to standard targeted therapy in BRAFV600E CRC. Overall, our data suggest that combining BETi with MAPK inhibition could be a novel therapeutic solution for BRAFV600E CRC. Citation Format: Hey Min Lee, Stefania Napolitano, Alexy Sorokin, Melanie N. Woods, Saikat Chowdhury, Jumanah Y. Alshenaifi, Anand K. Singh, John Paul Shen, Funda Meric-Bernstam, Kunal Rai, Scott Kopetz. Bromodomain and extraterminal (BET) protein inhibition sensitize BRAFV600E colorectal cancer to standard targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3275.
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Wong, Ambrose H. N., Brigette Ma, and Rashid N. Lui. "New developments in targeted therapy for metastatic colorectal cancer." Therapeutic Advances in Medical Oncology 15 (January 2023): 175883592211485. http://dx.doi.org/10.1177/17588359221148540.
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Colorectal cancer (CRC) is the second most lethal cancer worldwide and the prognosis of metastatic CRC (mCRC) remains poor. Recent advancements in translational research have led to the identification of several new therapeutic targets and improved the treatment outcome of patients with tumours harbouring BRAF V600E mutation, ( HER2) ErBB2 alterations, NTRK gene fusions and KRAS(G12C) mutation. Improved understanding towards the mechanism of resistance to targeted therapy such as anti-epidermal growth factor receptor antibodies and the evolving role of therapeutic monitoring with circulating tumour DNA (ctDNA) has enabled the longitudinal tracking of clonal evolution during treatment and the individualization of subsequent treatments. To broaden the community-based implementation of precision oncology in directing targeted therapies for patients with gastrointestinal cancers including mCRC, the feasibility of ‘Master Protocols’ that utilizes ctDNA-based genotyping platforms is currently being evaluated. Such protocols encompass both observational and interventional clinical trials of novel targeted therapies conducted within a large clinical trial network. In this review, we will discuss the latest developments in targeted therapies, and therapeutic strategies for overcoming acquired drug resistance in patients with mCRC.
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Martin, Matthew, Mengyao Sun, Aishat Motolani, and Tao Lu. "The Pivotal Player: Components of NF-κB Pathway as Promising Biomarkers in Colorectal Cancer." International Journal of Molecular Sciences 22, no. 14 (July 11, 2021): 7429. http://dx.doi.org/10.3390/ijms22147429.
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Over the last several decades, colorectal cancer (CRC) has been one of the most prevalent cancers. While significant progress has been made in both diagnostic screening and therapeutic approaches, a large knowledge gap still remains regarding the early identification and treatment of CRC. Specifically, identification of CRC biomarkers that can help with the creation of targeted therapies as well as increasing the ability for clinicians to predict the biological response of a patient to therapeutics, is of particular importance. This review provides an overview of CRC and its progression stages, as well as the basic types of CRC biomarkers. We then lay out the synopsis of signaling pathways related to CRC, and further highlight the pivotal and multifaceted role of nuclear factor (NF) κB signaling in CRC. Particularly, we bring forth knowledge regarding the tumor microenvironment (TME) in CRC, and its complex interaction with cancer cells. We also provide examples of NF-κB signaling-related CRC biomarkers, and ongoing efforts made at targeting NF-κB signaling in CRC treatment. We conclude and anticipate that with more emerging novel regulators of the NF-κB pathway being discovered, together with their in-depth characterization and the integration of large groups of genomic, transcriptomic and proteomic data, the day of successful development of more ideal NF-κB inhibitors is fast approaching.
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Xia, Xiaoyang, DongShan You, Jing Cao, JingHui Huang, Junling Zhang, Mengli Huang, Yanan Chen, Xihua Xia, and Yuezong Bai. "Abstract 5088: Identification of NOTCH mutation as novel predictor to efficacious immunotherapy in colorectal cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5088. http://dx.doi.org/10.1158/1538-7445.am2022-5088.
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Abstract Background: NOTCH, as an oncogene, has been shown to be closely associated with radiation and chemotherapy, hormone therapy, and other molecular targeted therapies (such as anti-EGFR and anti-PI3K molecular targeted therapies) in a variety of tumors, and even in drug resistance mechanisms. However, the correlation between NOTCH mutations and immunotherapy in colorectal cancer (CRC) has not been reported. Methods: We retrospectively identified NOTCH mutation and treatment outcomes. The relationship between clinical pathologic features and NOTCH were analyzed with using the two-sided chi-squared test or the Fisher exact test. Clinicopathologic characteristics associated with overall survival using Cox regression and the Kaplan-Meier method. Results: We retrospectively analyzed 108 CRC patients who received immunotherapy, including 31 patients with NOTCH mutation (MUT) and 78 patients with NOTCH wide-type (WT). NOTCH mutation was discovered to be enriched in MSI instable and associated with significant better overall survival (HR, 0.4; 95% CI, 018-0.9; P=0.0272). Although compared with NOTCH WT, no association was observed between NOTCH1/2/4 MUT and overall survival, Kaplan-Meier survival analysis showed that patients with NOTCH3 MUT obtained better OS (not reach vs. 14 months, HR, 0.17; 95% CI 0.04-0.74; P=0.0176). In addition, in an in-house Chinese CRC cohort (n=1968), we found 322 (16.4%) patients with NOTCH mutations, including NOTCH1/2/3/4 mutation frequency were 43.5%, 32.9%, 46.9% and 12.1%, respectively. 206 (60.4%) patients had one NOTCH mutation, and only 20 (6.2%) patients had more than four mutations. NOTCH mutations were significantly associated with higher TMB levels (P<0.0001) and PD-L1 positive (P=0.0011) in the in-house Chinese CRC cohorts. Conclusions: Our results suggest that NOTCH1/2/3/4 mutation may be a potential predictor to favorable ICI response in CRC patients. The exact mechanisms underlying NOTCH mutations are needed to be further evaluated. Citation Format: Xiaoyang Xia, DongShan You, Jing Cao, JingHui Huang, Junling Zhang, Mengli Huang, Yanan Chen, Xihua Xia, Yuezong Bai. Identification of NOTCH mutation as novel predictor to efficacious immunotherapy in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5088.
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Misbah, Md, Manoj Kumar, Kuen-Huar Lee, and Shing-Chuan Shen. "Identification of Novel miRNAs, Targeting Genes, Signaling Pathway, and the Small Molecule for Overcoming Oxaliplatin Resistance of Metastatic Colorectal Cancer." BioMed Research International 2022 (September 19, 2022): 1–20. http://dx.doi.org/10.1155/2022/3825760.
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One of the globally common cancers is colorectal cancer (CRC). At present, a surgical approach remains a good option for CRC patients; however, 20% of surgically treated CRC patients experience metastasis. Currently, even the first-line used drug, oxaliplatin, remains inadequate for treating metastatic CRC, and its side effect of neurotoxicity is a major problem when treating CRC. The Gene Omnibus GSE42387 database contains gene expression profiles of parental and oxaliplatin-resistant LoVo cell lines. Differentially expressed genes (DEGs) between parental and oxaliplatin-resistance LoVo cells, protein-protein interactions (PPIs), and a pathway analysis were determined to identify overall biological changes by an online DAVID bioinformatics analysis. The ability of DEGs to predict overall survival (OS) and disease-free survival (DFS) was validated by the SPSS 22.0, using liver metastasis CRC patient samples of GSE41258. The bioinformatics web tools of the GEPIA, the Human Protein Atlas, WebGestalt, and TIMER platforms were used. In total, 218 DEGs were identified, among which 105 were downregulated and 113 were upregulated. After mapping the PPI networks and pathways, 60 DEGs were identified as hub genes (with high degrees). Six genes (TGFB1, CD36, THBS1, FABP1, PCK1, and IRS1) were involved with malaria, PPAR signaling, and the adipocytokine signaling pathway. High expressions of CD36 and PCK1 were associated with the poor survival of CRC patients in the GSE41258 database. We predicted specific micro (mi)RNAs that targeted the 3 ′ untranslated region (UTR) of PCK1 by using miRWalk. It was found that three miRNAs, viz., miR-7-5p, miR-20a-3p, and miR-636, may be upstream targets of those genes. High expression levels of miR-7-5p, miR-20a-3p, and miR-636 were associated with poor OS of CRC patients, and the small-molecule compound, mersalyl, is a promising drug for treating oxaliplatin-resistant CRC. In conclusion, miR-7-5p miR-20a-3p, and miR-636 targeted the PCK1 biomarker in the PPAR signaling pathway, which is involved in oxaliplatin-resistant CRC. Meanwhile, mersalyl was identified as a potential drug for overcoming oxaliplatin resistance in CRC. Our findings may provide novel directions and strategies for CRC therapies.
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Francescangeli, Federica, Maria Laura De Angelis, and Ann Zeuner. "Dietary Factors in the Control of Gut Homeostasis, Intestinal Stem Cells, and Colorectal Cancer." Nutrients 11, no. 12 (December 3, 2019): 2936. http://dx.doi.org/10.3390/nu11122936.
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Colorectal cancer (CRC) is the third commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide. Global CRC burden is expected to increase by 60% in the next decade, with low-income countries experiencing an escalation of CRC incidence and mortality in parallel to the adoption of western lifestyles. CRC incidence is also sharply increasing in individuals younger than 50 years, often presenting at advanced stages and with aggressive features. Both genetic and environmental factors have been recognized as major contributors for the development of CRC, the latter including diet-related conditions such as chronic inflammation and obesity. In particular, a diet rich in fat and sugars (Western-style diet, WSD) has been shown to induce multiple pathophysiological changes in the intestine linked to an increased risk of CRC. In this scenario, dietary factors have been recently shown to play novel unexpected roles in the regulation of intestinal stem cells (ISCs) and of the gut microbiota, which represent the two main biological systems responsible for intestinal homeostasis. Furthermore, diet is increasingly recognized to play a key role in the neoplastic transformation of ISCs and in the metabolic regulation of colorectal cancer stem cells. This review illustrates novel discoveries on the role of dietary components in regulating intestinal homeostasis and colorectal tumorigenesis. Particular focus is dedicated to new areas of research with potential clinical relevance including the effect of food components on ISCs and cancer stem cells (CSCs), the existence of CRC-specific microbial signatures and the alterations of intestinal homeostasis potentially involved in early-onset CRC. New insights on the role of dietary factors in intestinal regulation will provide new tools not only for the prevention and early diagnosis of CRC but also for improving the effectiveness of current CRC therapies.
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Eide, Peter, Jarle Bruun, Anita Sveen, Astrid Murumägi, John Mpindi, Mariliina Arjama, Olli Kallioniemi, and Ragnhild A. Lothe. "Novel drug discovery by pharmacogenomic profiling of 36 colorectal cancer cell lines." Journal of Clinical Oncology 34, no. 4_suppl (February 1, 2016): 604. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.604.
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604 Background: Patients with advanced colorectal cancer (CRC) are commonly administered chemotherapy by 5-Fluorouracil in various combinations with leucovorin, oxaliplatin and irinotecan. Metastatic CRCs are additionally eligible for targeted anti-VEGF treatment and anti-EGFR therapy if the tumor is KRASwt. Unfortunately, the response rates are low and novel drugs are needed. Cell lines have successfully been employed to predict drug response and several studies have demonstrated that CRC cell lines recapitulate the genetic variation among primary CRCs. Methods: We performed a high-throughput drug screen (n= 461) of 36 CRC cell lines. A multiplexed assay assessed drug effects on cell viability and cytotoxicity from a five-fold concentration range. Sensitivities were measured by calculating a drug sensitivity score for each drug using a validated algorithm that estimates the relative inhibition by normalization against the top asymptote of the drug concentration curve. By integrating drug sensitivity data with in-house datasets on DNA copy number, gene expression and deep DNA sequencing, we aimed to validate genetically indicated drug sensitivities and identify novel drug sensitivities among subsets of CRCs. Results: Pharmacological relationships for molecular subgroups of CRC were revealed by clustering analyses, outlier analysis and t-tests of the drug sensitivity scores. We found robust correlations between BRAF-mutation status and response to BRAF-inhibitors, and lack of response to Fluorouracil and its prodrug Capecitabine for cell lines with microsatelite instability. These cell lines were sensitive to Topoisomerase I-inhibitors, such as Irinotecan, Valrubicin and Idarubicin. Cell lines with TP53wt were sensitive to the TP53-MDM2 interaction inhibitor Nutlin-3. We additionally identified a more potent novel TP53-MDM2 interaction inhibitor. Pharmacologic correlations for drug classes such as MEK-, EGFR-, Aurora A/B-, PI3K/AKT-, HSP90 and IGF1R-inhibitors were also found. Conclusions: A comprehensive drug screen of 36 CRC cell lines confirms pharmacogenomic relationships and reveals novel potentially relevant therapies for CRC.
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Xu, Jianing, Zhehao Zhang, Dong Shen, Ting Zhang, Jinsong Zhang, and Wei De. "Long noncoding RNA LINC01296 plays an oncogenic role in colorectal cancer by suppressing p15 expression." Journal of International Medical Research 49, no. 5 (May 2021): 030006052110044. http://dx.doi.org/10.1177/03000605211004414.
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Objective To examine the role of the long noncoding RNA LINC01296 in colorectal carcinoma (CRC) and to explore the underlying mechanism. Methods We detected LINC01296 expression levels in a cohort of 51 paired CRC and normal tissues. We also assessed the effects of LINC01296 on cell proliferation and apoptosis in CRC cells in vitro, and measured its effect on tumor growth in an in vivo mouse model. We identified the potential downstream targets of LINC01296 and assessed its regulatory effects. Results Expression levels of LINC01296 were elevated in 37/51 CRC tissues compared with the corresponding normal tissues and were significantly associated with tumor stage, lymph node metastasis, and distant metastasis. Knockdown of LINC01296 using antisense oligonucleotides inhibited cell proliferation and promoted apoptosis of colon cancer cells in vitro and inhibited tumor growth in vivo. Knockdown of LINC01296 also significantly increased the gene expression of p15 in colon cancer cells. LINC01296-specific suppression of p15 was validated by the interaction between enhancer of zeste homolog 2 and LINC01296. Conclusion Overexpression of LINC01296 suppressed the expression of p15 leading to CRC carcinogenesis. These findings may provide the basis for novel future CRC-targeted therapies.
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Choi, Jang-Hyun, Tae-Young Jang, So-El Jeon, Jee-Heun Kim, Choong-Jae Lee, Hyeon-Ji Yun, Ji-Youn Jung, So-Yeon Park, and Jeong-Seok Nam. "The Small-Molecule Wnt Inhibitor ICG-001 Efficiently Inhibits Colorectal Cancer Stemness and Metastasis by Suppressing MEIS1 Expression." International Journal of Molecular Sciences 22, no. 24 (December 14, 2021): 13413. http://dx.doi.org/10.3390/ijms222413413.
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Recurrence and metastasis remain major obstacles in colorectal cancer (CRC) treatment. Recent studies suggest that a small subpopulation of cells with a self-renewal ability, called cancer stem-like cells (CSCs), promotes recurrence and metastasis in CRC. Unfortunately, no CSC inhibitor has been demonstrated to be more effective than existing chemotherapeutic drugs, resulting in a significant unmet need for effective CRC therapies. In this study, transcriptomic profiling of metastatic tumors from CRC patients revealed significant upregulation in the Wnt pathway and stemness genes. Thus, we examined the therapeutic effect of the small-molecule Wnt inhibitor ICG-001 on cancer stemness and metastasis. The ICG-001 treatment efficiently attenuated self-renewal activity and metastatic potential. Mechanistically, myeloid ecotropic viral insertion site 1 (MEIS1) was identified as a target gene of ICG-001 that is transcriptionally regulated by Wnt signaling. A series of functional analyses revealed that MEIS1 enhanced the CSC behavior and metastatic potential of the CRC cells. Collectively, our findings suggest that ICG-001 efficiently inhibits CRC stemness and metastasis by suppressing MEIS1 expression. These results provide a basis for the further clinical investigation of ICG-001 as a targeted therapy for CSCs, opening a new avenue for the development of novel Wnt inhibitors for the treatment of CRC metastasis.
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Das, Plabon Kumar, Farhadul Islam, and Alfred K. Lam. "The Roles of Cancer Stem Cells and Therapy Resistance in Colorectal Carcinoma." Cells 9, no. 6 (June 3, 2020): 1392. http://dx.doi.org/10.3390/cells9061392.
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Cancer stem cells (CSCs) are the main culprits involved in therapy resistance and disease recurrence in colorectal carcinoma (CRC). Results using cell culture, animal models and tissues from patients with CRC suggest the indispensable roles of colorectal CSCs in therapeutic failure. Conventional therapies target proliferating and mature cancer cells, while CSCs are mostly quiescent and poorly differentiated, thereby they can easily survive chemotherapeutic insults. The aberrant activation of Wnt/β-catenin, Notch, Hedgehog, Hippo/YAP (Yes-associated protein) and phosphatidylinositol 3-kinase/protein kinase B facilitates CSCs with excessive self-renewal and therapy resistance property in CRC. CSCs survive the chemo-radiotherapies by escaping therapy mediated DNA damage via altering the cell cycle checkpoints, increasing DNA damage repair capacity and by an efficient scavenging of reactive oxygen species. Furthermore, dysregulations of miRNAs e.g., miR-21, miR-93, miR-203, miR-215, miR-497 etc., modulate the therapeutic sensitivity of colorectal CSCs by regulating growth and survival signalling. In addition, a reversible quiescent G0 state and the re-entering cell cycle capacity of colorectal CSCs can accelerate tumour regeneration after treatment. Moreover, switching to favourable metabolic signatures during a therapeutic regimen will add more complexity in therapeutic outcomes against CSCs. Therapeutic strategies targeting these underlying mechanisms of CSCs’ therapy resistance could provide a promising outcome, however, deep understanding and concerted research are necessary to design novel therapies targeting CSCs. To conclude, the understanding of these mechanisms of CSC in CRC could lead to the improved management of patients with CRC.
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Khawaja, Hajrah, Rebecca Briggs, Cheryl Latimer, Md A. M. B. Rassel, Daryl Griffin, Lyndsey Hanson, Alberto Bardelli, et al. "Bcl-xL and association with apoptosis following KRASG12C inhibition in KRASG12C mutant colorectal cancer." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 3557. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.3557.
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3557 Background: Novel covalent inhibitors of KRASG12C have shown modest response rates in KRASG12C mutant (MT) colorectal cancer (CRC) patients. Thus, novel KRASG12C inhibitor combination strategies that can achieve deep and durable responses are needed. Methods: The small molecule KRASG12C inhibitors AZ’1569 and AZ’8037 were employed. To identify novel candidate combination strategies for AZ’1569, we performed RNA sequencing, siRNA and high-throughput drug screening. Top hits were validated in a panel of KRASG12CMT CRC cells and in vivo xenograft models. AZ’1569 acquired resistant CRC models were generated and characterised. Results: Response to AZ’1569 was heterogeneous across the KRASG12CMT models. AZ’1569 was ineffective at inducing apoptosis when used as a single agent or combined with chemotherapy or agents targeting the EGFR/KRAS/AKT axis. Using a systems biology approach, we identified the anti-apoptotic BH3-family member BCL2L1/Bcl-xL as top hit mediating resistance to AZ’1569. Further analyses identified acute increases in the pro-apoptotic protein BIM following AZ’1569 treatment. ABT-263 (Navitoclax), a pharmacological Bcl-2 family-inhibitor that blocks the ability of Bcl-xL to bind and inhibit BIM, led to dramatic and universal apoptosis when combined with AZ’1569 in a panel of KRASG12C MT CRC cells. Furthermore, this combination also resulted in dramatically attenuated tumour growth in KRASG12C MT CRC xenografts. Finally, AZ’1569 acquired resistant KRASG12C MT CRC cells showed amplification of KRASG12C, EphA2/c-MET activation, increased pro-inflammatory chemokine profile and cross-resistance to standard-of-care chemotherapy and several targeted agents. Importantly, the KRAS amplification and AZ’1569-resistance were reversible upon drug withdrawal, arguing strongly for the use of drug holidays in the case of KRAS amplification. Conclusions: Combinatorial targeting of Bcl-xL and KRASG12C is highly effective, suggesting a novel therapeutic strategy for KRAS G12CMT CRC patients. The cross-resistance to other targeted therapies and importantly conventional chemotherapy in the AZ’1569 acquired resistant cells poses a challenge, with implications for the optimal use of KRASG12C inhibitors as a second or third line option.
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Khawaja, Hajrah, Rebecca Briggs, Cheryl Latimer, Md A. M. B. Rassel, Daryl Griffin, Lyndsey Hanson, Alberto Bardelli, et al. "Bcl-xL and association with apoptosis following KRASG12C inhibition in KRASG12C mutant colorectal cancer." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 3557. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.3557.
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3557 Background: Novel covalent inhibitors of KRASG12C have shown modest response rates in KRASG12C mutant (MT) colorectal cancer (CRC) patients. Thus, novel KRASG12C inhibitor combination strategies that can achieve deep and durable responses are needed. Methods: The small molecule KRASG12C inhibitors AZ’1569 and AZ’8037 were employed. To identify novel candidate combination strategies for AZ’1569, we performed RNA sequencing, siRNA and high-throughput drug screening. Top hits were validated in a panel of KRASG12CMT CRC cells and in vivo xenograft models. AZ’1569 acquired resistant CRC models were generated and characterised. Results: Response to AZ’1569 was heterogeneous across the KRASG12CMT models. AZ’1569 was ineffective at inducing apoptosis when used as a single agent or combined with chemotherapy or agents targeting the EGFR/KRAS/AKT axis. Using a systems biology approach, we identified the anti-apoptotic BH3-family member BCL2L1/Bcl-xL as top hit mediating resistance to AZ’1569. Further analyses identified acute increases in the pro-apoptotic protein BIM following AZ’1569 treatment. ABT-263 (Navitoclax), a pharmacological Bcl-2 family-inhibitor that blocks the ability of Bcl-xL to bind and inhibit BIM, led to dramatic and universal apoptosis when combined with AZ’1569 in a panel of KRASG12C MT CRC cells. Furthermore, this combination also resulted in dramatically attenuated tumour growth in KRASG12C MT CRC xenografts. Finally, AZ’1569 acquired resistant KRASG12C MT CRC cells showed amplification of KRASG12C, EphA2/c-MET activation, increased pro-inflammatory chemokine profile and cross-resistance to standard-of-care chemotherapy and several targeted agents. Importantly, the KRAS amplification and AZ’1569-resistance were reversible upon drug withdrawal, arguing strongly for the use of drug holidays in the case of KRAS amplification. Conclusions: Combinatorial targeting of Bcl-xL and KRASG12C is highly effective, suggesting a novel therapeutic strategy for KRAS G12CMT CRC patients. The cross-resistance to other targeted therapies and importantly conventional chemotherapy in the AZ’1569 acquired resistant cells poses a challenge, with implications for the optimal use of KRASG12C inhibitors as a second or third line option.
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Shin, Alice E., Kensuke Sugiura, Yasunori Masuike, Kensuke Suzuki, Christopher J. Lengner, and Anil K. Rustgi. "Abstract B007: LIN28B promotes collective cell invasion and colorectal cancer metastasis via a novel CLDN1 and NOTCH3 axis." Cancer Research 82, no. 23_Supplement_1 (December 1, 2022): B007. http://dx.doi.org/10.1158/1538-7445.crc22-b007.
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Abstract Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second most common cause of cancer death worldwide. The 5-year survival rate is 90% in patients with localized tumors, but the survival rate drastically decreases to 14% in patients with distant metastasis. Therefore, it is imperative to elucidate the molecular mechanisms underlying CRC metastasis. The RNA-binding protein LIN28B is overexpressed in over 30% of patients with CRC and is associated with poor prognosis. Indeed, our previous work revealed that LIN28B promotes liver metastasis in a subcutaneous xenograft model of CRC as well as a portal vein injection model. In the present study, we investigated the mechanism by which LIN28B promotes colorectal tumor progression and metastasis. To assess biological changes induced by LIN28B, we established CRC cells (DLD-1 and LoVo) with high expression of LIN28B (LIN28Bhigh). LIN28B overexpression upregulated Claudin-1 (CLDN1), a protein that functions as a major constituent of the tight junction complexes. RNA immunoprecipitation revealed that LIN28B directly binds to and stabilizes CLDN1 at a post-transcriptional level. Knockdown of CLDN1 expression in LIN28Bhigh cells suppresses cell aggregation, wound healing rate, and collective invasion. Using a mouse model of metastatic CRC, we reveal that knockdown of CLDN1 inhibits liver metastasis of LIN28Bhigh CRC cells. RNA-sequencing of metastatic liver tumors from LIN28Bhigh cells showed that NOTCH3 works downstream of the LIN28B-CLDN1 axis to induce cell aggregation, collective invasion, and metastatic liver tumor formation. Inhibition of Notch signaling by DAPT, an inhibitor of the γ-secretase complex, significantly reduced metastatic liver tumors in vivo. Taken together, our results indicate that LIN28B promotes cell aggregation, invasion, and liver metastasis in CRC through post-transcriptional induction of CLDN1 and upregulation of NOTCH3. Development of new therapies that target LIN28B-CLDN1-NOTCH3 axis may provide an effective strategy for stage 4 CRC. This work was supported by 9R01CA277795-22. Citation Format: Alice E. Shin, Kensuke Sugiura, Yasunori Masuike, Kensuke Suzuki, Christopher J. Lengner, Anil K. Rustgi. LIN28B promotes collective cell invasion and colorectal cancer metastasis via a novel CLDN1 and NOTCH3 axis [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B007.
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Aparicio, Cristina, Marina Belver, Lucía Enríquez, Francisco Espeso, Lucía Núñez, Ana Sánchez, Miguel Ángel de la Fuente, and Margarita González-Vallinas. "Cell Therapy for Colorectal Cancer: The Promise of Chimeric Antigen Receptor (CAR)-T Cells." International Journal of Molecular Sciences 22, no. 21 (October 29, 2021): 11781. http://dx.doi.org/10.3390/ijms222111781.
Full textAbstract:
Colorectal cancer (CRC) is a global public health problem as it is the third most prevalent and the second most lethal cancer worldwide. Major efforts are underway to understand its molecular pathways as well as to define the tumour-associated antigens (TAAs) and tumour-specific antigens (TSAs) or neoantigens, in order to develop an effective treatment. Cell therapies are currently gaining importance, and more specifically chimeric antigen receptor (CAR)-T cell therapy, in which genetically modified T cells are redirected against the tumour antigen of interest. This immunotherapy has emerged as one of the most promising advances in cancer treatment, having successfully demonstrated its efficacy in haematological malignancies. However, in solid tumours, such as colon cancer, it is proving difficult to achieve the same results due to the shortage of TSAs, on-target off-tumour effects, low CAR-T cell infiltration and the immunosuppressive microenvironment. To address these challenges in CRC, new approaches are proposed, including combined therapies, the regional administration of CAR-T cells and more complex CAR structures, among others. This review comprehensively summarises the current landscape of CAR-T cell therapy in CRC from the potential tumour targets to the preclinical studies and clinical trials, as well as the limitations and future perspectives of this novel antitumour strategy.
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Barchitta, Maugeri, Destri, Basile, and Agodi. "Epigenetic Biomarkers in Colorectal Cancer Patients Receiving Adjuvant or Neoadjuvant Therapy: A Systematic Review of Epidemiological Studies." International Journal of Molecular Sciences 20, no. 15 (August 6, 2019): 3842. http://dx.doi.org/10.3390/ijms20153842.
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Colorectal cancer (CRC) represents the third-most common cancer worldwide and one of the main challenges for public health. Despite great strides in the application of neoadjuvant and adjuvant therapies for rectal and colon cancer patients, each of these treatments is still associated with certain adverse effects and different response rates. Thus, there is an urgent need for identifying novel potential biomarkers that might guide personalized treatments for specific subgroups of patients. However, until now, there are no biomarkers to predict the manifestation of adverse effects and the response to treatment in CRC patients. Herein, we provide a systematic review of epidemiological studies investigating epigenetic biomarkers in CRC patients receiving neoadjuvant or adjuvant therapy, and their potential role for the prediction of outcomes and response to treatment. With this aim in mind, we identified several epigenetic markers in CRC patients who received surgery with adjuvant or neoadjuvant therapy. However, none of them currently has the robustness to be translated into the clinical setting. Thus, more efforts and further large-size prospective studies and/or trials should be encouraged to develop epigenetic biomarker panels for personalized prevention and medicine in CRC cancer.
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Greally, Megan, Yaelle Tuvy, Brittanie M. Millang, Eileen Mary O'Reilly, Rona Yaeger, Leonard B. Saltz, and Geoffrey Yuyat Ku. "Actionable alterations (AA) in gastrointestinal (GI) cancers: Rate of detection and receipt of matched therapies (MT)." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15677-e15677. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15677.
Full textAbstract:
e15677 Background: Next generation sequencing (NGS) is widely used in pts with advanced cancer to personalize care. Current NCCN guidelines endorse Her2, PD-L1 and MSI testing in esophagogastric cancer (EGC), RAS, BRAF, Her2 and MSI testing in colorectal cancer (CRC) and germline, somatic and MSI testing in pancreas cancer (PC). The proportion of GI cancer pts who receive MT based on NGS is unclear. Methods: We identified pts with advanced EGC (2016-18), PC (2017) and CRC (2016) who underwent NGS with MSK-IMPACT. We assessed the proportion of pts with ≥1 AA as defined by OncoKB (at the time of analysis, levels 1/2a were accepted practice and levels 2b/3/4 were investigational; Chakravaty, JCO PO 2017), those who received MT on trial or off label and 3 and 6 months (mos) progression-free survival (PFS). Results: We identified 260 EGC, 357 PC and 438 CRC pts. After excluding pts who had ongoing benefit from standard therapy (tx), were treated elsewhere or had no active stage IV disease, potential level 2/3/4 AAs occurred in 37% (n = 97) of EGC pts, 32.5% (n = 116) of PC pts and 26.7% (n = 117) of CRC pts (Table). 10, 1 and 17 pts with EGC, PC and CRC respectively were MSI. 1 pt in each subtype had an NTRK fusion (OncoKB level 1). In EGC, 6 pts (6.2% of those with AAs) received MT: 2 pts with MET amplification (a) and 1 each with BRCA2 mutation (m), TSC2m, ERBB2m and EGFRa. The pts with METa treated with crizotinib achieved 3 but not 6 mos PFS. In PC, 11 pts (9.5%) got MT: 10 pts for BRCAm and 1 for NTRK3 fusion. 9 pts with BRCAm treated with PARP inhibitors (i) achieved ≥3 mos PFS and 5 pts reached ≥6 mos PFS. The pt treated with NTRKi progressed rapidly. In CRC, 5 pts with ERBB2a and 9 pts with BRAFm received MT (12%). 3 pts and 2 pts treated with anti-Her2 tx achieved ≥3 and ≥6 mos PFS respectively. Of 6 pts treated with BRAF/MEKi plus irinotecan or anti-EGFR tx, all achieved ≥3 mos PFS; 3 reached ≥6 mos PFS. 3 pts received novel BRAF and ERK1/2i; none reached 3 mos PFS. Conclusions: NGS frequently identified OncoKB level 2 AAs. Few pts received MT, and of those, some achieved ≥6 mos PFS. Pts with CRC and PC received MT which subsequently became standard NCCN recommendations; therefore, a more current analysis may show increased MT use. Still, MT for level 3 and 4 alterations were rare, suggesting expectations of NGS must be managed appropriately. [Table: see text]
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Subramanian, Subbaya, Xianda Zhao, and Ce Yaun. "Tumor exosome mediated immune regulation in colorectal cancer." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 194.15. http://dx.doi.org/10.4049/jimmunol.202.supp.194.15.
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Abstract Colorectal cancer (CRC) remains the third most common cause of cancer-related deaths in the United States. Most (~85%) of CRC tumors are nonimmunogenic, i.e. they lack a significant number of tumor-infiltrating T cells, and are typically unresponsive to the current immune checkpoint inhibitor-based therapies. T cells isolated from nonimmunogenic, microsatellite stable (MSS) CRC have lower levels of CD28, which provides a costimulatory signal required for T-cell activation, trafficking, proliferation, differentiation, and cytotoxic activity. CRC tumors have elevated levels of miR-503 and its cluster member miR-424, both directly target CD28 in vitro. Our data also showed that these miRNAs are present in extracellular vesicles (EVs) secreted by CRC cells, which are taken up by T cells and affect its proliferation and function in the tumor microenvironment. Further, EVs with these immune suppressive miRNAs support tumor progression in CRC mouse models. Strikingly, in orthotopic models of CRC, mice preconditioned or treated with modified EVs (EVs lacking functional miR-503 and/or miR-424 (Δ503/424-EVs)) are protected against tumor formation and have a significantly reduced tumor burden, while mice receiving control EVs or PBS solution all form tumors. Our results provide preclinical evidence that treating CRC patients with modified EVs (lacking immunosuppressive miRNAs) will significantly improve antitumor immune response and reduce tumor burden. These results provide insights on how cancer cells modulate and suppress the immune response, provide novel targets, and form the basis for a new anti-cancer therapeutic strategy.
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Mokgautsi, Ntlotlang, Yu-Cheng Kuo, Chien-Hsin Chen, Yan-Jiun Huang, Alexander T. H. Wu, and Hsu-Shan Huang. "Multiomics Study of a Novel Naturally Derived Small Molecule, NSC772864, as a Potential Inhibitor of Proto-Oncogenes Regulating Cell Cycle Progression in Colorectal Cancer." Cells 12, no. 2 (January 16, 2023): 340. http://dx.doi.org/10.3390/cells12020340.
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Colorectal cancer (CRC) is one of the most prevalent malignant tumors, and it contributes to high numbers of deaths globally. Although advances in understanding CRC molecular mechanisms have shed significant light on its pathogenicity, current treatment options, including combined chemotherapy and molecular-targeted agents, are still limited due to resistance, with almost 25% of patients developing distant metastasis. Therefore, identifying novel biomarkers for early diagnosis is crucial, as they will also influence strategies for new targeted therapies. The proto-oncogene, c-Met, a tyrosine kinase that promotes cell proliferation, motility, and invasion; c-MYC, a transcription factor associated with the modulation of the cell cycle, proliferation, apoptosis; and cyclin D1 (CCND1), an essential regulatory protein in the cell cycle, all play crucial roles in cancer progression. In the present study, we explored computational simulations through bioinformatics analysis and identified the overexpression of c-Met/GSK3β/MYC/CCND1 oncogenic signatures that were associated with cancer progression, drug resistance, metastasis, and poor clinical outcomes in CRC. We further demonstrated the anticancer activities of our newly synthesized quinoline-derived compound, NSC772864, against panels of the National Cancer Institute’s human CRC cell lines. The compound exhibited cytotoxic activities against various CRC cell lines. Using target prediction tools, we found that c-Met/GSK3β/MYC/CCND1 were target genes for the NSC772864 compound. Subsequently, we performed in silico molecular docking to investigate protein–ligand interactions and discovered that NSC772864 exhibited higher binding affinities with these oncogenes compared to FDA-approved drugs. These findings strongly suggest that NSC772864 is a novel and potential antiCRC agent.
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Aparicio, Jorge, Francis Esposito, Sara Serrano, Esther Falco, Pilar Escudero, Ana Ruiz-Casado, Hermini Manzano, and Ana Fernandez-Montes. "Metastatic Colorectal Cancer. First Line Therapy for Unresectable Disease." Journal of Clinical Medicine 9, no. 12 (November 30, 2020): 3889. http://dx.doi.org/10.3390/jcm9123889.
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Colorectal cancer (CRC) is a commonly diagnosed malignancy. The prognosis of patients with unresectable, metastatic colorectal cancer (mCRC) is dismal and medical treatment is mainly palliative in nature. Although chemotherapy remains the backbone of treatment, the landscape is changing with the understanding of its heterogeneity and molecular biology. First-line therapy relies on a combination of chemotherapy and targeted therapies, according to clinical patient characteristics and tumor molecular profile. Here we review current evidence from randomized clinical trials for using chemotherapy doublets or triplets, and for the addition of bevacizumab or anti-epidermal growth factor receptor (EGFR) agents. Novel therapies developed for small, selected populations are also discussed.
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Huijberts, Sanne CFA, Robin MJM van Geel, Rene Bernards, Jos H. Beijnen, and Neeltje Steeghs. "Encorafenib, binimetinib and cetuximab combined therapy for patients with BRAFV600E mutant metastatic colorectal cancer." Future Oncology 16, no. 6 (February 2020): 161–73. http://dx.doi.org/10.2217/fon-2019-0748.
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Approximately 10–15% of colorectal cancers (CRCs) harbor an activating BRAF mutation, leading to tumor growth promotion by activation of the mitogen-activated protein kinases pathway. BRAFV600E mutations are prognostic for treatment failure after first-line systemic therapy in the metastatic setting. In contrast to the efficacy of combined BRAF and MEK inhibition in melanoma, BRAFV600E mutant CRC is intrinsically unresponsive due to upregulation of HER/EGFR. However, combining the EGFR inhibitor cetuximab, the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib improves overall survival. This review discusses the current treatment field for patients with BRAFV600E mutant metastatic CRC and summarizes the pharmacology, efficacy and safety of the novel doublet and triplet therapies consisting of encorafenib and cetuximab with or without binimetinib.
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Sun, Yan, Hongping Li, Zhiming Ma, Jianfei Wang, Huiyu Yang, Xiaopeng Zhang, and Bingrong Liu. "Identification of immune subtypes and their prognosis and molecular implications in colorectal cancer." PLOS ONE 17, no. 11 (November 23, 2022): e0278114. http://dx.doi.org/10.1371/journal.pone.0278114.
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Immune composition is commonly heterogeneous and varies among colorectal cancer (CRC) patients. A comprehensive immune classification may act as important characteristics to predict CRC prognosis. Thus, we aimed to identify novel immune specific subtypes to guide future therapies. Unsupervised clustering was used to classify CRC samples into different immune subtypes based on abundances of immune cell populations, during which TCGA and GSE17536 datasets were used as training and validation sets, respectively. The associations between the immune subtypes and patient prognosis were investigated. Further, we identified differentially expressed genes (DEGs) between immune high and low subtypes, followed by functional enrichment analyses of DEGs. The expression levels of 74 immunomodulators (IMs) across immune subtypes were analyzed. As a result, we clustered CRC samples into three distinct immune subtypes (immune high, moderate, and low). Patients with immune-high subtype showed the best prognosis, and patients with immune-low subtype had the worst survival in both TCGA and GSE17536 cohorts. A group of 2735 up-regulated DEGs were identified across immune high and low subtypes. The main DEGs were the members of complement components, chemokines, immunoglobulins, and immunosuppressive genes that are involved in immune modulation-related pathways (e.g., cytokine-cytokine receptor interaction) or GO terms (e.g., adaptive immune response and T cell activation). The expression levels of 63 IMs were significantly varied across immune subtypes. In conclusion, this study provides a conceptual framework and molecular characteristics of CRC immune subtypes, which may accurately predict prognosis and offer novel targets for personalized immunotherapy through modifying subtype-specific tumor immune microenvironment.
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Ross, Jeffrey S., Doron Lipson, Christine E. Sheehan, Geoff Otto, Roman Yelensky, Alex Parker, Mirna Jarosz, et al. "Use of next-generation sequencing (NGS) to detect a novel ALK fusion and a high frequency of other actionable alterations in colorectal cancer (CRC)." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 3533. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.3533.
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3533 Background: We hypothesized that NGS could identify genomic alterations that guide selection of targeted therapies and discover novel drug targets for primary and metastatic CRC. Methods: DNA was extracted and sequenced from 4 X 10 μ FFPE sections from 40 (32 primary and 8 metastatic) CRCs obtained from 2004-10 (52% male; 48% female; mean age 60 years; 10% Stages I/II; 40% Stage III; 40% Stage IV; 10% Stage unknown) using a targeted NGS assay in a CLIA laboratory (Foundation Medicine). 2574 exons of 145 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: NGS revealed 125 genomic alterations in 39/40 tumors (mean 3.1, range1-7) in 21 genes, including 80 base substitutions (64%), 39 insertions/deletions (31%), 4 CNAs (3%) and 2 gene fusions (1.6%). TP53 and APC were altered in 80% (32/40) and 67.5% (27/40) of CRCs respectively, with both mutated more frequently than reported in COSMIC. Alterations associated with potential sensitivity to targeted therapies were identified in 21 (52.5%) of CRCs including: 10 KRAS (TK/MEK inhibitors), 6 BRAF (BRAF inhibitors), 5 FBXW7 (mTOR inhibitors); 2 PIK3CA (PI3K/mTOR inhibitors); 2 BRCA2 (PARP inhibitors); 2 GNAS (MEK/ERK inhibitors) and 1 CDK8 (CDK inhibitors). In 1 CRC, a 5.2 Mb tandem duplication generated a novel C2orf44-ALK gene fusion starting at the canonical exon 20 recombination site previously reported for the majority of ALK gene fusions. cDNA sequencing identified an 90-fold increase in 3’ ALK expression, suggesting the C2orf44-ALK fusion results in ALK kinase domain overexpression and contains the same intracellular domain as other ALK fusions including the ALK inhibitor sensitive EML4-ALK. Conclusions: NGS of broad, cancer-related gene content from FFPE CRC samples uncovered an unexpectedly high frequency of genomic alterations, many of which may be clinically actionable by informing treatment decisions, including a novel ALK gene fusion. This previously unrecognized subset of CRC patients may be candidates for clinical trials of crizotinib or other ALK inhibitors.
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Dienstmann, Rodrigo, Ramon Salazar, and Josep Tabernero. "Molecular Subtypes and the Evolution of Treatment Decisions in Metastatic Colorectal Cancer." American Society of Clinical Oncology Educational Book, no. 38 (May 2018): 231–38. http://dx.doi.org/10.1200/edbk_200929.
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Colorectal cancer (CRC) has clinically relevant molecular heterogeneity at multiple levels: genomics, epigenomics, transcriptomics, and microenvironment features. Genomic events acquired during carcinogenesis remain drivers of cancer progression in the metastatic setting. For example, KRAS and NRAS mutations define a population refractory to epidermal growth factor receptor monoclonal antibodies, BRAFV600E mutations associate with poor outcomes under standard therapies and response to targeted inhibitors in combinations, and HER2 amplifications confer unique sensitivity to double HER2 blockade. Multiple rare gene alterations driving resistance to epidermal growth factor receptor monoclonal antibodies have been described, with substantial overlap in primary and acquired mechanisms, in line with a clonal selection process. In this context, sequential analysis of circulating tumor DNA has the potential to guide drug development in a treatment-refractory setting. Rare kinase fusion events and complex alterations in genes involved in DNA damage repair have been described, with emerging evidence for targetability. On the other hand, transcriptomic subtypes and pathway activation signatures have also shown prognostic and potential predictive value in metastatic CRC. These markers reflect stromal and immune microenvironment interactions with cancer cells. For example, the microsatellite instable or POLE ultramutant CRC population is particularly sensitive to immune checkpoint inhibitors, whereas tumors with a mesenchymal phenotype are characterized by activation of immunosuppressive molecules that mandate stratified development of novel immunotherapy combinations. Here, we review the expanding landscape of targetable oncogenic alterations and signatures in metastatic CRC and discuss the clinical implementation of novel molecular diagnostic tests.
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Eberhardt, Wolfgang, Kristina Haeussler, Usman Nasrullah, and Josef Pfeilschifter. "Multifaceted Roles of TRIM Proteins in Colorectal Carcinoma." International Journal of Molecular Sciences 21, no. 20 (October 13, 2020): 7532. http://dx.doi.org/10.3390/ijms21207532.
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Colorectal cancer (CRC) is one of the most frequently diagnosed tumor in humans and one of the most common causes of cancer-related death worldwide. The pathogenesis of CRC follows a multistage process which together with somatic gene mutations is mainly attributed to the dysregulation of signaling pathways critically involved in the maintenance of homeostasis of epithelial integrity in the intestine. A growing number of studies has highlighted the critical impact of members of the tripartite motif (TRIM) protein family on most types of human malignancies including CRC. In accordance, abundant expression of many TRIM proteins has been observed in CRC tissues and is frequently correlating with poor survival of patients. Notably, some TRIM members can act as tumor suppressors depending on the context and the type of cancer which has been assessed. Mechanistically, most cancer-related TRIMs have a critical impact on cell cycle control, apoptosis, epithelial–mesenchymal transition (EMT), metastasis, and inflammation mainly through directly interfering with diverse oncogenic signaling pathways. In addition, some recent publications have emphasized the emerging role of some TRIM members to act as transcription factors and RNA-stabilizing factors thus adding a further level of complexity to the pleiotropic biological activities of TRIM proteins. The current review focuses on oncogenic signaling processes targeted by different TRIMs and their particular role in the development of CRC. A better understanding of the crosstalk of TRIMs with these signaling pathways relevant for CRC development is an important prerequisite for the validation of TRIM proteins as novel biomarkers and as potential targets of future therapies for CRC.
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He, Liying, Hui Li, Jianye Cai, Liang Chen, Jia Yao, Yingcai Zhang, Wanfu Xu, et al. "Prognostic Value of the Glasgow Prognostic Score or Modified Glasgow Prognostic Score for Patients with Colorectal Cancer Receiving Various Treatments: a Systematic Review and Meta-Analysis." Cellular Physiology and Biochemistry 51, no. 3 (2018): 1237–49. http://dx.doi.org/10.1159/000495500.
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Background/Aims: Increasing evidence indicates that the systemic inflammatory response plays a vital role in carcinogenesis. The Glasgow Prognostic Score or modified Glasgow Prognostic Score (GPS/mGPS) is a novel inflammatory indicator which consists of CRP and albumin. Here, we performed a meta-analysis to evaluate the prognostic value of the GPS/ mGPS in patients with colorectal cancer (CRC) and to assess its consistency in different CRC therapies. Methods: The electronic databases PubMed, Embase, Scopus, Web of Science, and Cochrane Library were searched from inception through December 2017 for the association between the GPS/mGPS and clinical outcomes. Study characteristics and prognostic data were extracted from each relevant study. Overall survival (OS) and cancer-specific survival (CSS) were considered the primary outcomes, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. The quality of each study was pooled using the random-effects Mantel-Haenszel model. Finally, subgroup analyses were performed to detect the heterogeneity of different CRC treatments. Results: Thirty-four studies, with a combined total of 8834 patients, were eligible for this meta-analysis. Data on OS and CSS were available in 23 and 22 studies, respectively. By comparing the prognostic values of different levels of the GPS in CRC patients, the summary HRs for OS and CSS were 2.18 (95% CI 1.83-2.60) and 1.82 (95% CI 1.57-2.11), respectively. According to the different tumor stages, the subgroup analyses were stratified by different treatments, including curative or palliative therapy. The results robustly confirmed the prognostic role of the GPS/mGPS. Conclusion: Our results suggest that the GPS/mGPS is a novel and effective prognostic indicator for the OS and CSS of patients with CRC.
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Mármol, Inés, Nerea Jiménez-Moreno, Carmen Ancín-Azpilicueta, Jesús Osada, Elena Cerrada, and María Jesús Rodríguez-Yoldi. "A Combination of Rosa Canina Extracts and Gold Complex Favors Apoptosis of Caco-2 Cells by Increasing Oxidative Stress and Mitochondrial Dysfunction." Antioxidants 9, no. 1 (December 24, 2019): 17. http://dx.doi.org/10.3390/antiox9010017.
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Given the alarming increase in colorectal cancer (CRC) worldwide, novel therapies are urgently needed. Plant-derived extracts have gained considerable interest in the last years due to their strong anticancer effect mediated by their unique bioactive compounds. Specifically, rosehips from Rosa canina have been successfully tested against several cancer models, including colon cancer. Moreover, gold derivatives are a promising alternative to the current platinum-based drugs commonly used in CRC chemotherapy due to their lack of affinity for DNA. Herein we have investigated the antitumor potential of a drug combination made of acidic polyphenols extracted from R. canina and the gold complex (Au(C≡C-2-NC5H4) (PTA)) in Caco-2 cell line as a model of CRC. The combination triggered strong apoptosis mediated by a blockage of the autophagic flux, which might be a consequence of a reactive oxygen species (ROS) increase and mitochondrial dysfunctionality. Our results suggest that the clinical application of plant polyphenols might enhance the anticancer effect of metallodrugs and reduce drug exposure time and therefore its side effects.
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Fasano, Candida, Valentina Grossi, Giovanna Forte, and Cristiano Simone. "Short Linear Motifs in Colorectal Cancer Interactome and Tumorigenesis." Cells 11, no. 23 (November 23, 2022): 3739. http://dx.doi.org/10.3390/cells11233739.
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Colorectal tumorigenesis is driven by alterations in genes and proteins responsible for cancer initiation, progression, and invasion. This multistage process is based on a dense network of protein–protein interactions (PPIs) that become dysregulated as a result of changes in various cell signaling effectors. PPIs in signaling and regulatory networks are known to be mediated by short linear motifs (SLiMs), which are conserved contiguous regions of 3–10 amino acids within interacting protein domains. SLiMs are the minimum sequences required for modulating cellular PPI networks. Thus, several in silico approaches have been developed to predict and analyze SLiM-mediated PPIs. In this review, we focus on emerging evidence supporting a crucial role for SLiMs in driver pathways that are disrupted in colorectal cancer (CRC) tumorigenesis and related PPI network alterations. As a result, SLiMs, along with short peptides, are attracting the interest of researchers to devise small molecules amenable to be used as novel anti-CRC targeted therapies. Overall, the characterization of SLiMs mediating crucial PPIs in CRC may foster the development of more specific combined pharmacological approaches.