Document text
Principal Investigator: Daniel V. LaBarbera
Organization: UNIVERSITY OF COLORADO DENVER
Fiscal Year: 2024
Award: $400,544
Funding agency: National Cancer Institute
Colorectal cancer (CRC) is the third most prevalent type of cancer diagnosed each year and CRC patients have
the second highest mortality rate, worldwide. Standard of care treatments for CRC is largely ineffective against
metastatic CRC (mCRC), which has an 11% 5-year overall survival rate. Aberrant T-Cell Factor (TCF)
transcription is a major driver of tumor progression to mCRC. Therapeutic development directly targeting the
inhibition of TCF-transcription of genes associated with mCRC may be an effective therapeutic strategy for
mCRC, and currently no such therapies are clinically approved. Using a cohort of ~600 CRC patient tumor
samples (GEOdataset (GSE40967) and CU AMC GI tissue bank), we have identified an oncogene, known as
CHD1L, to be linked as a driver of mCRC and patient poor prognosis. We have characterized CHD1L to be a
required component of TCF-transcription during malignant gene expression. We hypothesize that CHD1L is a
molecular target that functions as a DNA binding factor for the TCF-transcription complex, and CHD1L is
specifically recruited to activate mesenchymal genes and other genes associated with mCRC. Currently there
are no known inhibitors of CHD1L. Thus, we conducted HTS drug discovery targeting recombinant CHD1L
ATPase to identify the first-in-class inhibitors of CHD1L. In Aim 1 we will validate these CHD1L inhibitors as
lead drugs using a hit-to-lead schema in sequence. In Aim 2 we will conduct drug design and medicinal chemistry
based on a validated lead CHD1L inhibitor pharmacophore. In Aim 3 we will prioritize 15 lead CHD1L inhibitors
for in vivo pharmacology, including pharmacokinetics, pharmacodynamics, and efficacy in patient derived
xenografts. This research will lead to a diversity of novel CHD1L inhibitors that can be developed as molecular
probes or potential therapeutics that would be expected to impact our understanding and treatment of mCRC.
Terms: <3-D><3-Dimensional><3D><ATP phosphohydrolase><ATPase><Adenosine Triphosphatase><Assay><Athymic Mice><Athymic Nude Mouse><Basal Transcription Factor><Basal transcription factor genes><Bioassay><Biochemical><Biological Assay><Blood Plasma><Breast><CHD1><CHD1 gene><Cancer Genes><Cancer Model><Cancer-Promoting Gene><CancerModel><Cancers><Cell Body><Cell model><Cells><Cellular model><Chemicals><Chromodomain Helicase DNA-Binding Protein 1><Clinical><Colorectal Cancer><Complex><Coupled><DNA Binding><DNA Binding Interaction><DNA bound><Data><Death Rate><Development><Diversity Library><Dose><Drug Design><Drug Kinetics><Drug Targeting><Drug Therapy><Drug resistance><Drug usage><Drugs><Epithelium><GI cancers><GI malignancies><GI tract cancers><Gastrointestinal Cancer><Gastrointestinal Tract Cancer><Gene Expression><General Transcription Factor Gene><General Transcription Factors><Genes><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioma><Goals><HCT 116 Cells><HCT- 116><HCT-116><HCT116><HCT116 Cells><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Heterograft><Heterologous Transplantation><High Throughput Assay><Human><IVIS SpectrumCT><IVIS imaging><IVIS optical imaging><IVIS spectral imaging><IVIS spectrum><IVIS system><In Vitro><Invaded><Knowledge><LEF Transcription Factor><Lead><Ligands><Link><Literature><Liver Cells><Lymphoid Enhancer Factor><Lytotoxicity><Malignant><Malignant - descriptor><Malignant Gastrointestinal Neoplasm><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of gastrointestinal tract><Malignant neoplasm of lung><Maximal Tolerated Dose><Maximally Tolerated Dose><Maximum Tolerated Dose><Measures><Medication><Medicinal Chemistry><Mesenchymal><Methodology><Microsomes><Modeling><Modern Man><Molecular Probes><Molecular Target><Neuroglial Neoplasm><Neuroglial Tumor><Nude Mice><Oncogenes><Oncogenic><Organoids><Outcome><PDX model><Pathology><Patient derived xenograft><Patients><Pb element><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Pharmaceutical Preparations><Pharmacodynamics><Pharmacokinetics><Pharmacological Study><Pharmacology><Pharmacology Study><Pharmacotherapy><Phase><Plasma><Plasma Serum><Prognosis><Property><Pulmonary Cancer><Pulmonary malignant Neoplasm><Recombinants><Reporter><Reporting><Research><Reticuloendothelial System, Serum, Plasma><Role><SW-620><SW620><Safety><Sampling><Solid><Solid Neoplasm><Solid Tumor><Solubility><Stem Cell like><Survival Rate><T Cell Factor><TCF Transcription Factor><Testing><Therapeutic><Tissue Banks><Tissue Collection><Tissue repository><Toxic effect><Toxicities><Transcription Factor Proto-Oncogene><Transcription factor genes><Transfection><Transforming Genes><Tumor Cell><Validation><Work><Xenograft><Xenograft procedure><Xenotransplantation><analog><anti-tumor agent><cancer diagnosis><cancer progression><cancer type><cell transduction><cellular transduction><clinical practice><cohort><colon cancer patients><colorectal cancer patients><colorectal cancer therapy><colorectal cancer treatment><cytotoxicity><design><designing><determine efficacy><developmental><driving force><drug discovery><drug resistant><drug treatment><drug use><drug/agent><effective therapy><effective treatment><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><gastrointestinal><gastrointestinal malignancies><glial-derived tumor><heavy metal Pb><heavy metal lead><high throughput screening><high-throughput drug screening><in vivo><in vivo Model><in vivo imaging system><inhibitor><knock-down><knockdown><lipophilicity><lung cancer><malignancy><metastatic colo-rectal><metastatic colo-rectal cancer><metastatic colo-rectal carcinoma><metastatic colon cancer><metastatic colorectal><metastatic colorectal cancer><metastatic colorectal carcinoma><meter><mortality rate><mortality ratio><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><neuroglia neoplasm><neuroglia tumor><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><overexpress><overexpression><patient derived xenograft model><pharmacophore><recruit><resistance to Drug><resistant to Drug><response><small molecular inhibitor><small molecule><small molecule inhibitor><social role><standard of care><stem cell characteristics><stemness><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic agent development><therapeutic development><therapeutically effective><three dimensional><tool><transcription factor><transduced cells><tumor><tumor growth><tumor progression><validations><virtual><xeno-transplant><xeno-transplantation>