Molecular pathways, targeted therapies and proteomic investigations of colorectal cancer

2021 ◽  
Vol 22 ◽  
Author(s):  
Azmi Yerlikaya ◽  
Sezgin Zeren
Keyword(s):  
Colorectal Cancer ◽  
Targeted Therapies ◽  
Checkpoint Inhibitors ◽  
Molecular Characteristics ◽  
Molecular Pathways ◽  
Colorectal Carcinomas ◽  
Treatment Protocols ◽  
Mutational Status ◽  
Novel Biomarkers ◽  
Refined Carbohydrates

Abstract: According to the GLOBOCAN 2020 data, colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer-related death. The risk factors for colorectal cancer include a diet abundant with fat, refined carbohydrates, animal protein, low fiber content, alcoholism, obesity, long-term cigarette smoking, low physical inactivity, and aging. Colorectal carcinomas are classified as adenocarcinoma, neuroendocrine, squamous cell, adenosquamous, spindle cell, and undifferentiated carcinomas. In addition, many variants of colorectal carcinomas are recently distinguished based on histological, immunological, and molecular characteristics. Recently developed targeted molecules in conjunction with standard chemotherapeutics or immune checkpoint inhibitors provide promising treatment protocols for colorectal cancer. However, the benefit of targeted therapies is strictly dependent on the mutational status of signaling molecules (e.g., KRAS) or mismatch repair systems. Here it is aimed to provide a comprehensive view of colorectal cancer types, molecular pathways-associated, recently developed targeted therapies as well as proteomic investigations applied to colorectal cancer for the discovery of novel biomarkers as well as new targets for treatment protocols.

scholarly journals Evidence-Based Second-Line Treatment in RAS Wild-Type/Mutated Metastatic Colorectal Cancer in the Precision Medicine Era

2021 ◽  
Vol 22 (14) ◽  
pp. 7717
Author(s):  
Guido Giordano ◽  
Pietro Parcesepe ◽  
Giuseppina Bruno ◽  
Annamaria Piscazzi ◽  
Vincenzo Lizzi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Checkpoint Inhibitors ◽  
Line Treatment ◽  
Second Line ◽  
Wild Type ◽  
First Line ◽  
Braf Mutations ◽  
Mutational Status ◽  
First Line Treatment

Target-oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first-line treatment and are eligible for second-line approaches. In such a context, antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second-line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices. Patients harboring K- and N-RAS mutations are not eligible for anti-EGFR treatments, and bevacizumab is the only antiangiogenic agent that improves survival in combination with chemotherapy in first-line, regardless of RAS mutational status. Thus, the choice of an appropriate therapy after the progression to a bevacizumab or an EGFR-based first-line treatment should be evaluated according to the patient and disease characteristics and treatment aims. The continuation of bevacizumab beyond progression or its substitution with another anti-angiogenic agents has been shown to increase survival, whereas anti-EGFR monoclonals represent an option in RAS wild-type patients. In addition, specific molecular subgroups, such as BRAF-mutated and Microsatellite Instability-High (MSI-H) mCRCs represent aggressive malignancies that are poorly responsive to standard therapies and deserve targeted approaches. This review provides a critical overview about the state of the art in mCRC second-line treatment and discusses sequential strategies according to key molecular biomarkers.

scholarly journals Phase Ib/II trial evaluating the safety, tolerability and immunological activity of durvalumab (MEDI4736) (anti-PD-L1) plus tremelimumab (anti-CTLA-4) combined with FOLFOX in patients with metastatic colorectal cancer

ESMO Open ◽  
2018 ◽  
Vol 3 (4) ◽  
pp. e000375 ◽  
Author(s):  
Jean-David Fumet ◽  
Nicolas Isambert ◽  
Alice Hervieu ◽  
Sylvie Zanetta ◽  
Jean-Florian Guion ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Checkpoint Inhibitors ◽  
Target Therapy ◽  
Performance Status ◽  
Human Monoclonal Antibody ◽  
Eastern Cooperative Oncology Group ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Mutational Status

Background5-Fluorouracil plus irinotecan or oxaliplatin alone or in association with target therapy are standard first-line therapy for metastatic colorectal cancer (mCRC). Checkpoint inhibitors targeting PD-1/PD-L1 demonstrated efficacy on mCRC with microsatellite instability but remain ineffective alone in microsatellite stable tumour. 5-Fluorouracil and oxaliplatin were known to present immunogenic properties. Durvalumab (D) is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor. Tremelimumab (T) is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). This study is designed to evaluate whether the addition of PD-L1 and CTLA-4 inhibition to oxaliplatin, fluorouracil and leucovorin (FOLFOX) increases treatment efficacy.MethodsThis phase II study (ClinicalTrials.gov NCT03202758) will assess the efficacy and safety of FOLFOX/D/T association in patients with mCRC (n=48). Good performance status patients (Eastern Cooperative Oncology Group <2) with untreated, RAS mutational status mCRC will be eligible. Prior adjuvant therapy is allowed provided recurrence is >6 months postcompletion. There is a safety lead in nine patients receiving FOLFOX/D/T. Assuming no safety concerns the study will go on to include 39 additional patients. Patients will receive folinic acid (400 mg/m²)/5-fluorouracil (400 mg/m² as bolus followed by 2400 mg/m2 as a 46-hour infusion)/oxaliplatin (85 mg/m2) every 14 days with D (750 mg) D1 every 14 days and T (75 mg) D1 every 28 days. After six cycles of FOLFOX only D/T will continue until disease progression, death, intolerable toxicity, or patient/investigator decision to stop. Primary endpoint is safety and efficacy according to progression-free survival (PFS); secondary endpoints include overall response rate and quality of life. Hypothesis is that a PFS of 50% at 6 months is insufficient and a PFS of 70.7% is expected (with α=10%, β=10%). Blood, plasma and tumour tissue will be collected and assessed for potential prognostic and predictive biomarkers.

Chemotherapy for Metastatic Colorectal Cancer

2005 ◽  
Vol 3 (4) ◽  
pp. 525-529 ◽  
Author(s):  
Joseph Rosales ◽  
Lucille A. Leong
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Targeted Therapies ◽  
Advanced Colorectal Cancer ◽  
First Line ◽  
Treatment Protocols ◽  
The Past ◽  
Significant Survival ◽  
Combination Regimens ◽  
The Ideal

The past decade has seen a significant survival improvement for patients with metastatic colorectal cancer, fueled in large part by the arrival of active novel chemotherapeutic drugs and their incorporation into combination regimens. Several randomized trials have successfully integrated oxaliplatin and irinotecan into previously existing 5-fluorouracil (5-FU)-based regimens for advanced colorectal cancer, resulting in median survivals that have risen from 9 months to almost 2 years. Even as the ideal combinations and sequences of these regimens are elucidated, targeted therapies such as recently approved bevacizumab and cetuximab have been added to treatment protocols, with favorable consequences. We review the evolution of primary chemotherapy for advanced colorectal cancer, focusing on the trials that have led to the new standard first-line treatments. We also review the data on newer targeted therapies, especially in combination with cytotoxic therapy.

scholarly journals Immunotherapies and Targeted Therapies in the Treatment of Metastatic Colorectal Cancer

2019 ◽  
Vol 7 (8) ◽  
pp. 83 ◽  
Author(s):  
Prashanth Rawla ◽  
Adam Barsouk ◽  
Andreas V. Hadjinicolaou ◽  
Alexander Barsouk
Keyword(s):  
Colorectal Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Targeted Therapies ◽  
Checkpoint Inhibitors ◽  
Growth Factor Receptor ◽  
Her2 Positive ◽  
Cancer Hallmarks ◽  
Epidermal Growth

Colorectal cancer (CRC) is the third leading cause of cancer deaths, and while mortality has largely improved in the developed world, five-year survival for metastatic disease remains dismally low at only 15%. Fortunately, nearly a dozen targeted therapies and immunotherapies have been FDA approved in the past decade for certain patient profiles with metastatic CRC (mCRC), and many others are under development. Checkpoint inhibitors such as pembrolizumab have proven effective at extending survival for mismatch repair (MMR)-deficient and high microsatellite instability (MSI) mCRC patients. In combination with chemotherapy in first- and second-line treatment, antiangiogenic (anti-vascular endothelial growth factor (anti-VGEF)) agent bevacizumab has been shown to increase mCRC survival. Anti-epidermal growth factor receptor (anti-EGFR) agents panitumumab and cetuximab, in combination with chemotherapy, have also prolonged survival among KRAS and all RAS wild-type mCRC patients. Among these patients, anti-EGFR therapy has been found to be more efficacious than bevacizumab. Improved selectivity has allowed small-molecule receptor tyrosine kinase (RTK) inhibitors to target VEGF and EGFR with greater efficacy and tolerability. Combinations of immunotherapies, RTKs, monoclonal antibodies, and cytotoxic drugs are being investigated to provide broad-spectrum protection against relapse by simultaneously targeting many cancer hallmarks. Lastly, human epidermal growth factor receptor 2 (HER2) therapy has shown promise for HER2-positive mCRC patients, though larger clinical trials are required to secure FDA approval.

Alterations of DNA damage repair genes in Chinese colorectal cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16121-e16121
Author(s):  
Wenliang Li ◽  
Zhu Zhu ◽  
Ning Xu ◽  
Wei Huang ◽  
Junping Shi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Excision Repair ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Dna Damage Repair ◽  
Molecular Characteristics ◽  
Damage Repair

e16121 Background: Colorectal cancer (CRC) is the second most common cancer in women and third in men. DNA damage repair (DDR) deficiency has emerged as a predictive biomarker for chemotherapy, PARP and immune checkpoint inhibitors. However, comprehensive molecular characteristics of DDR variants in Chinese CRC patients is lacking. Methods: Formalin fixed, paraffin embedded (FFPE) tumor tissues and matched blood samples were collected for targeted next-generation sequencing (NGS) assay. The testing was carried out in a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Alterations of six functional gene sets involved in DDR pathways: homologous recombination (HR), mismatch repair (MMR), base excision repair (BER), nonhomologous end-joining (NHEJ), checkpoint factors (CPF) and Fanconi anemia (FA) were analyzed. The association of DDR gene mutations with TMB/MSI was assessed. Results: In total, 319 CRC patients were recruited, 127 female and 192 male with a median age of 59 (range 23-92). Over one third (36%,115/319) patients had at least one mutation in DDR genes. Mutation rates varied in different DDR pathway: HR (20.7%), CPF (15.1%), FA (11.3%), MMR (10.3%), BER (8.8%), and NHEJ (5.3%). The most frequently mutated DDR genes were ARID1A (13.4%), ATM (10.2%), BRCA2 (6.8%), MLH1 (5.6%), MSH6 (5.6%), POLE (5.0%). Germline mutations in MLH1 (2.5%), BRCA2 (1.2%), MSH2 (0.9%), MSH6 (0.9%), FANCA (0.9%), ATM (0.6%), BRCA1 (0.3%), and CHEK2 (0.3%) were detected in 24 patients. DDR variations were enriched in the right-side CRC compared to the left side CRC (50% vs. 32.8%, p= 0.024). Early stage (I-II) harbored more DDR variations. 20.1% of patients had high TMB (≥10 muts/Mb) with a median of 51 muts/Mb (10-326.7 mus/Mb). Patients with DDR mutations had a significantly higher TMB than patients with wild type DDR (8.5 vs. 4.6 muts/Mb, p< 0.001). All CRC tumors with high MSI harbored DDR mutations. Importantly, the mutations in “HM” (HR/MMR), but not BER/CPF/NHEJ/FA mutations, were significantly correlated with high MSI ( p< 0.001). Conclusions: DDR gene alterations occurred in 36% of Chinese CRC patients and were enriched in right sided tumors. DDR pathway alterations are relatively frequent in CRC and consideration for biomarker-enriched clinical trials with PARP, immune checkpoint inhibitors, and novel combinations are warranted.

scholarly journals Antibiotic-Related Changes in Microbiome: The Hidden Villain behind Colorectal Carcinoma Immunotherapy Failure

2021 ◽  
Vol 22 (4) ◽  
pp. 1754
Author(s):  
Tsvetelina Velikova ◽  
Boris Krastev ◽  
Stefan Lozenov ◽  
Radostina Gencheva ◽  
Monika Peshevska-Sekulovska ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colorectal Carcinoma ◽  
Immune Responses ◽  
Intestinal Microbiota ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Intestinal Bacteria ◽  
Molecular Pathways ◽  
Microbiota Composition ◽  
Direct Observations

The interplay between drugs and microbiota is critical for successful treatment. An accumulating amount of evidence has identified the significant impact of intestinal microbiota composition on cancer treatment response, particularly immunotherapy. The possible molecular pathways of the interaction between immune checkpoint inhibitors (ICIs) and the microbiome can be used to reverse immunotherapy tolerance in cancer by using various kinds of interventions on the intestinal bacteria. This paper aimed to review the data available on how the antibiotic-related changes in human microbiota during colorectal cancer (CRC) treatment can affect and determine ICI treatment outcomes. We also covered the data that support the potential intimate mechanisms of both local and systemic immune responses induced by changes in the intestinal microbiota. However, further better-powered studies are needed to thoroughly assess the clinical significance of antibiotic-induced alteration of the gut microbiota and its impact on CRC treatment by direct observations of patients receiving antibiotic treatment.

scholarly journals We need to bring R0 < 1 to treat cancer too

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Devabhaktuni Srikrishna ◽  
Kris Sachsenmeier
Keyword(s):  
Colorectal Cancer ◽  
Growth Rate ◽  
Cell Growth ◽  
Cancer Cell ◽  
Targeted Therapies ◽  
Checkpoint Inhibitors ◽  
Clinical Results ◽  
Cell Growth Rate ◽  
Cancer Cell Growth ◽  
Killing Rate

AbstractIf each cancer cell produces on average more than one cancer cell, we see a net growth of the tumors and metastases and vice versa. We review recent clinical results for microsatellite stable metastatic colorectal cancer (MSS-mCRC) suggesting immunotherapy combinations with personalized vaccines, checkpoint inhibitors, targeted therapies, multikinase inhibitors, chemotherapies, and radiation that simultaneously slow cancer cell growth rate and enhance T cell killing rate of cancer cells may in future synergize to control the disease.

scholarly journals Landscape of Current Targeted Therapies for Advanced Colorectal Cancer

2021 ◽  
Author(s):  
Ana João Pissarra ◽  
Catarina Abreu ◽  
André Mansinho ◽  
Ana Lúcia Costa ◽  
Sara Dâmaso ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Disease ◽  
Targeted Therapies ◽  
High Throughput Sequencing ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Her2 Overexpression ◽  
Braf Mutations ◽  
Therapeutic Landscape ◽  
Cancer Types

Colorectal cancer (CRC) is one of the most frequent and lethal cancer types worldwide. While surgery with chemotherapy and radiotherapy remains the only curative approach for localized CRC, for metastatic disease the therapeutic landscape has significantly evolved over the last years. Development and approval of novel targeted therapies, such as monoclonal antibodies against EGFR and VEGF, have significantly increased the median survival of patients with metastatic disease, with some trials reporting a benefit over 40 months. Increasing accessibility of high throughput sequencing has unraveled several new therapeutic targets. Actionable alterations, such as HER2 overexpression, BRAF mutations, and NTRK fusions, are currently available in metastatic disease, providing significant therapeutic opportunities for these patients, while new emerging agents, as immune checkpoint inhibitors, promise better treatment options in the near future. In this chapter, an overview of established and future CRC targeted therapies in the clinical setting is provided, as well as their mechanism of action, limitations, and future applicability.

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.

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