scholarly journals Colorectal Cancer: From Genetic Landscape to Targeted Therapy

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Mouade El Bali ◽  
Joaira Bakkach ◽  
Mohcine Bennani Mechita
Keyword(s):  
Colorectal Cancer ◽  
Targeted Therapy ◽  
Clinical Investigation ◽  
Acquired Resistance ◽  
Predictive Biomarkers ◽  
Molecular Characteristics ◽  
Molecular Heterogeneity ◽  
Molecular Pathways ◽  
Cancer Type ◽  
Genetic Landscape

Colorectal cancer (CRC) is the third most common cancer type and the second cause of death worldwide. The advancement in understanding molecular pathways involved in CRC has led to new classifications based on the molecular characteristics of each tumor and also improved CRC management through the integration of targeted therapy into clinical practice. In this review, we will present the main molecular pathways involved in CRC carcinogenesis, the molecular classifications. The anti-VEGF and anti-EGFR therapies currently used in CRC treatment and those under clinical investigation will also be outlined, as well as the mechanisms of primary and acquired resistance to anti-EGFR monoclonal antibodies (cetuximab and panitumumab). Targeted therapy has led to great improvement in the treatment of metastatic CRC. However, there has been variability in CRC treatment outcomes due to molecular heterogeneity in colorectal tumors, which underscores the need for identifying prognostic and predictive biomarkers for CRC-targeted drugs.

Therapeutic Strategies in Diseases of the Digestive Tract - 2015 and Beyond Targeted Therapies in Colon Cancer Today and Tomorrow

2016 ◽  
Vol 34 (5) ◽  
pp. 574-579 ◽  
Author(s):  
Michael Pohl ◽  
Wolff Schmiegel
Keyword(s):  
Targeted Therapies ◽  
Immune Checkpoint ◽  
Predictive Biomarkers ◽  
Therapeutic Strategies ◽  
New Drugs ◽  
Diagnostic Tools ◽  
Molecular Heterogeneity ◽  
Cancer Type ◽  
Significant Progress ◽  
Ras Genes

Background: Colorectal cancer (CRC) is the third most common cancer type in Western countries. Significant progress has been made in the last decade in the therapy of metastatic CRC (mCRC) with a median overall survival (OS) of patients exceeding 30 months. The integration of biologic targeted therapies and anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MABs) in the treatment of patients with genomically selected all-RAS wild-type mCRC leads to a significant progress in advanced incurable disease state. After the introduction of the anti-VEGF MAB bevacizumab, the FDA approved with ramucirumab the second antiangiogenic MAB for the mCRC treatment. Further new drugs are on the horizon and new diagnostic tools will be introduced soon. Key Messages: Molecular heterogeneity of mCRC has been recognized as pivotal in the evolution of clonal populations during anti-EGFR therapies. Mutations in RAS genes predict a lack of response to anti-EGFR MABs. Mutations in the mitogen-activated protein kinase-phosphoinositide 3-kinase pathways like BRAF or PIK3CA mutations or HER2/ERBB2 or MET amplifications bypass EGFR signaling and also may confer resistance to anti-EGFR MABs. HER2/ERBB2 amplification is a further driver of resistance to anti-EGFR MABs in mCRC. The phase II study of HER2 Amplification for Colo-Rectal Cancer Enhanced Stratification (HERACLES) discovers that a dual HER2-targeted therapy may be an option for HER2-amplified mCRC. The mismatch repair deficiency predicts responsiveness to an immune checkpoint blockade with the anti-PD-1 immune checkpoint inhibitor pembrolizumab. Conclusions: The understanding of primary (de novo) and secondary (acquired) resistance to anti-EGFR therapies, new targeted therapies, immuno-oncology and about predictive biomarkers in mCRC is guiding the development of rational therapeutic strategies. Combinations of targeted therapies are necessary to effectively treat drug-resistant cancers. Liquid biopsy is an upcoming new tool in the primary diagnosis and follow-up analysis of mutations in circulating tumor DNA.

scholarly journals Her2-Targeted Therapy Induces Autophagy in Esophageal Adenocarcinoma Cells

2018 ◽  
Vol 19 (10) ◽  
pp. 3069 ◽  
Author(s):  
Félice Janser ◽  
Olivia Adams ◽  
Vanessa Bütler ◽  
Anna Schläfli ◽  
Bastian Dislich ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Esophageal Adenocarcinoma ◽  
Acquired Resistance ◽  
Therapy Resistance ◽  
Her2 Status ◽  
Autophagic Flux ◽  
Cancer Type ◽  
Cancer Resistance ◽  
Her2 Positive ◽  
Autophagy Inhibition

Esophageal adenocarcinoma (EAC) is a highly lethal cancer type with an overall poor survival rate. Twenty to thirty percent of EAC overexpress the human epidermal growth factor receptor 2 (Her2), a transmembrane receptor tyrosine kinase promoting cell growth and proliferation. Patients with Her2 overexpressing breast and gastroesophageal cancer may benefit from Her2 inhibitors. Therapy resistance, however, is well documented. Since autophagy, a lysosome-dependent catabolic process, is implicated in cancer resistance mechanisms, we tested whether autophagy modulation influences Her2 inhibitor sensitivity in EAC. Her2-positive OE19 EAC cells showed an induction in autophagic flux upon treatment with the small molecule Her2 inhibitor Lapatinib. Newly generated Lapatinib-resistant OE19 (OE19 LR) cells showed increased basal autophagic flux compared to parental OE19 (OE19 P) cells. Based on these results, we tested if combining Lapatinib with autophagy inhibitors might be beneficial. OE19 P showed significantly reduced cell viability upon double treatment, while OE19 LR were already sensitive to autophagy inhibition alone. Additionally, Her2 status and autophagy marker expression (LC3B and p62) were investigated in a treatment-naïve EAC patient cohort (n = 112) using immunohistochemistry. Here, no significant correlation between Her2 status and expression of LC3B and p62 was found. Our data show that resistance to Her2-directed therapy is associated with a higher basal autophagy level, which is not per se associated with Her2 status. Therefore, we propose that autophagy may contribute to acquired resistance to Her2-targeted therapy in EAC, and that combining Her2 and autophagy inhibition might be beneficial for EAC patients.

Predictive biomarkers with potential of converting conventional chemotherapy to targeted therapy in patients with metastatic colorectal cancer

2011 ◽  
Vol 47 (3) ◽  
pp. 340-355 ◽  
Author(s):  
Niels Frank Jensen ◽  
David Hersi Smith ◽  
Sune Boris Nygård ◽  
Maria Unni Rømer ◽  
Kirsten Vang Nielsen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Targeted Therapy ◽  
Metastatic Colorectal Cancer ◽  
Predictive Biomarkers ◽  
Conventional Chemotherapy

scholarly journals Molecular Landscape of Acquired Resistance to Targeted Therapy Combinations in BRAF-Mutant Colorectal Cancer

2016 ◽  
Vol 76 (15) ◽  
pp. 4504-4515 ◽  
Author(s):  
Daniele Oddo ◽  
Erin M. Sennott ◽  
Ludovic Barault ◽  
Emanuele Valtorta ◽  
Sabrina Arena ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Targeted Therapy ◽  
Acquired Resistance ◽  
Molecular Landscape ◽  
Braf Mutant

Broad RTK-targeted therapy overcomes molecular heterogeneity-driven resistance to cetuximab via vectored immunoprophylaxis in colorectal cancer

2016 ◽  
Vol 382 (1) ◽  
pp. 32-43 ◽  
Author(s):  
Shi Hu ◽  
Haibin Dai ◽  
Tian Li ◽  
Ying Tang ◽  
Wenyan Fu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Targeted Therapy ◽  
Molecular Heterogeneity

Role of Molecular Agents and Targeted Therapy in Clinical Trials for Women With Ovarian Cancer

2011 ◽  
Vol 21 (4) ◽  
pp. 763-770 ◽  
Author(s):  
Jonathan A. Ledermann ◽  
Christian Marth ◽  
Mark S. Carey ◽  
Michael Birrer ◽  
David D.L. Bowtell ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trials ◽  
Targeted Therapy ◽  
Predictive Biomarkers ◽  
Therapeutic Agents ◽  
Careful Consideration ◽  
Consensus Conference ◽  
Molecular Pathways ◽  
New Agents

There is now a greater understanding of the molecular pathways in ovarian cancer, and using this knowledge, a large number of new therapeutic agents can be tested. The success of these drugs will depend on selecting drugs that target known key dysfunctional molecular pathways. To make best use of these compounds, prognostic and predictive biomarkers need to be identified. Novel methods of assessment such as functional imaging need to be developed as additional biological end points to evaluate these therapies. Promising antitumor activity has been observed with some drugs, and careful consideration is needed to determine in what circumstances new agents, such as antiangiogenic compounds, could be considered as a standard therapy. These areas were discussed at the 4th Ovarian Cancer Consensus Conference.

scholarly journals Immunotherapy for Colorectal Cancer: Mechanisms and Predictive Biomarkers

2021 ◽  
Author(s):  
Lindsey Carlsen ◽  
Kelsey E. Huntington ◽  
Wafik S. El-Deiry
Keyword(s):  
Colorectal Cancer ◽  
Immune System ◽  
Cancer Cells ◽  
Mismatch Repair ◽  
Early Stage ◽  
Adoptive Cell Therapy ◽  
Acquired Resistance ◽  
Predictive Biomarkers ◽  
Immune Checkpoint Blockade ◽  
Oncolytic Viruses

Though early-stage colorectal cancer has a high 5-year survival rate of 65-92% depending on the specific stage, this probability drops to 13% after the cancer metastasizes. Frontline treatments for colorectal cancer such as chemotherapy and radiation often produce dose-limiting toxicities in patients and acquired resistance in cancer cells. Additional targeted treatments are needed to improve patient outcomes and quality of life. Immunotherapy involves treatment with peptides, cells, antibodies, viruses, or small molecules to engage or train the immune system to kill cancer cells. Preclinical and clinical investigations of immunotherapy for treatment of colorectal cancer including immune checkpoint blockade, adoptive cell therapy, monoclonal antibodies, oncolytic viruses, anti-cancer vaccines, and immune system modulators have been promising, but demonstrate limitations for patients with proficient mismatch repair enzymes. In this review, we discuss preclinical and clinical studies investigating immunotherapy for treatment of colorectal cancer and predictive biomarkers for response to these treatments. We also consider open questions including optimal combination treatments to maximize efficacy, minimize toxicity, and prevent acquired resistance and approaches to sensitize mismatch repair proficient patients to immunotherapy.

scholarly journals Molecular and Immunohistochemical Markers with Prognostic and Predictive Significance in Liver Metastases from Colorectal Carcinoma

2018 ◽  
Vol 19 (10) ◽  
pp. 3014 ◽  
Author(s):  
Gianluca Lopez ◽  
Francesca Boggio ◽  
Stefano Ferrero ◽  
Nicola Fusco ◽  
Alessandro Del Gobbo
Keyword(s):  
Colorectal Cancer ◽  
Targeted Therapy ◽  
Colorectal Carcinoma ◽  
Liver Metastases ◽  
Predictive Biomarkers ◽  
Treatment Modalities ◽  
Multiple Treatment ◽  
The Past ◽  
Immunohistochemical Markers ◽  
Current State

Despite the significant recent achievements in the diagnosis and treatment of colorectal cancer (CRC), the prognosis of these patients has currently plateaued. During the past few years, the opportunity to consider multiple treatment modalities (including surgery and other locoregional treatments, systemic therapy, and targeted therapy) led to the research of novel prognostic and predictive biomarkers in CRC liver metastases (CRCLM) patients. In this review, we seek to describe the current state of knowledge of CRCLM biomarkers and to outline impending clinical perspectives, in particular focusing on the cutting-edge tools available for their characterization.

Integrating Biomarkers and Targeted Therapy Into Colorectal Cancer Management

2019 ◽  
pp. 207-215 ◽  
Author(s):  
Christopher H. Lieu ◽  
Ryan B. Corcoran ◽  
Michael J. Overman
Keyword(s):  
Colorectal Cancer ◽  
Decision Making ◽  
Clinical Trials ◽  
Targeted Therapy ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Prognostic Indicators ◽  
Molecular Characteristics ◽  
Cancer Management ◽  
The Past

There have been substantial advances in the treatment of metastatic colorectal cancer (mCRC) over the past 15 years. Molecular characteristics of mCRC and identification of specific mutations can serve as predictive and prognostic indicators of disease and response to targeted therapies. When incorporated into clinical decision-making, these biomarkers can serve as critical tools in personalizing therapy to ensure the best outcomes. Additional improvements in the survival of patients with mCRC will be made possible with the identification of new predictive molecular biomarkers and their evaluation using rational and innovative clinical trials.

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