Document text
Principal Investigator: MARGIE L. CLAPPER
Organization: RESEARCH INST OF FOX CHASE CAN CTR
Fiscal Year: 2024
Award: $515,612
Funding agency: National Cancer Institute
Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. In the Unites States, an estimated 151,300 Americans will be diagnosed with CRC and over 52,580 are expected to die from the disease in 2022 alone (https://seer.cancer.gov/statfacts/html/colorect.html). While the five-year survival rate for localized CRC is excellent at 90%, more than half of new CRC cases have the disease spread to regional lymph nodes and/or distant organs at the time of diagnosis. CRC with distant metastasis has a dismal five-year survival rate of 14.7%. These data clearly indicate that CRC-related mortality can be significantly improved if the disease is detected early and proper interventions could be deployed. Because CRC typically originates from precancerous colorectal polyps, routine colonoscopy screening provides an excellent opportunity to detect precursor or early lesions and reduce CRC-related morbidity and mortality. Indeed, the US Preventive Services Task Force recently updated its recommendation on CRC screening, noting the evidence that the screening in average-risk asymptomatic adults aged 50 to 75 years is of substantial benefit. Risk factors for CRC include age (>50), race (African American), obesity, cigarette smoking, type II diabetes, history of inflammatory bowel diseases, family history of colorectal polyps or CRC, and inherited genetic syndromes known to increase the CRC risks, such as familial adenomatous polyposis (FAP) and Lynch syndrome. FAP and Lynch syndrome are caused by germline mutations in the APC gene and DNA mismatch repair genes, respectively. The management of individuals with hereditary gastrointestinal cancer syndromes requires additional measures beyond what is recommended for the average-risk population to minimize the overall risk of cancer-associated morbidity and mortality. Management options for the confirmed mutation carriers include multiple aggressive screening, chemopreventive strategies, and prophylactic surgery. However, these interventions are associated with various degrees of adverse effects. Safer and more effective preventive measures are urgently needed for the individuals with FAP, Lynch syndrome, and other hereditary gastrointestinal cancer syndromes. Fusobacteria are common human oral gram-negative anaerobic microflora isolated from dental plaque and gum diseases, but rarely detectable in the colorectum of healthy individuals. In recent years, the enrichment of a specific pathotype, Fusobacterium nucleatum (Fn), has been demonstrated in the colonic tissues and stools from patients with colorectal adenomas and CRC. Clinical evidence suggests that the prevalence of Fn progressively increases from dysplasia, adenomas to CRC and the higher amount of Fn is significantly associated with CRC with high microsatellite instability, which is caused by DNA MMR deficiencies as seen in Lynch syndrome-associated CRC. The potential association of Fn with CRC tumorigenesis has been examined in a mouse model of FAP. ApcMin/+ mice, which carry a nonsense mutation at codon 850 of the Apc gene, had a significantly accelerated onset and increased multiplicity of both small intestinal and colorectal tumors after oral inoculation of Fn. These data strongly suggested the tumor-promoting role of Fn in ApcMin/+ mice. Interestingly, Fn did not induce colitis in these animals, in contrast to enterotoxigenic Bacteroides fragilis, which has been shown to cause colitis and accelerate tumorigenesis in ApcMin/+ mice. It has also been demonstrated that Fn promotes CRC, breast, and cervical cancer metastasis and can metastasizes with tumor cells. Although how Fn contributes to CRC tumorigenesis has yet to be fully elucidated, emerging evidence points to its virulence factors, such as FadA and Fap2, as potential enhancers of CRC tumorigenesis and progression. The Fap2 has been shown to bind to human T-cell immunoglobulin ITIM domain (TIGIT), an immunoglobulin superfamily receptor known to function as an immune co-inhibitory molecule. Fap2-binding to TIGIT on NK and other T cells protects tumor cells from NK cell-mediated cytotoxicity and blocks effector T cell functions in the tumor microenvironment. TIGIT has also been shown to promote Treg function. Taken together, Fn may exert tumor promoting effects not only by promoting CRC tumor growth, but also by exploiting the immune-suppressive function of TIGIT via its virulence factor protein and contributing to tumor immune evasion mechanisms. Cancers caused by infectious agents are theoretically preventable, if one can prevent the infection, eradicate oncogenic pathogens before tumor development, or suppress the functions of oncogenic molecules. Prophylactic vaccines for human papillomavirus and hepatitis B virus have been associated with significant reductions in infection rates, which are expected to result in the dramatic decrease in the incidence of cervical cancers and hepatocellular carcinoma, respectively. Compared to the prevention of infection, the eradication of oncogenic infectious agents already colonized in the host is in general highly challenging, if not impossible. For example, the well-established eradication regimens for Helicobacter pylori, which increases the risk of noncardia gastric cancers, do not eradicate the bacteria in all cases. Rather, emerging resistance to multiple antibiotics appears to be contributing to the recent decline in the eradication rate. Alternatively, the host immune defense system may be fortified by pathogen-targeted vaccines, if they can boost anti-pathogen immunity and lead to the containment of infection or suppression of pathogen-mediated tumorigenic functions. Fn is a gram-negative anaerobic bacillus, and can be isolated from 60-70% of children aged 5-7 years. As with other gram-negative bacteria, Fn produces outer membrane vesicles (OMVs), which contain much of the biological content of the Fn, but without replicative capacity and some of the soluble proteins found in OMVs may elicit anti-Fn immunity. As part of the PREVENT project to develop Fn OMV based anti-Fn vaccine (https://reporter.nih.gov/project-details/9358850), the proteomic characterization of Fn OMV led to the identification of putative immunogenic components, some of which may be useful as anti-Fn vaccine antigens. Lipid nanoparticle (LNP)-encapsulated mRNA vaccines against COVID-19 revolutionized the implementation of mRNA-based vaccinology. In addition to modifications of mRNA such as with pseudouridine incorporation to reduce innate immune responses and mRNA purification methodologies to remove contaminants, the development of biocompatible LNPs significantly boosted the advancement of COVID and other mRNA-based vaccines. LNP-RNA vaccine platform offers several advantages over conventional protein-based vaccination, including a rapid development, refined adjustment of antigenic epitopes, easier scale-up and timely deployment. The current study aims to develop and evaluate the immunogenicity of soluble protein-based and LNP-RNA-based Fn vaccines and to determine anti-Fn activity and immunopreventive efficacy of Fn-associated CRC, using mouse models of FAP and Lynch syndrome.
Terms: <0-11 years old><2019-nCoV vaccine><21+ years old><APC - Adenomatous Polyposis Coli><APC Protein><APC gene><APC genes><APC tumor suppressor><Acceleration><Adenomatosis Polyposis Coli Gene><Adenomatous Polyposis Coli><Adenomatous Polyposis Coli Protein><Adult><Adult Human><Adult-Onset Diabetes Mellitus><Adverse effects><African American><Afro American><Afroamerican><Age><American><Animals><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Antigenic Determinants><Antigens><Antisera><ApcMin/+><ApcMin/+ mice><B fragilis><B. fragilis><Bacillus><Bacteria><Bacteroides fragilis><Binding><Binding Determinants><Biological><Body Tissues><Breast Cancer><C fusiforme><C pylori><C. fusiforme><C. pylori><COVID-19><COVID-19 vaccine><CRC screening><CV-19><Campylobacter pylori><Cancer Cause><Cancer Etiology><Cancers><Cell Function><Cell Physiology><Cell Process><Cell Protection><Cell-Mediated Cytolysis><Cell-Mediated Lympholysis><Cellular Cytotoxicity><Cellular Function><Cellular Physiology><Cellular Process><Cervical Cancer><Cervix Cancer><Chemopreventive><Chemopreventive Agent><Child><Child Youth><Children (0-21)><Clinical><Codon><Codon Nucleotides><Colitis><Colon><Colon or Rectum><Colonoscopy><Colorectal><Colorectal Adenoma><Colorectal Adenomatous Polyp><Colorectal Cancer><Colorectal Neoplasms><Colorectal Polyp><Colorectal Tumors><Containment><Coronavirus Infectious Disease 2019><Corynebacterium fusiforme><Cytoprotection><Cytotoxic cell><DNA><DP2.5><Data><Dental Plaque><Deoxyribonucleic Acid><Development><Diagnosis><Disease><Disorder><Distant><Distant Cancer><Distant Metastasis><Dysplasia><Early Diagnosis><Encapsulated><Enhancers><Epitopes><F fusiformis><F nucleatum><F nucleatus><F. fusiformis><F. nucleatum><F. nucleatus><Familial Adenomatous Polyposis Syndrome><Familial Nonpolyposis Colon Cancer><Familial Polyposis Syndrome><Family Medical History><Family Medical History Epidemiology><Family history of><Feces><Fortification><Fusiformis fusiformis><Fusiformis nucleatus><Fusobacteria><Fusobacterium><Fusobacterium nucleatum><GI cancers><GI malignancies><GI tract cancers><GPDE-phosphodiesterase><Gastric Body Cancer><Gastric Cancer><Gastric Cardia Cancer><Gastric Fundus Cancer><Gastric Pylorus Cancer><Gastrointestinal Cancer><Gastrointestinal Tract Cancer><Genetic><Germ-Line Mutation><Germline Mutation><Goals><Gram-Negative Bacteria><H pylori><H pylory><H. pylori><H. pylory><HBV><HNPCC><HPV Vaccine><Helicobacter pylori><Hepatitis B Virus><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatoma><Hereditary><Hereditary Colo-rectal Endometrial Cancer Syndrome><Hereditary Colorectal Endometrial Cancer Syndrome><Hereditary Defective Mismatch Repair Syndrome><Hereditary Mutation><Hereditary Non-Polyposis Colon Cancer><Hereditary Nonpolyposis Colo-rectal Cancer><Hereditary Nonpolyposis Colo-rectal Neoplasms><Hereditary Nonpolyposis Colon Cancer><Hereditary Nonpolyposis Colorectal Cancer><Hereditary Nonpolyposis Colorectal Neoplasms><History><Homologous Serum Hepatitis Virus><Human><Human Papilloma Virus Vaccine><Human papillomavirus Vaccine><ITIM><Immune><Immune Globulins><Immune Sera><Immunes><Immunity><Immunoglobulins><Immunoreceptor Tyrosine-Based Inhibitory Motif><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Incidence><Individual><Infection><Infection prevention><Infectious Agent><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Inherited><Innate Immune Response><Intervention><Intervention Strategies><K lymphocyte><Ketosis-Resistant Diabetes Mellitus><LS/HNPCC><Large Bowel Adenoma><Large Bowel Adenomatous Polyp><Large Bowel Tumor><Large Intestine Adenoma><Large Intestine Neoplasm><Large Intestine Tumor><Lesion><Liver Cells Carcinoma><Lymphocyte Cytotoxicity><Lymphocytotoxicity><Lynch Syndrome><MMR deficiency><Malignant Breast Neoplasm><Malignant Cervical Neoplasm><Malignant Cervical Tumor><Malignant Gastric Neoplasm><Malignant Gastric Tumor><Malignant Gastrointestinal Neoplasm><Malignant Neoplasm of the Cervix><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Cervix><Malignant Tumor of the Cervix Uteri><Malignant Uterine Cervix Neoplasm><Malignant Uterine Cervix Tumor><Malignant neoplasm of cervix uteri><Malignant neoplasm of gastrointestinal tract><Maturity-Onset Diabetes Mellitus><Measures><Mediating><Membrane><Messenger RNA><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methodology><Microsatellite Instability><Miscellaneous Antibiotic><Mismatch Repair><Mismatch Repair Deficiency><Modeling><Modern Man><Modification><Molecular Interaction><Morbidity><Morbidity - disease rate><NIDDM><NK Cells><Natural Killer Cells><Neoplasm Metastasis><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Non-Polyadenylated RNA><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nonsense Mutation><Obesity><Oncogenesis><Oncogenic><Operative Procedures><Operative Surgical Procedures><Oral><Organ><Pathogenicity Factors><Patients><Phase><Population><Post-Replication Mismatch Repair><Pre-clinical Drug Testing/Development><Preclinical Drug Development><Preclinical Drug Testing/Development><Prevalence><Prevent infection><Preventative measure><Preventative strategy><Preventative vaccine><Prevention strategy><Preventive><Preventive measure><Preventive strategy><Preventive vaccine><Primary carcinoma of the liver cells><Program Development><Prophylactic vaccine><Proteins><Proteomics><Pseudouridine><RNA><RNA Gene Products><RNA vaccine><RNA-based vaccine><Race><Races><Receptor Protein><Recommendation><Recording of previous events><Regimen><Regulatory T-Lymphocyte><Reporter><Resistance><Ribonucleic Acid><Risk><Risk Factors><Role><SARS-CoV-2 vaccine><SARS-coronavirus-2 vaccine><Secondary Neoplasm><Secondary Tumor><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe acute respiratory syndrome coronavirus 2 vaccine><Slow-Onset Diabetes Mellitus><Small Bowel Tumor><Small Intestinal Neoplasm><Small Intestine Neoplasm><Small Intestine Tumor><Sphaerophorus><Stable Diabetes Mellitus><Stomach Cancer><Subcellular Process><Surgical><Surgical Interventions><Surgical Procedure><Survival Rate><Syndrome><System><T-Cells><T-Lymphocyte><T2 DM><T2D><T2DM><Teff cell><Time><Tissues><Treg><Tumor Cell><Tumor Escape><Tumor Immune Escape><Tumor Promotion><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><U.S. Preventative Services Task Force><U.S. Preventative Task Force><U.S. Preventive Services Task Force><U.S. Preventive Task Force><US Preventative Services Task Force><US Preventative Task Force><US Preventive Health Services Task Force><US Preventive Services Task Force><US Preventive Task Force><USPSTF><United States><United States Preventative Services Task Force><United States Preventative Task Force><United States Preventive Services Task Force><United States Preventive Task Force><Update><Uterine Cervix Cancer><Vaccination><Vaccine Antigen><Vaccines><Vesicle><Virulence Factors><Wild Type Mouse><adenoma><adiposity><adult onset diabetes><adulthood><aged><ages><anti-carcinogenic><anticarcinogenic><base><bases><biocompatibility><biologic><biomaterial compatibility><cancer evasion><cancer immune escape><cancer immune evasion><cancer metastasis><cancer microenvironment><cancer risk><cell mediated cytotoxicity><chemoprevention agent><cigarette smoking><cigarette use><colorectal cancer detection><colorectal cancer early detection><colorectal cancer risk><colorectal cancer screening><colorectal neoplasia><colorectum><coronavirus disease 2019><coronavirus disease 2019 vaccine><coronavirus disease-19><coronavirus disease-19 vaccine><coronavirus infectious disease-19><corpulence><cytoprotective><design><designing><detect colorectal cancer><developmental><draining lymph node><dyscrasia><early detection><effector T cell><efficacy testing><familial adenomatous polyposis><familial polyposis><gastric malignancy><gastrointestinal malignancies><gene repair><germ-line defect><germline variant><glycerophosphodiester phosphodiesterase><glycerophosphosphoryl diester phosphodiesterase><hereditary non-polyposis colo-rectal cancer><hereditary non-polyposis colorectal cancer><histories><immune serum><immune suppression><immune suppressive activity><immune suppressive function><immunogen><immunogenic><immunogenicity><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><in vivo><infection rate><infectious organism><inflammatory disease of the intestine><inflammatory disorder of the intestine><interventional strategy><intestinal autoinflammation><ketosis resistant diabetes><kids><large bowel neoplasm><large bowel polyp><large intestine polyp><lipid based nanoparticle><lipid nanoparticle><liver carcinoma><mRNA><mRNA vaccine><mRNA-based vaccine><malignancy><malignant breast tumor><malignant stomach neoplasm><malignant stomach tumor><maturity onset diabetes><membrane structure><microbial consortia><microbial flora><microbiota><microflora><mortality><mouse model><multispecies consortia><murine model><mutation carrier><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><neoplasm/cancer><neoplastic cell><non-sense mutation><pathogen><pre-clinical drug development><pre-clinical efficacy><precancer><precancerous><preclinical efficacy><premalignant><prevent><preventing><prophylactic><racial><racial background><racial origin><rate of infection><receptor><regional lymph node><regulatory T-cells><resistant><scale up><screening><screenings><small bowel neoplasm><social role><stomach fundus cancer><stomach pylorus cancer><stool><surgery><thymus derived lymphocyte><tumor><tumor cell metastasis><tumor evasion><tumor growth><tumor immune evasion><tumor microenvironment><tumorigenesis><tumorigenic><type 2 DM><type II DM><type two diabetes><vaccine against 2019-nCov><vaccine against COVID-19><vaccine against SARS-CoV-2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine candidates against SARS-CoV-2><vaccine for novel coronavirus><vaccine platform><vaccines preventing COVID><vaccines to prevent COVID><vaccinology><wildtype mouse><youngster>