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Colorectal cancer screening from 45 years of age: Thesis, antithesis and synthesis

2019, World Journal of Gastroenterology

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Home > Eppley Institute > Theses & Dissertations

Theses & Dissertations: Cancer Research

Theses/dissertations from 2024 2024.

Novel Spirocyclic Dimer (SpiD3) Displays Potent Preclinical Effects in Hematological Malignancies , Alexandria Eiken

Dying Right: Supporting Anti-Cancer Therapy Through Immunogenic Cell Death , Elizabeth Schmitz

Therapeutic Effects of BET Protein Inhibition in B-cell Malignancies and Beyond , Audrey L. Smith

Identifying the Molecular Determinants of Lung Metastatic Adaptation in Prostate Cancer , Grace M. Waldron

Identification of Mitotic Phosphatases and Cyclin K as Novel Molecular Targets in Pancreatic Cancer , Yi Xiao

Theses/Dissertations from 2023 2023

Development of Combination Therapy Strategies to Treat Cancer Using Dihydroorotate Dehydrogenase Inhibitors , Nicholas Mullen

Overcoming Resistance Mechanisms to CDK4/6 Inhibitor Treatment Using CDK6-Selective PROTAC , Sarah Truong

Theses/Dissertations from 2022 2022

Omics Analysis in Cancer and Development , Emalie J. Clement

Investigating the Role of Splenic Macrophages in Pancreatic Cancer , Daisy V. Gonzalez

Polymeric Chloroquine in Metastatic Pancreatic Cancer Therapy , Rubayat Islam Khan

Evaluating Targets and Therapeutics for the Treatment of Pancreatic Cancer , Shelby M. Knoche

Characterization of 1,1-Diarylethylene FOXM1 Inhibitors Against High-Grade Serous Ovarian Carcinoma Cells , Cassie Liu

Novel Mechanisms of Protein Kinase C α Regulation and Function , Xinyue Li

SOX2 Dosage Governs Tumor Cell Identity and Proliferation , Ethan P. Metz

Post-Transcriptional Control of the Epithelial-to-Mesenchymal Transition (EMT) in Ras-Driven Colorectal Cancers , Chaitra Rao

Use of Machine Learning Algorithms and Highly Multiplexed Immunohistochemistry to Perform In-Depth Characterization of Primary Pancreatic Tumors and Metastatic Sites , Krysten Vance

Characterization of Metastatic Cutaneous Squamous Cell Carcinoma in the Immunosuppressed Patient , Megan E. Wackel

Visceral adipose tissue remodeling in pancreatic ductal adenocarcinoma cachexia: the role of activin A signaling , Pauline Xu

Phos-Tag-Based Screens Identify Novel Therapeutic Targets in Ovarian Cancer and Pancreatic Cancer , Renya Zeng

Theses/Dissertations from 2021 2021

Functional Characterization of Cancer-Associated DNA Polymerase ε Variants , Stephanie R. Barbari

Pancreatic Cancer: Novel Therapy, Research Tools, and Educational Outreach , Ayrianne J. Crawford

Apixaban to Prevent Thrombosis in Adult Patients Treated With Asparaginase , Krishna Gundabolu

Molecular Investigation into the Biologic and Prognostic Elements of Peripheral T-cell Lymphoma with Regulators of Tumor Microenvironment Signaling Explored in Model Systems , Tyler Herek

Utilizing Proteolysis-Targeting Chimeras to Target the Transcriptional Cyclin-Dependent Kinases 9 and 12 , Hannah King

Insights into Cutaneous Squamous Cell Carcinoma Pathogenesis and Metastasis Using a Bedside-to-Bench Approach , Marissa Lobl

Development of a MUC16-Targeted Near-Infrared Antibody Probe for Fluorescence-Guided Surgery of Pancreatic Cancer , Madeline T. Olson

FGFR4 glycosylation and processing in cholangiocarcinoma promote cancer signaling , Andrew J. Phillips

Theses/Dissertations from 2020 2020

Cooperativity of CCNE1 and FOXM1 in High-Grade Serous Ovarian Cancer , Lucy Elge

Characterizing the critical role of metabolic and redox homeostasis in colorectal cancer , Danielle Frodyma

Genomic and Transcriptomic Alterations in Metabolic Regulators and Implications for Anti-tumoral Immune Response , Ryan J. King

Dimers of Isatin Derived Spirocyclic NF-κB Inhibitor Exhibit Potent Anticancer Activity by Inducing UPR Mediated Apoptosis , Smit Kour

From Development to Therapy: A Panoramic Approach to Further Our Understanding of Cancer , Brittany Poelaert

The Cellular Origin and Molecular Drivers of Claudin-Low Mammary Cancer , Patrick D. Raedler

Mitochondrial Metabolism as a Therapeutic Target for Pancreatic Cancer , Simon Shin

Development of Fluorescent Hyaluronic Acid Nanoparticles for Intraoperative Tumor Detection , Nicholas E. Wojtynek

Theses/Dissertations from 2019 2019

The role of E3 ubiquitin ligase FBXO9 in normal and malignant hematopoiesis , R. Willow Hynes-Smith

BRCA1 & CTDP1 BRCT Domainomics in the DNA Damage Response , Kimiko L. Krieger

Targeted Inhibition of Histone Deacetyltransferases for Pancreatic Cancer Therapy , Richard Laschanzky

Human Leukocyte Antigen (HLA) Class I Molecule Components and Amyloid Precursor-Like Protein 2 (APLP2): Roles in Pancreatic Cancer Cell Migration , Bailee Sliker

Theses/Dissertations from 2018 2018

FOXM1 Expression and Contribution to Genomic Instability and Chemoresistance in High-Grade Serous Ovarian Cancer , Carter J. Barger

Overcoming TCF4-Driven BCR Signaling in Diffuse Large B-Cell Lymphoma , Keenan Hartert

Functional Role of Protein Kinase C Alpha in Endometrial Carcinogenesis , Alice Hsu

Functional Signature Ontology-Based Identification and Validation of Novel Therapeutic Targets and Natural Products for the Treatment of Cancer , Beth Neilsen

Elucidating the Roles of Lunatic Fringe in Pancreatic Ductal Adenocarcinoma , Prathamesh Patil

Theses/Dissertations from 2017 2017

Metabolic Reprogramming of Pancreatic Ductal Adenocarcinoma Cells in Response to Chronic Low pH Stress , Jaime Abrego

Understanding the Relationship between TGF-Beta and IGF-1R Signaling in Colorectal Cancer , Katie L. Bailey

The Role of EHD2 in Triple-Negative Breast Cancer Tumorigenesis and Progression , Timothy A. Bielecki

Perturbing anti-apoptotic proteins to develop novel cancer therapies , Jacob Contreras

Role of Ezrin in Colorectal Cancer Cell Survival Regulation , Premila Leiphrakpam

Evaluation of Aminopyrazole Analogs as Cyclin-Dependent Kinase Inhibitors for Colorectal Cancer Therapy , Caroline Robb

Identifying the Role of Janus Kinase 1 in Mammary Gland Development and Breast Cancer , Barbara Swenson

DNMT3A Haploinsufficiency Provokes Hematologic Malignancy of B-Lymphoid, T-Lymphoid, and Myeloid Lineage in Mice , Garland Michael Upchurch

Theses/Dissertations from 2016 2016

EHD1 As a Positive Regulator of Macrophage Colony-Stimulating Factor-1 Receptor , Luke R. Cypher

Inflammation- and Cancer-Associated Neurolymphatic Remodeling and Cachexia in Pancreatic Ductal Adenocarcinoma , Darci M. Fink

Role of CBL-family Ubiquitin Ligases as Critical Negative Regulators of T Cell Activation and Functions , Benjamin Goetz

Exploration into the Functional Impact of MUC1 on the Formation and Regulation of Transcriptional Complexes Containing AP-1 and p53 , Ryan L. Hanson

DNA Polymerase Zeta-Dependent Mutagenesis: Molecular Specificity, Extent of Error-Prone Synthesis, and the Role of dNTP Pools , Olga V. Kochenova

Defining the Role of Phosphorylation and Dephosphorylation in the Regulation of Gap Junction Proteins , Hanjun Li

Molecular Mechanisms Regulating MYC and PGC1β Expression in Colon Cancer , Jamie L. McCall

Pancreatic Cancer Invasion of the Lymphatic Vasculature and Contributions of the Tumor Microenvironment: Roles for E-selectin and CXCR4 , Maria M. Steele

Altered Levels of SOX2, and Its Associated Protein Musashi2, Disrupt Critical Cell Functions in Cancer and Embryonic Stem Cells , Erin L. Wuebben

Theses/Dissertations from 2015 2015

Characterization and target identification of non-toxic IKKβ inhibitors for anticancer therapy , Elizabeth Blowers

Effectors of Ras and KSR1 dependent colon tumorigenesis , Binita Das

Characterization of cancer-associated DNA polymerase delta variants , Tony M. Mertz

A Role for EHD Family Endocytic Regulators in Endothelial Biology , Alexandra E. J. Moffitt

Biochemical pathways regulating mammary epithelial cell homeostasis and differentiation , Chandrani Mukhopadhyay

EPACs: epigenetic regulators that affect cell survival in cancer. , Catherine Murari

Role of the C-terminus of the Catalytic Subunit of Translesion Synthesis Polymerase ζ (Zeta) in UV-induced Mutagensis , Hollie M. Siebler

LGR5 Activates TGFbeta Signaling and Suppresses Metastasis in Colon Cancer , Xiaolin Zhou

LGR5 Activates TGFβ Signaling and Suppresses Metastasis in Colon Cancer , Xiaolin Zhou

Theses/Dissertations from 2014 2014

Genetic dissection of the role of CBL-family ubiquitin ligases and their associated adapters in epidermal growth factor receptor endocytosis , Gulzar Ahmad

Strategies for the identification of chemical probes to study signaling pathways , Jamie Leigh Arnst

Defining the mechanism of signaling through the C-terminus of MUC1 , Roger B. Brown

Targeting telomerase in human pancreatic cancer cells , Katrina Burchett

The identification of KSR1-like molecules in ras-addicted colorectal cancer cells , Drew Gehring

Mechanisms of regulation of AID APOBEC deaminases activity and protection of the genome from promiscuous deamination , Artem Georgievich Lada

Characterization of the DNA-biding properties of human telomeric proteins , Amanda Lakamp-Hawley

Studies on MUC1, p120-catenin, Kaiso: coordinate role of mucins, cell adhesion molecules and cell cycle players in pancreatic cancer , Xiang Liu

Epac interaction with the TGFbeta PKA pathway to regulate cell survival in colon cancer , Meghan Lynn Mendick

Theses/Dissertations from 2013 2013

Deconvolution of the phosphorylation patterns of replication protein A by the DNA damage response to breaks , Kerry D. Brader

Modeling malignant breast cancer occurrence and survival in black and white women , Michael Gleason

The role of dna methyltransferases in myc-induced lymphomagenesis , Ryan A. Hlady

Design and development of inhibitors of CBL (TKB)-protein interactions , Eric A. Kumar

Pancreatic cancer-associated miRNAs : expression, regulation and function , Ashley M. Mohr

Mechanistic studies of mitochondrial outer membrane permeabilization (MOMP) , Xiaming Pang

Novel roles for JAK2/STAT5 signaling in mammary gland development, cancer, and immune dysregulation , Jeffrey Wayne Schmidt

Optimization of therapeutics against lethal pancreatic cancer , Joshua J. Souchek

Theses/Dissertations from 2012 2012

Immune-based novel diagnostic mechanisms for pancreatic cancer , Michael J. Baine

Sox2 associated proteins are essential for cell fate , Jesse Lee Cox

KSR2 regulates cellular proliferation, transformation, and metabolism , Mario R. Fernandez

Discovery of a novel signaling cross-talk between TPX2 and the aurora kinases during mitosis , Jyoti Iyer

Regulation of metabolism by KSR proteins , Paula Jean Klutho

The role of ERK 1/2 signaling in the dna damage-induced G2 , Ryan Kolb

Regulation of the Bcl-2 family network during apoptosis induced by different stimuli , Hernando Lopez

Studies on the role of cullin3 in mitosis , Saili Moghe

Characteristics of amyloid precursor-like protein 2 (APLP2) in pancreatic cancer and Ewing's sarcoma , Haley Louise Capek Peters

Structural and biophysical analysis of a human inosine triphosphate pyrophosphatase polymorphism , Peter David Simone

Functions and regulation of Ron receptor tyrosine kinase in human pancreatic cancer and its therapeutic applications , Yi Zou

Theses/Dissertations from 2011 2011

Coordinate detection of new targets and small molecules for cancer therapy , Kurt Fisher

The role of c-Myc in pancreatic cancer initiation and progression , Wan-Chi Lin

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Recent Advancements, Limitations, and Future Perspectives of the use of Personalized Medicine in Treatment of Colon Cancer

1 Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Chennai, India

Abhijit Mitra

Surajit pathak, suhanya prasad.

2 Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Bialystok, Białystok, Poland

Alexander Sun Zhang

3 Department of Oncology-Pathology, Karolinska Institute, Solna, Sweden

4 School of Medicine, Department of Medical Sciences, Orebro University, Örebro, Sweden

Xiao-Feng Sun

5 Department of Oncology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden

Antara Banerjee

Due to the heterogeneity of colon cancer, surgery, chemotherapy, and radiation are ineffective in all cases. The genomic profile and biomarkers associated with the process are considered in personalized medicine, along with the patient's personal history. It is based on the response of the targeted therapies to specific genetic variations. The patient's genetic transcriptomic and epigenetic features are evaluated, and the best therapeutic approach and diagnostic testing are identified through personalized medicine. This review aims to summarize all the necessary, updated information on colon cancer related to personalized medicine. Personalized medicine is gaining prominence as generalized treatments are finding it challenging to contain colon cancer cases which currently rank fourth among global cancer incidence while being the fifth largest in total death cases worldwide. In personalized therapy, patients are grouped into specific categories, and the best therapeutic approach is chosen based on evaluating their molecular features. Various personalized strategies are currently being explored in the treatment of colon cancer involving immunotherapy, phytochemicals, and other biomarker-specific targeted therapies. However, significant challenges must be overcome to integrate personalized medicine into healthcare systems completely. We look at the various signaling pathways and genetic and epigenetic alterations associated with colon cancer to understand and identify biomarkers useful in targeted therapy. The current personalized therapies available in colon cancer treatment and the strategies being explored to improve the existing methods are discussed. This review highlights the advantages and limitations of personalized medicine in colon cancer therapy. The current scenario of personalized medicine in developed countries and the challenges faced in middle- and low-income countries are also summarized. Finally, we discuss the future perspectives of personalized medicine in colon cancer and how it could be integrated into the healthcare systems.

Introduction

Colon cancer is one of the most common malignancies alongside prostate, lung, and breast cancer. Small growths, called polyps, start to form in the colon and then translate into cancerous tumors, which can metastasize to other body parts. The advancement of colon cancer can be described in four developing stages. Initially, at stages 0 and 1, the tumor grows in the inner layers of the colon, called the “polyp.” During stage 2, cancer moves beyond the walls of the colon and starts to develop in the outer layers but does not advance to the lymph nodes when it is recognized as “adenomas.” The tumor reaches the lymph nodes in stage 3 and forms “carcinoma”; finally, stage 4 has metastasized in the body. 1

The standard treatments available for colon cancer are surgery, chemotherapy, and radiotherapy. Surgery is the best option possible when the tumor is localized. Preoperative chemotherapy and radiotherapy can sometimes aid surgery. 2 Post-operative adjuvant chemotherapy is given universally for stage 3 colon cancer patients, while for stage 2 patients, the treatment remains debatable. 3 Even with the availability of these treatments, the number of deaths and new cases has been on the rise. The cost of the treatment could be an essential factor, but the main reason is the ineffectiveness of the therapeutic in dealing with all the cases. 4 , 5

Colon cancer is a heterogeneous disease attributed to the accumulation of molecular changes within cells. These genetic and epigenetic mutations vary in patients. This can explain the difference in efficacy of the same treatments in different individuals. Therefore, there is a great need to venture into personalized medicine and harness its potential to respond to the increasing burden of this chronic disease. 6 , 7

The concept of personalized healthcare is focused on therapeutic or preventive measures taken concurrently with the type of cancer currently known. Colon cancer has distinct genetic and epigenetic components, and biomarkers that can be employed for its early diagnosis are well established. Colonoscopy screening has also effectively identified colon cancer in its earliest stages when polyps form. Microsatellite instability (MSI), correlation of mutations, and hypermethylation in tumors from specific patients help separate the subgroups likely and unlikely to respond to a particular therapy regimen. These aid in treating colon cancer in its early stages, when many patients live for at least 5 years following diagnosis, and the malignancies are considered cured if any recurrence is not seen within the next 5 years. 8

Personalized treatment involves therapies in a very coordinated and integrated way. It helps start treatments in the preliminary phases as personalized medicine can utilize the molecular understanding of a specific disease. The main objective of advancing these individualized therapies is to provide the best available treatment suited to an individual patient. 9 – 11

The ability to precisely diagnose patients who can benefit from targeted therapy is essential for the success of customized medications. Targeted therapy, the foundation of personalized medicine, focuses on the current information about the altered route and the components contributing to cancer. For instance, medical professionals now often use the overexpression of human epidermal growth factor receptor type 2 (HER2) as a diagnostic tool to identify breast cancers. 12 – 14

This review looks at the present targeted drugs in personalized medicine for colon cancer, followed by the discussion of many approaches being investigated to create novel treatments. The review's objective is to evaluate the possibilities of personalized medicine in treating colon cancer. In addition, it includes the most updated trends and strategies currently involved with targeted colon cancer therapy. This information will be helpful for understanding and optimizing personalized colon cancer treatment regimes.

Pathophysiology

Around 60-65% of colon cancer are sporadic and caused due to the accumulation of genetic changes brought along by various environmental factors. 15 The most significant risk factor for colon cancer is age; those over 50 have a higher risk. 16 Other factors include smoking, alcohol consumption, poor dietary patterns, lack of physical activity, and obesity. About 25% of colon cancer cases are related to family without any identified hereditary syndrome. Approximately 5% of the cases are related to inherited syndromes such as familial adenomatous polyposis (<1%) or hereditary nonpolyposis colorectal cancer (CRC), also called Lynch syndrome (2%-4%). 17 The remaining cases are related to lower-level penetration variations in genes (<1%) and unknown hereditary genomic alterations. 18 – 20

Carcinogenesis: Mechanism of Colon Cancer

Colon cancer is developed by transforming normal colonic mucosa into a precancerous lesion called adenomatous polyps and, ultimately, invasive cancer. The development of the polyps into invasive carcinoma requires neoplastic changes in a timeframe of approximately 10-15 years. 21 This period can be utilized to diagnose and remove the polyps. Colon cancer is linked to three main molecular mechanisms, the pathway of chromosomal instability, the microsatellite instability pathway, and the aberrant hypermethylated pathway, as described below.

The Chromosomal Instability Pathway

It results from a remarkable surge in adding or removing the whole or major part of the chromosomes. Chromosomal instability (CIN) is observed in 80-85% of all colon cancer cases; hence, it is also regarded as the primary pathway associated with it. 22 In the process, oncogenes such as B-rapidly accelerated fibrosarcoma (BRAF) and Kirsten rat sarcoma viral oncogene homolog (KRAS) are activated, tumor suppressor genes (TSGs) such as tumor protein 53 (TP53) and adenomatous polyposis coli (APC) get inactivated, and finally chromosome 18's long arm loses its heterozygosity (18q LOH). 23 , 24 Vogelstein and Fearon devised a multistep model 25 in which the APC gene gets silenced initially, mutations in the KRAS oncogenes occur next, followed by 18q chromosome being deleted, and finally, TP53 getting inactivated. Transforming growth factor β receptor (TGF-βR) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) genes are also affected. 26 , 27

APC mutation takes place in the early stages of the CIN pathway. It is a crucial alteration seen in about 80% of sporadic cases of colon cancer and the inherited familial adenomatous polyposis (FAP) syndrome. 28 , 29 The APC gene plays a pivotal role in β-catenin regulation and indirectly controls the expression of β-catenin oncogene targets. Mutation in the APC gene leads to the expression of abnormal truncated APC proteins, which cannot control β-catenin levels. 30 As a result, overexpression of β-catenin takes place; it accumulates in the nucleus and activates transcription of genes such as cyclin D1 and c-Myc even in “Wnt off” condition, which facilitates tumor formation. 31

APC alterations are followed by mutations that help the tumor change from a benign to a malignant phase. The KRAS gene mutation is the initial step in developing from adenoma to cancer. KRAS gene expresses the K-Ras protein, which interacts with GTPase and sends signals for cell growth, proliferation, and differentiation. This step is controlled in normal functioning. During mutation of the KRAS gene, the K-Ras proteins remain overly activated, and cell growth and proliferation of tumor cells take place in an uncontrolled way. KRAS mutation is seen in about 40% of sporadic colon cancer cases. 32

An allelic loss at chromosome 18q follows KRAS mutation, often called loss of heterozygosity (LOH) of chromosome 18q. It is seen in around 70% of colorectal cases, especially in the advanced stages. 33 Deleted in colorectal carcinoma (DCC) and suppressor of mothers against decapentaplegic −4 and −2 (SMAD4 and SMAD2) are some of the tumor suppressor genes located in chromosome 18, which help in growth, apoptosis, and cell differentiation. Allelic loss of the 18q chromosome leads to mutation in these genes and aids in tumor growth. 34

TP53 mutation is the final step in the CIN pathway. It is seen in 50%-75% of colorectal cancer cases. TP53 gene abnormalities occur either through mutation or an allelic loss (LOH) of the 17p chromosome where it is located. When TP53 is usually functional, it expresses the p53 protein, which is essential for suppressing tumor growth. TP53 gene mutation results in the expression of an aberrant stable protein that cannot perform its intended role of aiding in DNA repair. The change from adenoma to adenocarcinoma occurs relatively late. 35

The Microsatellite Instability Pathway

It is a hypermutable pathway in which the loss of mechanisms of DNA repair takes place. 36 Small tandem repeats (STR) of DNA sequences called microsatellites cause errors during replication because of continuous structural repeats, which are generally repaired by the mismatch repair (MMR) system. 37 In this pathway, the ability to repair such microsatellites decreases, and mutations occur in those areas. They affect both the coding and non-coding regions, so the working of tumor suppressor genes is affected. MLH1, PMS1, PMS2, MSH2, and MSH6 are examples of MMR genes. 38 Microsatellite instability is seen in around 15% of sporadic colon cancer cases and in almost all hereditary nonpolyposis colorectal cancer (HNPCC) cases, also called Lynch syndrome, where germline mutations occur in DNA mismatch repair genes 39 , 40 . The CIN and MSI pathways are depicted in Figure 1 .

Role of CIN and MSI pathways in colon cancer progression.

CpG Island Methylator Phenotype Pathway

It is an epigenetic instability pathway first identified by Toyota M. et al. 41 Profuse groups of cytosine/guanine (CpG) dinucleotides called CpG islands are abundantly present in gene promoter sites. 42 In normal cells, these regions are protected from methylation and keep genes active, whereas hypermethylation of CpG island regions inactivates the transcription of several tumor suppressor genes. 42 , 43 As a result, gene silencing occurs, and a tumor is eventually formed. 44 These occur in about 20% of colorectal cancer cases. 45 , 46 It is correlated with BRAF, microsatellite instability, and KRAS mutations. MINT1, MINT31, MINT2, p16, and MLN1 are common CpG island mythelator phenotype (CIMP) markers. 47 , 48 The involvement of CIMP in colon cancer is depicted in Figure 2 .

Depiction of chromosomal instability due to hypermethylation of CpG island in CRC.

Important Factors Influencing Tumor Growth

Many environmental- and individual-specific factors contribute to the development of CRC. The age distribution of CRC patients in underdeveloped nation provides more evidence of the significant contribution of environmental factors. Young adults now have a higher chance of developing CRC as a result of lifestyle changes such as alterations related to dietary practices, specifically increasing consumption of fat and meat. 49 Studies reported strong evidences linking several dietary and lifestyle choices to the emergence of colorectal cancer. One of the main risk factors for the development of CRC is alcohol consumption, a prevalent and growing habit in modern society. Many genetic, epigenetic, cell signaling, and immunological processes can be triggered by its oxidative and non-oxidative metabolism and the metabolites and ROS that are produced as by-products of alcohol consumption. 50

A complex population of microorganisms, particularly in the colon, are found in the gastrointestinal system and are crucial for preserving homeostasis. However, numerous studies in recent years have linked microbiome modifications to the emergence of colorectal cancer. The colon is thought to contain 10 14 microorganisms, the majority of which are bacteria. The two phyla that predominate in the large intestine are Bacteroidetes and Firmicutes , followed by Actinobacteria and Verrucomicrobia . There are also members of the phylum Proteobacteria ; however they are less numerous. Initially, specific pathogenic organisms like Escherichia coli , Streptococcus gallolyticus , or Helicobacter pylori were linked to colon cancer. Inflammation, dysplasia, and cancer may begin to develop in the colon because of changes in the colon's microbiota's composition, distribution, and metabolism. According to studies, people who have a diverse gut microbiota respond to immunotherapy better than those who have a homogeneous microbiome. 49 It has been suggested that intestinal microbiota can produce commensal-specific memory T lymphocytes that cross-react with antigens related to tumors. Indeed, CD4  +  and CD8 + T cells specific for Enterococcus hirae , Bacteroides fragilis , and Akkermansia muciniphila memory responses are associated with favorable clinical outcome in cancer patients, indicating that microbe-specific T lymphocytes may contribute to anti-tumor immune responses. 51

Molecular Pathologic Epidemiology of Colorectal Cancer

The idea of molecular pathological epidemiology (MPE) as an integrative field resulted from the fusion of molecular pathology and epidemiology. Because epidemiology is specifically a subject of data science, MPE is a mix of pathology and data science. MPE can therefore satisfy the requirement to convert pathological findings into data science. The MPE approach can be merged with pharmacoepidemiology potentially to uncover new indications for and to repurpose common drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and statins. 52 A high level of MSI is associated with proximal colorectal carcinoma, whereas the distal carcinoma has an inversely proportional relation with the level of MSI. The “colorectal continuum model” proposed in MPE is a useful tool to distinguish between proximal and distal colorectal carcinoma. 52 MPE is being used to correlate the interrelationship between genetic, epigenetic, tumoral molecular signatures and tumor progression in colorectal cancer. MPE targets to discuss whether particular exposure factors like diet, lifestyle modifications, smoking, and obesity are associated with a specific molecular change in colorectal cancer pathogenesis which might affect with clinical outcome. Taking into consideration the heterogeneity of colorectal cancer, traditional epidemiology and MPE will continue to provide profound insights on carcinogenic process and help us optimize prevention and treatment strategies. 53

Conventional Therapeutic Strategies Against Colon Cancer

The most practiced approaches to deal with colon cancer are surgery, chemotherapy, and radiotherapy. Though these are associated with several risks, to date, these are the most fruitful tools used in cancer treatment. Depending on the location or stage of cancer, these interventions are used alone or in combination.

For colon cancer, surgery is the most widely used treatment. The total mesorectal excision (TME) technique is commonly used in rectal cancer. The entire rectum is removed along with the engulfing mesorectum utilizing this method, and the dissection is done around the visceral fascia plane. 54 It has been the standard effective procedure for rectal cancer for the past two decades. 55 For colon cancer, a technique having similar principles as TME has been used and is called “complete mesocolic excision (CME).” In CME, the afflicted colon and mesocolon are removed within a dissected peritoneal envelope, supplying arteries are centrally ligated, and extended lymphadenectomy is carried out. 56 In a study, patients who had surgery using CME increased their disease-free survival by 4years compared to those who had surgery using traditional procedures. In this technique, a high number of lymph nodes are yielded, which improves survival. 57 However, it remains problematic compared to traditional colectomies, and parts involved in the procedure have a high risk of creating fatal complications for the patient.

Endoscopic full-thickness resection (EFTR) is a modern surgical procedure to remove the tumor through the gastrointestinal tract (GIT) using an endoscope. It is a minimally invasive surgical therapy that helps treat deep-layer lesions in the GIT. In addition, it can treat small local tumors up to 2-2.5 cm in diameter. 58 The procedure, however, is associated with perforation risk that can lead to its spread in the peritoneum. 59

If the metastasis is resectable, removal of both the primary and the metastatic tumors is carried out. According to studies, resection of both tumors gave over a 50% chance of 5-year survival. 60 – 62

Chemotherapy

Surgery for colon cancer is usually accompanied by chemotherapy. Fluoropyrimidines incite disturbance in DNA duplication and transcription, which leads to cellular death. Fluoropyrimidines such as 5-fluorouracil (5-FU) and capecitabine have been used as a single treatment post-surgery or in conjugation with folic acid analogs such as leucovorin, a noncytotoxic compound that enhances the therapeutic efficacy of 5-FU. 63 , 64 Oxaliplatin is a platinum-containing compound classified as an alkylating agent as it forms cross-linking in DNA. These linkages are identified as defects by the repair pathways, such as base excision repair (BER); consequently, cell cycle arrest and apoptosis are initiated. 65 Currently, oxaliplatin and fluoropyrimidine are used to treat metastatic colon cancer and in adjuvant therapy. The death risk decreases by 10%-15% for stage 3 colon cancer using only fluoropyrimidine, while a combination with oxaliplatin further reduces it by 4%-6%. 66 In stage 2 colon cancer, single treatment 5-FU has a 2%-5% survival benefit. Irinotecan interferes with DNA duplication by inhibiting the topoisomerase I enzyme, which causes cell death. Combined with fluoropyrimidines, it produces remarkable results in overall survival. 67 Chemotherapeutic combinations commonly used are FOLFOX, a combination of 5-FU, leucovorin, and oxaliplatin; FOLFOXIRI, a combination of 5-FU, leucovorin, irinotecan, and oxaliplatin; and FOLFIRI, a combination of 5-FU, leucovorin, and irinotecan. 68 – 70

Radiotherapy

Radiotherapy is a therapeutic procedure that utilizes high-intensity x-rays to destroy tumor cells. It is generally used along with chemotherapy and only used under certain conditions. It can be used to aid surgical procedures along with chemotherapy to help shrink a tumor before surgery. In addition, radiotherapy can kill cancer cells if there is any evidence of a tumor left after the primary surgery in the surrounding regions. It is used more commonly in rectal than colon cancer. 71 – 74

Different Genetic Determinants of Colon Cancer

Ras mutations.

RAS are proteins that are expressed in all mammalian cells. They act as switches controlling cell proliferation, migration, differentiation, and survival pathways. These proteins are often mutated in human cancer. Three forms of RAS proteins are expressed: Harvey Ras (H-Ras), Kirsten Ras (K-Ras), and neuroblastoma Ras (N-Ras). 75

KRAS is the gene that expresses the K-Ras protein. It is the most mutated gene in the RAS family. About 40% of sporadic CRC cases have mutations in KRAS, which are mainly seen in codons 12 (70%-80%), and 13 (15%-20%) of exon 2. 76 Codon 12 mutations are related to colorectal cancer of mucin, while codon 13 mutations are a more aggressive form with great potential of metastasis. Comparatively a less frequent mutations can be seen in codons 61 and 63. Few mutations are also seen in exons 3 and 4. Some of the exon 2 KRAS mutations are G12D (32.4%), G13D (14.1%), G12V (11.3%), G12S (9.9%), G12C (8.5%), and G12A (2.8%). 76

NRAS gene expresses the N-Ras protein. It is found in 3%-5% of metastatic colon cancer patients. It is mainly found on the left side of the colon. Women are primarily affected by this mutation. The gene is mutated in codons 2, 3, and 4. 77

BRAF Mutations

The BRAF gene found in chromosome 7q34 expresses the B-Raf protein, a serine-threonine protein kinase and a RAS downstream target. 78 In addition, the protein plays an essential role in the mitogen-activated protein kinase (MAPK) signaling pathway which takes part in cell growth, survival, and proliferation. 79

About 10% of total metastatic colorectal cancer cases contain BRAF mutations, mostly present along with RAS mutations. 80 Categorically, BRAS mutations occur as V600E (valine (V) is substituted by glutamic acid (E) at amino acid 600) and non-V600E mutations. V600E mutations are often related to female patients, colon cancer on the right side, and metastases at lymph nodes and peritoneum. Non-V600E mutations are associated with males and show fewer peritoneal metastases as compared to V600E. 81

PIK3CA Mutations

The expression of the PIK3CA gene takes place in all cells. It is responsible for encoding phosphoinositide 3-kinase (PI3K), a class of lipid kinases involved in phosphorylating the 3-hydroxyl group of phosphoinositides. They are a part of the PI3K/AKT/mTOR pathway which regulates various cellular processes including cell growth, survival, proliferation, metabolism, and angiogenesis. They also interact with the Ras/MAPK pathway. 82

Somatic activating mutations in PIK3CA are seen in 10%-20% of colon cancer cases. 83 These mutations result in the PI3K pathway being overly activated, causing Akt serine/threonine kinase family (AKT) activation, irregular cell developments, and the angiogenic factors being downregulated.

TP53 Mutations

TP53 gene is present in chromosome 17 at the p (short) arm. It expresses the tumor protein p53 (p53). The function of p53 is to control cell division by keeping in check cells from growing and proliferating in an uncontrolled manner. When DNA is damaged, p53 plays a pivotal role in deciding whether the DNA can be repaired or the cell will undergo apoptosis. In the case of DNA repair, other genes are activated by p53 to help repair the damage. When the DNA cannot be repaired, p53 inhibits cell division and sends signals for apoptosis or senescence. When the cell is mutated, p53 aids in preventing the development of tumors by inhibiting cell division. The p-arm of chromosome 17 gets deleted in over 70% of colorectal carcinomas. 84 In the TP53 gene, most alterations occur in exons 5-8. In the case of the p53 protein, the mutations take place in L2, L3, and loop-sheet-helix structural domains. 85 The mutations result in the formation of a very stable protein that loses the ability to bind to DNA and cannot activate target genes to repair DNA damage. 86

APC Mutations

The APC gene is in the long arm (q) of chromosome 5. It is a tumor suppressor gene. It expresses the APC protein. The protein's function is to regulate cell growth, ie, it keeps the cells in control and does not allow growth and proliferation in an uncontrolled way. It regulates the number of cell divisions and how it attaches to other cells. The APC protein also helps ensure the number of chromosomes in a cell after cell division is correct. It associates with other proteins, mainly those involved in cell adhesion and signaling, to accomplish these functions. β-Catenin is a protein that associates with APC. Through its association with β-catenin, APC indirectly controls the transcription of some critical cell proliferation genes. 87 , 88 The interaction of APC and β-catenin results in the breakdown of β-catenin as a signal that is no longer required. The loss of APC function in case of mutation leads to the accumulation of β-catenin in the nucleus and an increase in transcription of oncogenes such as cellular myelocytomatosis (c-Myc), cyclin D, caspases, and ephrins. 89 , 90

APC is mutated in inherited FAP (familial adenomatous polyposis) and about 80% of sporadic colon cancer cases. When the mutation occurs in the APC gene, mostly the APC protein produced is small. This abnormal protein cannot control the overgrowth in cells resulting in polyps’ formation due to abnormal growth, which can potentially become cancerous. The deletion of five nucleotide blocks in the APC gene is the most common mutation seen in FAP, and this subsequently changes the sequence of amino acids in the corresponding APC protein. 91

β-Catenin Mutations

β-Catenin is primarily present at the junction of many cells and tissues, helping in cell adhesion and communication between cells. β-Catenin plays a significant role in the Wnt signaling pathway. The Wnt signaling pathway involves cell division, proliferation, and differentiation. In this pathway, β-catenin binds to specific proteins, which allows β-catenin to move inside the cell nucleus. β-Catenin associates with other proteins to express various target genes, including cell proliferation, survival, differentiation, migration, and angiogenesis. In normal cell functioning, the level of β-catenin is regulated. When it is not needed, APC interacts with it and breaks it down. In case of aberrations in the function of APC, there is an unregulated accumulation of β-catenin in the nucleus and uncontrolled expression of target oncogenes such as cellular myelocytomatosis (c-Myc), cyclin D, telomerase reverse transcriptase (TRET), caspases, and ephrins. Mutation in β-catenin is seen in about 10% of sporadic colorectal cancer. 92 , 93

SMAD4 Mutations

SMAD4 is a gene present at the 18q chromosome. It is also called the DPC4 gene. SMAD4 gene expresses the SMAD4 protein which helps transmit signals from the cell's surface to the nucleus. It is involved in a signaling pathway called the TGF-β (transforming growth factor-beta), which controls various cellular processes. Initially, TGF-β binds to receptor proteins on the cell surface and activates some SMAD proteins. These proteins bind specifically to SMAD4 protein and move to the nucleus. The complex formed binds to specific areas of DNA inside the nucleus and regulates the function of certain genes. In this way, it controls the development of cells and characterization. 94 Allelic loss of 18q and other factors may contribute to SMAD4 mutation which can lead to uncontrolled cell proliferation and ultimately tumor growth. 95

Significance and Progression of Personalized Medicine

According to GLOBOCAN 2020 estimates, 1.15 million new instances of colon cancer worldwide were reported in 2020, which is expected to rise to 1.92 million by 2040. Despite existing treatment procedures such as surgery, chemotherapy, and radiation therapy, more than 0.5 million deaths were recorded worldwide in 2020 due to colon cancer. 96 A statistic like this emphasizes that the generalized treatment regime may not be effective and precise enough to handle all colon cancer cases. Thus, a great need is to understand the disease in individual patients.

In the past, factors such as the progression of cancer in the body, the patient's age, and gender were thought to be enough to decide the treatment regime of an individual. 97 However, it is seen that genes, their composition, expression, and response vary from individual to individual. This plays an essential role in variable responses across generic chemotherapy and radiotherapy treatments.

To understand the complex biology, molecular landscape, and tumor heterogeneity of colon cancer, the application of omics-based strategies has witnessed a tremendous increase due to the demand for personalized medicine. Worth mentioning, an integrative multi-omics approach revealed the role of a RUNX2 transcription factor as a prognostic biomarker of advanced metastatic colon cancer at the epigenetic level through the regulation of epithelial-mesenchymal transition (EMT) process and drug resistance in a panel of colon cancer cell lines with varying Wnt/β-catenin signaling activity. 98 The advancements in high-throughput technology, specifically at single-cell resolution, have allowed for the identification of colorectal cancer subtypes based on the intrinsic epithelial cell type and fibrosis using single-cell RNA sequencing (scRNA-seq), which led to the modification of previous consensus molecular subtype (CMS) grouping established from the bulk transcriptome profiles. This precise molecular classification can aid in the administration of immunotherapy and chemotherapeutics. 99 To address the need for therapeutic intervention, combining drug sensitivity testing in advanced colorectal cancer patients-derived organoids with proteotranscriptomic analysis facilitated the measurement of overexpressed peroxiredoxin 6 (PRDX6), aldehyde dehydrogenase 9 A1 (ALDH9A1) proteins, and functional enrichment of the t-RNA aminoacylation process associated with oxaliplatin resistance. 100 The apparent potential of incorporating comprehensive omics analysis with colorectal cancer organoid models provided insights into the metastatic role of SMAD4 loss via the upregulated expression of epithelial-mesenchymal transition (EMT) promoting tumor growth, activation of Wnt, and TGF-β signaling pathways. 101 In the era of big data, which is being driven by artificial intelligence and machine learning data analytics, knowledge extracted from the incorporation of patient demographics with omics data, clinicopathological features, and tissue scan images are capable of better-stratifying patients which can refine prognosis prediction, biomarker identification, and individualized treatment. Much recently, an AI-based pre-screening tool for the prediction of MSI/mismatch repair deficiency (dMMR) status using routine histopathology slides was able to distinguish between the colorectal cancer patient cohorts which did not require molecular MSI testing, thereby improving early diagnostics. 102

Interestingly, machine learning models based on different omics highlighted the prediction performance of metagenomics data in the 3-year survival rate of colorectal cancer patients with an area under the curve (AUC) of 0.755. 103 The gut microbial signature as a candidate functional biomarker for dysbiosis could discriminate colorectal cancer patients from controls across cohorts. Reportedly, Fusobacterium , Peptostreptococcus species, and Porphyromonas asaccharolytica are enriched in the stool samples, and also their abundance is correlated positively in the advanced metastasizing stages of cancer. 104 It should be mentioned that researchers have identified the diagnostic potential of circulating microbial DNA that can drive systemic immune activation in colorectal cancer patients in whom the epithelial barrier function is disrupted resulting in gut microbiota translocation to the bloodstream. 105 The potential of modulating intestinal microbiota with prebiotics and/or probiotics is currently being explored as adjuvant cancer therapy, for example, a clinical trial {"type":"clinical-trial","attrs":{"text":"NCT04021589","term_id":"NCT04021589"}} NCT04021589 was conducted for monitoring treatment efficacy in colorectal cancer patients undergoing chemotherapy. 106

Personalized medicine aims to understand the underlying mechanisms and characterized genetic changes and responses to environmental factors specific to a disease. This can lead to identifying key biological molecules or processes known as biomarkers that play a specific role throughout the course. These biomarkers can be targeted, and specific therapies can be devised. 107 – 110

Translating a developed therapy into personalized medicine according to patient's condition is a challenging process. Initially, specific gene and mutation data are studied and understood precisely before considering a drug for clinical research. These data are obtained using various techniques such as genome sequencing technologies and transcriptomic, proteomic, and metabolomic studies. Then, patients are categorized into groups for clinical trials based on their data on genes and mutations, and therapy suited to specific individuals is identified. 111 The term “personalized” is often misleading as the therapy does not involve devising unique treatments for every individual patient. Instead, it is the selection of the best-suited therapy/therapies from the existing therapeutic regime based on the patient's genetic mutations and other related molecular biological data while also considering the patient's age, gender, overall health, cancer progression, and lifestyle factors.

Companion diagnostics are typically used to gather the patient's molecular data (CDx). They are tests that assess the presence of specific genes, proteins, or mutations and can assist in pinpointing the best course of action for treating a patient's disease. 112 Real-time PCR analysis and next-generation sequencing-based tests are specific techniques for detecting KRAS mutations. 113 , 114 For detecting biomarkers such as KRAS, NRAS, and BRAF, several commercially available kits have been developed to help make identifying key biological factors easier. 115

The main issue with such general therapy is that not all patients respond to the treatment in the same way. Some medications may work great on certain patients, while they may be less effective or not effective at all for some patients. Even the side effects and their extent can vary from individual to individual. Finding the exact therapy that can work well for an individual can be very challenging.

Personalized medicine is a step taken in the direction of finding the best-fit therapy for a particular patient. In addition to the patient information taken in conventional treatments, an individual's genetic and molecular profile is studied, while the environmental factors and lifestyle are also considered. Accordingly, the most suited treatment is prescribed. Personalized medicine is also, therefore, called precision therapy. Pembrolizumab is an example of targeted therapy in colon cancer where it is specifically used to treat high microsatellite instability or deficient mismatch repair metastatic colorectal cancer.

For conventional medicine, drugs are developed to treat colon cancer or its symptoms directly. Therefore, a large group of colon cancer patients is involved in testing drugs for clinical trials. The Food and Drug Administration (FDA) approval comes when a drug shows a promising activity in most patients. However, this cannot guarantee success for all patients. On the other hand, personalized medicine is much more precise.

In colon cancer, KRAS mutations are seen in many colon cancer patients. Specific micromolecules, adagrasib, and sotorasib (AMG 510) target and inhibit KRASGI2C. Another example is the identification of encorafenib in colon cancer therapy. BRAF mutations are seen in a few metastatic colorectal cases. Encorafenib inhibits BRAFV600E and can be explicitly used in treatments related to BRAF mutations. 116 , 117

FDA Accepted Personalized Medicine Therapy in Colon Cancer

Bevacizumab.

It is a monoclonal immunoglobulin G1 (IgG1) antibody specific to the VEGF-A protein. 118 It specifically binds to the circulating VEGF-A protein and inhibits its binding to the VEGFR1 and VEGFR2 receptors on the cell surface. As a result, the microvascular growth of the tumor's blood vessels is reduced, and blood supply to these tumor tissues is reduced. 119 , 120 Bevacizumab does not have a direct anti-tumor effect, but it helps improve the efficacy of the accompanying chemotherapy. 121 After the administration of bevacizumab, the blood vessels associated with the tumor morphologically normalize and become organized. The pressure of oxygen and interstitial fluid supply is decreased. The delivery of the chemotherapeutic agents is improved; thus, their efficacy in acting on the tumor increases. 122 It is generally used with FOLFOXIRI. 123

It is a chimeric monoclonal IgG1 antibody of the epidermal growth factor receptor (EGFR). 124 It selectively binds to the extracellular region of the EGFR and blocks the domain from binding to epidermal growth factor (EGF) and other ligands. 125 This blockage results in cell growth inhibition, increased apoptosis of tumor cells, reduced angiogenesis, and metastasis. 126 It is a first-line colon cancer drug used along with chemotherapy. Monotherapy with cetuximab is an option for metastatic colorectal cancer patients with EGFR-expressing, K-Ras wild-type tumors who resist chemotherapy. 127 , 128

Panitumumab

It is an IgG2 kappa monoclonal antibody (mAb) of EGFR. 129 It has a mechanism of action similar to cetuximab. It binds specifically to EGFR and does not allow other ligands to bind to it. This causes cell growth inhibition, tumor cell apoptosis induction, decreased angiogenesis, and metastasis. 130 It was approved in 2006 for treating metastatic colon cancer by the FDA. It is used as a single treatment of metastatic colorectal cancer having EGFR expression or along with chemotherapy.

Ziv-Aflibercept

It is a recombinant protein formed by the fusion of the constant region (Fc) of human IgG1, the second immunoglobulin (Ig) region of human VEGFR-1, and the third Ig region of VEGFR-2. 131 It acts as a decoy receptor for VEGF-A, VEGF-B, and placental growth factor (PIGF) 1 and 2 and inhibits their interactions with VEGFR-1 and VEGFR-2. This inhibition leads to a decrease in angiogenesis, tumor growth, and metastasis. 132 It was approved by the FDA in 2012 for the treatment of metastatic colorectal cancer. It is used in combination with FOLFIRI. 133

Regorafenib

Regorafenib is a small monohydrate molecule multi-kinase inhibitor that inhibits abnormally activated or mutated kinases in tumor cells or those helping in oncogenesis such as VEGFRs, BRAF, platelet-derived growth factor receptor (PDGFR), c-Kit, and Tie-2. 134 As a result, there is inhibition of angiogenesis, cell proliferation, and tumor apoptosis. 135 In 2012, it was approved by the FDA for the treatment of metastatic colorectal cancer. It is used as a single treatment in anti-VEGF therapy, anti-EGFR therapy in KRAS wild-type tumors, and in metastatic colon cancer patients who have previously undergone chemotherapy. 136

Ramucirumab

It is a recombinant immunoglobulin G1 (IgG1) monoclonal antibody of VEGFR-2. 137 It specifically identifies and binds to the domain of VEGFR-2 and blocks the binding of all ligands associated with VEGFR-2, including VEGF-A, VEGF-C, and VEGF-D. 120 This inhibits tumor cell proliferation, migration, and angiogenesis. Ramucirumab completely blocks the signaling related to VEGFR-2, and hence it has the potential to overcome resistance associated with bevacizumab. 138 The FDA first approved ramucirumab in 2014 for gastric cancer; in 2015, it was approved for metastatic colon cancer.

Pembrolizumab

It is a monoclonal immunoglobulin G4 (IgG4) antibody of programmed cell death protein 1 (PD-1). 139 It binds to the PD-1 receptor and blocks the interaction of programmed death ligands 1 (PD-L1) and 2 (PD-L2) with the PD-1 receptor. PD-L1 can aid in cell proliferation and survival in cancer cells, while PD-L2 supports tumor metastasis. The binding of PD-L1 and PD-L2 to the cytotoxic tumor T cells can thus act as a mechanism for cancer cells to evade immunity. 140 Blocking of the PD-1 receptor can therefore inhibit T-cell cytotoxicity response. Pembrolizumab was first approved for microsatellite instability-high cancer in 2017, and in 2020, it was approved for metastatic colon cancer patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) as first-line treatment.. 141

It is a monoclonal IgG4 antibody of the PD-1 receptor. 142 The mechanism of action of nivolumab is like that of pembrolizumab. It specifically binds to PD-1 and inhibits PD-L1 and PD-L2 from binding to PD-1 receptor. Nivolumab was approved for the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer in 2017. It is used either as a single drug therapy or in association with ipilimumab after metastatic colorectal cancer with MSI-H or dMMR has progressed following the use of fluoropyrimidine, irinotecan, and oxaliplatin treatment regime. 143

Ipilimumab is a monoclonal IgG1 antibody of CTLA-4 (cytotoxic T-lymphocyte antigen 4). 144 Ipilimumab binds explicitly to CTLA-4 and inhibits the interaction of ligands such as CD80 and CD86 to CTLA-4. This blocking mechanism leads to aiding the activation and proliferation of T cells and T-effector cells. This ultimately contributes to increased T-cell responsiveness, including immune response for battling tumor activity. It was approved in 2018 by the FDA for combinational therapy with nivolumab for the treatment of metastatic colorectal cancer with MSI-H or dMMR. It is used in combination with nivolumab after metastatic colorectal cancer with MSI-H or dMMR has progressed following the use of fluoropyrimidine, irinotecan, and oxaliplatin treatment regime for adult and pediatric patients above 12 years old. 145

Encorafenib

Encorafenib was initially approved for the targeted therapy of melanoma in a multicenter trial (COLUMBUS; {"type":"clinical-trial","attrs":{"text":"NCT01909453","term_id":"NCT01909453"}} NCT01909453 ), mediated by its inhibitory action against the MAPK signal transduction pathway as it binds to the BRAF protein resulting in cell cycle arrest and senescence. Much recently, the clinical use of encorafenib and cetuximab received FDA approval specifically targeting the BRAF V600E-mutant with the improved response rate in the BEACON trial ( {"type":"clinical-trial","attrs":{"text":"NCT01909453","term_id":"NCT01909453"}} NCT01909453 ) with adult metastatic colorectal cancer patients post-systemic therapy ( Table 1 ). 117 , 146

FDA-Approved Personalized Targeted Drugs for Colon Cancer Therapy

Recent Update on Personalized Therapeutics in Perspective of Various Targeted Strategies

Different types of mutation, responsible for colon cancer progression and targeted therapy, explicitly evolved for it is described in the following subsections, and a pictorial representation is depicted in Figure 3 .

Molecular pathways in normal and colon cancer cells and potential targeted therapies.

RAS Mutation Targeted Therapy

Chemotherapy with bevacizumab is the preferred treatment for KRAS mutation; however, currently, minimal data is available. 147 Targeted therapy with micromolecules, adagrasib, and sotorasib has shown a promising activity recently. They target KRASG12C and inhibit it irreversibly. 76 Adagrasib monotherapy, in combination with cetuximab, was found to be potent. Currently, a combination of adagrasib and cetuximab and another one of sotorasib and panitumumab are being evaluated for phase III trials. 148 A combination of MEK inhibitors with an anti-PD-L1 has synergized tumor regression. 149 A combination of atezolizumab and cobimetinib (MEK inhibitor) is being studied in phase Ib trials ( {"type":"clinical-trial","attrs":{"text":"NCT03785249","term_id":"NCT03785249"}} NCT03785249 ). 150 In a phase II study, the addition of atezolizumab to FOLFOXIRI, bevacizumab, and fluorouracil regime showed significant results. 151 Immunotherapy has also been tried in RAS-mutated patients. Tumor-infiltrating lymphocyte (TIL) therapy showed good activity in KRASG12D mutation. 129

BRAF Mutation Targeted Therapy

For the initial management of BRAFV600E mutations, FOLFOXIRI has been used with bevacizumab. 152 , 153 Antiangiogenic agents such as ramucirumab and aflibercept, combined with FOLFIRI, showed a potent activity in second-line BRAFV600E mutation studies. 154 , 155 BRAFV600E inhibitors have been recently used in the treatment process. They show less activity when used alone, as seen in a study involving vemurafenib, a BRAFV600E inhibitor. 156 The inhibitors are now combined with other agents such as anti-EGFR and MEK inhibitors. 157 – 160 There is a lot of interest in the FDA-approved BRAFV600E inhibitor encorafenib. A study showed that encorafenib with anti-EGFR inhibitor, cetuximab, and MEK inhibitor binimetinib (triplet therapy) and another combination of encorafenib and cetuximab (doublet therapy) showed greater effects than the standard therapy of FOLFIRI. 161 , 162 Non-BRAFV600E mutations have shown to respond to anti-EGFR treatments. 162 – 166

Microsatellite Instability Targeted Therapy and Immunotherapy

About 16% of stage 2 and 3 colon cancer cases have MSI. Fluoropyrimidines have been used in MSI colon cancers. However, it does not show satisfactory results in MSI stage 2 cases; a study even found it detrimental to overall survival. 167 – 169 So, it is not currently used for MSI stage 2 patients. When compared to stable microsatellite tumors, fluoropyrimidines and oxaliplatin show excellent results for disease-free survival (DFS) and overall survival (OS) in stage 3 patients (MSS). 170 Some studies found irinotecan to be sensitive to MSI cancer. 171 However, there seem to be other studies with conflicting results. 172 Bevacizumab has been studied recently in combination with traditional treatments.

Immunotherapy is recently gaining interest, especially in studies related to high levels of microsatellite instability (MSI-H)/deficient mismatch repair (dMMR). Immune checkpoint inhibitor (ICI) class of molecules like anti-PD-1, anti-PD-L1, and anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) are used in immunotherapy. 173 Anti-PD-L1 agent, atezolizumab, is currently being studied with FOLFOX in stage 3 MSI colon cancer. 174 Another anti-PD-L1 agent, avelumab, has also been assessed in another study on stage 3 cancer. 175 Nivolumab, an anti-PD-1 immunoglobulin G4 (IgG4) antibody, in combination with ipilimumab, an anti-CTLA-4 IgG1 monoclonal antibody, showed a promising activity in a phase II study. 176 In a phase III study, pembrolizumab, another anti-PD-1 IgG4 antibody, showed longer progressive-free survival (PFS) than chemotherapy in first-line treatment. 141

NTRK Gene Fusion Targeted Therapy

The neurotrophic tyrosine receptor kinase (NTRK) genes are cancer driver genes encoding dysfunctional tropomyosin receptor kinase (TRK) proteins in NTRK fusion tumor types more prevalent in microsatellite instability (MSI-H)/mismatch repair deficient (dMMR) and metastatic patients with RAS/BRAF wild-type in frequencies from 5% to 15%, respectively. A subset of adult and pediatric patients with various gastrointestinal cancers having targetable TRK mutations were administered larotrectinib (Vitrakvi) in the NAVIGATE basket trial ( {"type":"clinical-trial","attrs":{"text":"NCT02576431","term_id":"NCT02576431"}} NCT02576431 ). Currently, the FDA-approved larotrectinib and entrectinib are recommended treatment options for NTRK fusions. At the same time, the assessed long-term comparative efficacy favored larotrectinib with substantial life expectancy for colorectal cancer patients. 177

Phytochemical-Based Targeted Therapy

Phytochemicals have always provided significant resources for cancer therapy. Vinca alkaloids inhibiting microtubules and camptothecin inhibiting the DNA topoisomerase I are well-established natural plant products showing therapeutic potential. 178 A survey conducted in the USA through the National Cancer Institute found that approximately 69% of the drugs used in cancer between 1980 and 2002 were derived from natural products or devised accordingly based on natural products. 179

Curcumin has been widely studied for different cancer treatments. Curcumin was found to inhibit cell growth in HCT-116 and HT29 colon cancer cell lines. 180 , 181 It interacts with many targets and thus influences key signaling pathways related to colon cancer, such as receptor tyrosine kinase (RTK) signaling, Wnt signaling pathway, Notch signaling, and p53 pathway. Resveratrol, a natural phenol derived from grapes, raspberries, and mulberries, is another phytochemical with anti-colon cancer potential. It has shown a significant activity against breast cancer. 182 It has demonstrated inhibiting and antigenotoxic effects in SW480 and HL60 colorectal cell lines, respectively. 183 , 184 It functions similarly to curcumin and influences several signaling pathways, including the RTK, notch, and Wnt signaling. Luteolin, a flavone produced from Reseda luteola L., may be utilized in targeted therapy to prevent colon cancer. 185 It aids in the anti-angiogenesis of tumor cells by preventing VEGF from attaching to its receptor. It also inhibits GSK-3B and thus influences the Wnt signaling pathway. Quercetin is another phytochemical that affects the Wnt signaling pathways and T-cell signaling receptor pathways and is a potential targeted therapy drug. Gallic acid and apigenin are EGFR inhibitors and HER2 inhibitors, respectively. Gallic acid also modulates the T-cell signaling receptor pathway. Integration of phytochemicals in targeted therapy could potentially overcome the problems of drug resistance. Various phytochemicals and their interaction with the pathways in colon cancer are depicted in Figure 4 .

Phytochemical-based targeted therapy in colon cancer.

Personalized Medicine in Global Healthcare Systems

Personalized medicine has the potential to revolutionize colon cancer therapy. While personalized medicine has great promise to improve the standard of healthcare systems and the treatment of diseases, its effect on a global level must be considered. Personalized medicine is very active in the healthcare systems in the UK, US, and European countries. Contrary to it, the scenario is very different in middle and low-income countries of Africa and South Asia. Even though many of these countries have started to adopt the use of personalized medicine, they face monumental difficulties in their development, and transition into healthcare systems.

One of the major challenges with the implementation of personalized medicine is the high cost of the treatments. New cancer drugs are costly. For example, the average price of colon cancer drugs such as nivolumab and ipilimumab in the US exceeds 0.1 million USD per patient yearly. 186 The personalized treatment regime's expenses are even comparatively higher than that of conventional treatments. For instance, a three-week chemotherapy cycle for the treatment of metastatic colon cancer costs about 5.6K USD when bevacizumab alone is used. 187 In developed countries, where the per capita income is considerably higher, the cost of treatments from the personalized treatment of colon cancer is feasible. However, patients in middle and low-income nations struggle mightily to cover the costs of personalized medicine, and the majority are left with little choice but to rely on traditional treatments. A possible solution can be to identify and develop similar drugs with identical therapeutic efficacy at a substantially cheaper cost.

The development of personalized medicine requires technologies such as sophisticated imaging modalities, high genome sequencing, proteome, transcriptome, and others which are very expensive. For example, a positron emission tomography (PET) scan, which can help reveal bodily biochemical functions, for a single patient can cost around a thousand USD. 188 Even the companion diagnostic kits available currently for identifying specific biomarkers are comparatively costlier than tests in other treatment regimes. The development of good network models of health insurance and government-based finances available to patients can significantly encourage the use of personalized medicine.

A fundamental aspect of the development of personalized medicine is the support from the government. The UK's National Health Service (NHS) is well supported and endorsed by the government for adopting personalized medication. 189 In the UK, a budget of around 0.2 million euros is allocated annually for developing policies on genomics in healthcare. 190 Substantial funding is provided by the governments in the UK, the USA, and Canada for research in personalized medicine. 190 – 192 Similarly in Australia, the governance at the state and national levels has a good framework for promoting the integration and implementation of genomics in the healthcare system. 193 In low- and middle-income countries, the research on personalized medicine is mainly based at the institutional level, with funding from the government, the university, or foreign collaborators. Currently, insufficient funding is a significant issue in developing and sustaining personalized medicine. Only a handful source of large-scale funded research projects and initiatives remain, such as the Agency for Science, Technology and Research (A*STAR) in Singapore and TCELS, a Thai Ministry of Science and Technology organization in Thailand. 194 Low- and middle-income countries need to adopt models for healthcare systems like that of the developed nations. Along with granting adequate funding for research in personalized medicine, specific committees need to be assigned from the grass root level to the highest national levels to implement and monitor the development of personalized medicine in the respective countries. In the healthcare systems, professionals must be trained well to meet the demands of personalized medicine. There is a great need to create awareness in public and patients regarding the benefits and uses of personalized medicine through campaigns and digital media. Though the development of personalized medicine is comparatively slower in low- and middle-income countries, great efforts could see the gap between them, and the developed countries decrease in the coming years.

Advantages and Limitations of Personalized Medicine

One main advantage of personalized medicine is it can help decide which drug can have the best effect on a particular individual. Conventional therapies are prescribed for a large group of patients. So, the treatment may not be very effective for all patients. Depending upon the genetic makeup of a particular individual, personalized medicines are prescribed. So, the chances of the drug being effective are very high compared to traditional medicine.

Cancer drugs tend to be toxic and cause side effects. In personalized therapy, tailored medications are prescribed depending upon the genetic constituents. Since specific mutations are identified, only a few specific drugs are administered. So, unnecessary drugs with potential side effects can be avoided. Also, the cost of the treatment can be less to a certain extent as only particular drugs are required.

Personalized medicine can be used in combination with traditional therapies. It can help improve the choices in treatments and help implement optimized strategies in healthcare systems, including behavior, lifestyle, and surgical changes.

The development of genetic mapping has allowed us to finally comprehend the impact that genes have on a person's health, which further expands our understanding of how to treat chronic illnesses like cancer or diabetes. But the key idea behind this approach is that patients should receive care tailored to their individual needs and the common understanding of their symptoms and conditions. The effectiveness of personalized medicine for the prevention of chronic diseases may necessitate a population-based strategy, notwithstanding the inherent tension between individual health measures that benefit the population and personalized medicine for the benefit of the public. 195

Decisions in personalized medicine are based on the patient's unique circumstances, which may impact their health. Today, patients are responsible for making treatment decisions because doctors do not always know the results of a particular treatment or how it will affect a specific person. With the accuracy of personalized medicine, healthcare professionals can provide each patient with a unique treatment plan, increasing the likelihood that they will recover.

Genetic mapping-based targeted treatment can help save healthcare costs by enabling more intelligent treatment choices that are more likely to succeed. In addition, with a focus on preventive care rather than the treatment of disease, the cost is predicted to be potentially lower.

Finding the general causes of diseases and developing effective treatments can benefit from studying the genetic patterns of a population both as a whole and in portions. Predicting the risk of diseases and their early identification will be much easier with the help of genetic research on certain populations.

The benefits listed above make it appear like an appealing investment to use personalized medication. These areas have already been recognized and are planned to be covered by other concepts and programs. Still, the impact that personalized medicine could have on healthcare is significant and far-reaching.

For personalized medicine to function at its highest level, a sizable and diversified set of genomic data must be gathered. Legal ownership of the data is allegedly ambiguous when such a vast volume of data is compiled. The FDA has prohibited people from obtaining their own genetic information from businesses, and the government does not assume responsibility for the data. Additionally, privacy concerns may arise from the storing and collecting of such massive volumes of data. Therefore, there would be a lot of opposition to the implementation of such a proposal.

Personalized medicine has the potential to have a significant influence on healthcare, but it will take time to implement and will require substantial infrastructure investments. Fundamental modifications are required in the infrastructure and methods of data collecting, exchange, and storage to achieve customized treatment. It is unknown who will be responsible for paying the remaining balance of the budget, such as the state or federal government, patients, or providers. The federal cash set aside for the development of customized medicine will not be sufficient to satisfy the demand.

In general, precision medicine can reduce the flow of money from the healthcare system by removing frequent errors and readmissions and helping to take certain preventive steps against the disease. However, it necessitates a large infrastructure investment for the gathering, archiving, and distribution of this data. Investments in security infrastructure are necessary to safeguard the data and other costs that are becoming burdensome.

Personalized treatment is continuously changing the way we think about medicine. It offers numerous opportunities to improve prevention, prediction, and post-care benefitting the patients. With evidence-based action, sound scientific knowledge, and appropriate priority-setting in basic education, it will be possible to take as many opportunities as possible while avoiding unwelcome developments.

Future Perspectives and Conclusion

In the past few years, there has been a significant change in how colon cancer is treated. The disease's variability has caused the treatment to change to a more individualized strategy. Identifying the simple status of KRAS, BRAF, and other mutations and their specific biomarker therapies have massively improved the overall survival of patients. The development of cetuximab and bevacizumab in 2004 made colon cancer-targeted therapy possible. Targeted therapies’ precision has produced positive outcomes and reduced treatment costs by preventing the necessity for some operations. A different class of drugs depending on specific genetic variations is being investigated. Immunotherapy is one such branch that is being explored which has an excellent potential. Treatment with drugs such as ipilimumab, pembrolizumab, and nivolumab has produced good results in colon cancer therapy.

There are currently very few practical instances of individualized therapy. To successfully adopt personalized medications, infrastructure, and technology to molecular assay analytes and collaboration between all stakeholders is needed. To improve the genotype-phenotype relationship and advance personalized treatment, it is critical to discover essential proteins, gene variations, and various expression patterns linked to the disease or disease propensity. The development of personalized medicine is expected to have positive effects on the therapeutic and diagnostic sectors. Personalized pharmaceuticals are expected to have a positive impact on many consumer-focused sectors in addition to the services and core products. Personalized medicine has a lot to offer for enhancing and advancing cancer treatment for today and tomorrow as the field slowly but steadily develops.

Accessing patient samples, creating trustworthy testing models, and the inherent genetic and non-genetic diversity present in ever-evolving cancer provide many difficulties for developing precision medicine solutions for cancer.

Though there is a sound level of optimism, the reality is there are very few studies available as evidence. Despite the advantages of personalized medicine, the options for oncologists and doctors for individualized therapies are minimal. Extensive research in biomarker discovery is ongoing, yet their translation to therapeutics has not been excellent. The existing identified biomarkers need to be exploited well. New molecular methods need to be devised for biomarker discovery, and the existing ones need to be reviewed and optimized. In terms of technology, a lot of technical improvement needs to be made to upgrade the accuracy and precision of data obtained from the human tissues. Developing more specific assays and incorporating them in clinical trials for validation is also a great challenge for personalized medicine. However, there is a greater hope that these studies can be translated into life-saving therapies in the near future.

Acknowledgments

The authors are thankful to the Chettinad Academy of Research and Education (CARE) for providing the infrastructural and to DST-SERB for providing financial support to complete this piece of work. The authors declare that they have no conflict of interest.

Abbreviation

Author Contributions: Conceptualization: S.P., A.B., H.Z., and X.F.S. Writing—original draft preparation: AM , A.D., A.B., A.S.H., and S.P. Writing—review and editing: S.P., A.B., A.S.H., H.Z., and X.F.S. Supervision: S.P., X.F.S., A.B., and H.Z. All authors have read and agreed to the published version of the manuscript.

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Science and Engineering Research Board (grant number EMR/2017/001877).

ORCID iD: Antara Banerjee https://orcid.org/0000-0002-5519-6878