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Principal Investigator: GEORGE ENG
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2023
Award: $196,204
Funding agency: National Cancer Institute
Project Summary/Abstract
This proposal details a five-year training plan for the development of a research program focused on
elucidating the therapeutic potential of superimposed additional Wnt signaling on colonic neoplasia.
The molecular driver shared across the vast majority of colonic neoplasms is constitutive Wnt
signaling, most commonly caused by loss of function mutations in the APC gene. The loss of function
of APC permits beta catenin to constitutively translocate to the nucleus and induce the formation of
colonic adenomas which can further mutate into colon cancer. To date, strategies to inhibit Wnt
signaling for therapeutic purposes have failed. However, other elements of the beta catenin
destruction complex that work with APC, such as GSK3 alpha and beta can be pharmacologically
inhibited. Therefore, instead of inhibiting Wnt signaling, and informed by the concept that a “just right”
amount of Wnt signaling may be selected for in tumor cells, we hypothesized additional Wnt signaling
would be deleterious to tumor cells but would simultaneously enhance the function of normal cells.
This project will elucidate fundamental dependencies of Wnt signaling in normal tissues as well as
tumors. Ultimately, I believe this will engender a specific therapy for adenomas, to which there is no
existing medical therapy other than polypectomy, and additionally provide a broadly applicable and
potentially safe approach to treat colorectal cancer.
I am clinically trained pathologist and physician scientist seeking K08 support for mentored research.
This work will be mentored by Prof. Omer Yilmaz and Prof. Robert Langer. Prof. Yilmaz is a
pathologist and physician-scientist, and studies the effects of diet on intestinal stem cells and state-
of-the-art intestinal organoid models. Prof. Langer has fundamentally transformed and defined
biomedical engineering, is the most cited engineer in history, and most recently his expertise in
nanoparticle delivery provided the foundation for the Moderna COVID-19 vaccine. The work will be
conducted at the Massachusetts Institute of Technology and Massachusetts General Hospital, both
world class institutions of the highest caliber. I have assembled a scientific advisory committee
consisting of world class cancer biologists to help guide my scientific progress, consisting of Prof.
Tyler Jacks, Prof. Michael Yaffe, and Prof. William Kaelin. This K08 mentored research award will
ensure I have the time and resources to develop expertise in cancer biology and explore this
promising therapeutic and biologically intriguing concept of increased Wnt signaling to specifically
treat colonic neoplasia. This topic will provide ample substrate for me to grow as an independent
physician scientist.
Terms: <APC - Adenomatous Polyposis Coli><APC Protein><APC gene><APC genes><APC mutation><APC tumor suppressor><ATP-protein phosphotransferase><Adenocarcinoma><Adenomatosis Polyposis Coli Gene><Adenomatous Polyposis Coli><Adenomatous Polyposis Coli Protein><Adenomatous Polyposis Coli mutation><Advisory Committees><Affect><Agonist><Allelic Loss><Antioncogene Protein p53><Assay><Award><Beta Cadherin-Associated Protein><Beta-1 Catenin><Bioassay><Biologic Assays><Biological Assay><Biomedical Engineering><C-K-RAS><CRISPR interference><CRISPR-dCas9-mediated repression><CRISPR/dCas9 interference><CRISPR/dCas9-mediated transcriptional inhibition><CRISPRi><CUL-2><Caliber><Cancer Biology><Cancer Model><CancerModel><Cancers><Carcinoma><Cell Body><Cell Communication and Signaling><Cell Function><Cell Growth in Number><Cell Multiplication><Cell Nucleus><Cell Process><Cell Proliferation><Cell Signaling><Cell physiology><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular Proliferation><Cellular Tumor Antigen P53><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats interference><Colo-rectal Cancer><Colon><Colon Adenocarcinoma><Colon Cancer><Colon Carcinoma><Colon Neoplasms><Colon Tumor><Colonic Adenocarcinoma><Colonic Adenoma><Colonic Adenomatous Polyp><Colonic Mass><Colonic Neoplasms><Colonic Tumor><Colorectal Cancer><Complex><DP2.5><Data><Dependence><Development Plans><Diet><Dose><Elements><Engineering><Ensure><Epithelial cancer><Epithelium><Essential Genes><Exhibits><Foundations><Frequencies><GSK-3><General Hospitals><Generalized Growth><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Glycogen Synthase Kinase 3><Growth><History><Human><Institution><Intestinal><Intestines><Intracellular Communication and Signaling><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KRAS><KRAS2><KRAS2 gene><Ki-RAS><Kinase Family Gene><Knock-out><Knockout><Lesion><Location><Loss of Heterozygosity><Maintenance><Malignant Adenoma><Malignant Epithelial Neoplasms><Malignant Epithelial Tumors><Malignant Neoplasms><Malignant Tumor><Massachusetts><Medical><Mentors><Mice><Mice Mammals><Modeling><Modern Man><Moderna COVID-19 vaccine><Moderna coronavirus disease 2019 vaccine><Molecular><Murine><Mus><Mutate><Mutation><Normal Cell><Normal Tissue><Normal tissue morphology><Nucleus><Oncogene K-Ras><Oncogenic><Oncoprotein p53><Organoids><P53><PLYPCMY><PRO2286><Pathologist><Pathway interactions><Patients><Phosphoprotein P53><Phosphoprotein pp53><Physicians><Polypectomy><Pre-Clinical Model><Preclinical Models><Progenitor Cells><Protein Kinase><Protein TP53><Proteins><RASK2><RNA Seq><RNA sequencing><RNAseq><Recording of previous events><Research><Research Resources><Research Specimen><Resources><Rho-associated kinase><Rho-kinase><Scientist><Signal Transduction><Signal Transduction Systems><Signaling><Specimen><Stereotyping><Subcellular Process><TP53><TP53 gene><TRP53><Task Forces><Technology><Therapeutic><Time><Tissue Growth><Toxic effect><Toxicities><Training><Tumor Cell><Tumor Protein p53><Tumor Protein p53 Gene><WNT Signaling Pathway><WNT signaling><Wnt proteins><Work><adenoma><advisory team><beta catenin><bio-engineered><bio-engineers><bioengineering><biological engineering><biological signal transduction><bowel><cancer in the colon><clinical care><colon adenoma><colon adenomatous polyp><colon cancer therapy><colon cancer treatment><colon neoplasia><diets><epithelial carcinoma><genome mutation><glycogen synthase a kinase><gsk-3 Gene Product><histories><human model><hydroxyalkyl protein kinase><improved><in vivo><inhibitor><knock-down><knockdown><loss of function><loss of function mutation><mRNA-1273><mRNA1273><malignancy><model of human><mouse model><murine model><mutant><nano particle><nano particle delivery><nano-sized particle><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><neoplasm/cancer><neoplastic cell><novel><ontogeny><p53 Antigen><p53 Genes><p53 Tumor Suppressor><pathway><pharmacologic><phosphorylase b kinase kinase><progenitor><programs><protein p53><repressing CRISPR-dCas9 system><small molecule inhibitor><stem cells><success><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transcriptome sequencing><transcriptomic sequencing><transcriptomics><tumor><tumor growth><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog><β-catenin>