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Principal Investigator: William H. Gmeiner
Organization: WAKE FOREST UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2023
Award: $592,748
Funding agency: National Cancer Institute
PROJECT SUMMARY
Metastatic colorectal cancer (mCRC) remains highly lethal despite decades of optimizing 5-fluorouracil (5-FU)-
based combination chemotherapy regimens that are central to treatment. The causes of treatment failure with
5-FU-based regimens include decreased metabolism to FdUMP, the primary active metabolite, and
overexpression of thymidylate synthase (TS), the molecular target of FdUMP. To improve outcomes and
overcome resistance we have developed a nanoscale FP polymer, CF10, that is comprised of FdUMP monomers
linked in a single-stranded DNA backbone that releases FdUMP in a single step. CF10 displays markedly
improved anti-tumor activity with low systemic toxicity relative to 5-FU and is a candidate for clinical translation.
We hypothesize that nanoformulation of CF10 to increase plasma retention and actively target malignant tissue
will improve anti-tumor activity and specificity. Lipid nanoparticle (LNP) formulation has proven to be a robust
delivery strategy for multiple nucleic acid drugs, and in collaboration with NanoVation Therapeutics (NTx) in Aim
1 we will test two CF10:LNP formulations designed to differentially target CF10 to liver and more broadly to target
metastatic tissue while protecting CF10 from degradation in plasma. In Aim 2, we will investigate PEGylation of
CF10 together with active targeting to tumor tissue through conjugation with a cyclic RGD peptide that targets
integrin V3 expressed specifically in malignant tissue. We will test our novel nanomaterials for improved anti-
metastatic activity using: (i) a novel genetically engineered mouse model, iKAP, that forms tumors specifically in
the colon with metastatic progression to the liver and lung; and (ii) a rat model of established colorectal liver
metastases (CRLMs). Pharmacokinetic profiling (PK) will be evaluated using LC/MS/MS. In Aim 3, we will
develop a 3rd generation FP polymer that includes 5-ethynyl-2’-deoxyuridine (EdU), a thymidine analog that is
cytotoxic through complementary mechanisms to FdU. We will use the optimal LNP formulation and PEGylation
strategies determined for CF10 in Aims 1 and 2 to develop a highly novel nanomaterial with exceptional potential
for improved treatment of mCRC.
Terms: <5-FU><5-Fluracil><5FU><Adjuvant><Arg-Gly-Asp><Arginine-Glycine-Aspartic Acid Cell Adhesion Domain><Bile><Bile Juice><Bile fluid><Biodistribution><Blood Plasma><Body Tissues><Cancer Model><CancerModel><Chemistry><Chemotherapy Protocol><Chemotherapy Regimen><Chemotherapy-Oncologic Procedure><Collaborations><Colo-rectal Cancer><Colon><Colon Cancer><Colon Carcinoma><Colon or Rectum><Colorectal><Colorectal Cancer><Combination Chemotherapy Regimen><Combination Drug Therapy><Common Rat Strains><Cyclicity><DNA><Deoxyribonucleic Acid><Deoxyuridine><Dose><Drug Kinetics><Drugs><Extrahepatic><Fluoro Uracil><Fluorouracil><Fluoruracil><Fluouracil><Formulation><GEM model><GEMM model><Generations><Genetically Engineered Mouse><Goals><Half-Life><Hepatic><Hepatic Neoplasm Secondary><Hepatic metastasis><Immune response><Immunological response><In Vitro><Injections><Integrins><Integrins Extracellular Matrix><Intermediary Metabolism><LC/MS><Link><Liver><Liver secondaries><Liver secondary cancer><Lung><Lung Respiratory System><Lytotoxicity><Macrogols><Malignant><Malignant - descriptor><Malignant Cell><Medication><Metabolic Processes><Metabolism><Metastatic Neoplasm to the Liver><Metastatic Tumor to the Liver><Metastatic malignant neoplasm to liver><Methodology><Methods><Mice><Mice Mammals><Modeling><Molecular Target><Murine><Mus><Nanodelivery><Nucleic Acids><Peptides><Periodicity><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacokinetics><Phase><Plasma><Plasma Enhancement><Plasma Serum><Polychemotherapy><Polyethylene Glycols><Polyethylene Oxide><Polyethyleneoxide><Polymers><Polyoxyethylenes><Prevention><Property><Pyrimidine Metabolism Pathway><Quimioterapia><RGD (sequence)><RGD Cell Adhesion Domain><RGD Domain><RGD Motif><RGD Tripeptide Sequence><RGD peptide><RGD tripeptide><Rat><Rats Mammals><Rattus><Recurrence><Recurrent><Recurrent disease><Regimen><Relapse><Relapsed Disease><Resistance><Reticuloendothelial System, Serum, Plasma><Rhythmicity><Ribonucleoside Phosphates><Ribonucleotides><Risk><Risk Reduction><Single-Stranded DNA><Specificity><Spinal Column><Spine><System><TMP synthetase><Testing><Therapeutic><Thymidin><Thymidine><Thymidylate Synthase><Thymidylate Synthetase><Time><Tissues><Toxic effect><Toxicities><Toxicity Testing><Toxicity Tests><Toxicology><Treatment Failure><Tumor Tissue><Vertebral column><analog><anti-cancer activity><anticancer activity><arginyl-glycyl-aspartic acid><backbone><cancer cell><cancer chemotherapy><cancer in the colon><clinical candidate><clinical development><clinical translation><clinically translatable><colo-rectal><colo-rectal cancer patients><colon cancer patients><colorectal cancer patients><colorectum><combination chemotherapy><combination pharmacotherapy><combined drug therapy><copolymer><cytotoxic><cytotoxicity><dTMP Synthase><design><designing><drug/agent><fluoropyrimidine><genetically engineered mouse model><genetically engineered murine model><hepatic body system><hepatic organ system><host response><immune system response><immunoresponse><improved><improved outcome><in vivo evaluation><in vivo testing><lipid based nanoparticle><lipid nanoparticle><liquid chromatography mass spectrometry><liver metastases><malignant liver neoplasm, specified as secondary><metastasis in the liver><metastasis to the liver><metastasize to the liver><metastatic cancer to liver><metastatic colo-rectal><metastatic colo-rectal cancer><metastatic colo-rectal carcinoma><metastatic colon cancer><metastatic colorectal><metastatic colorectal cancer><metastatic colorectal carcinoma><metastatic liver><metastatic liver neoplasm><monomer><mouse model><murine model><nano formulation><nano materials><nano meter scale><nano meter sized><nano polymer><nano scale><nanoformulation><nanomaterials><nanometer scale><nanometer sized><nanopolymer><nanoscale><new approaches><novel><novel approaches><novel strategies><novel strategy><nucleotide analog><overexpress><overexpression><pharmacologic><polymer><polymeric><potency testing><pre-clinical><pre-clinical study><preclinical><preclinical study><pulmonary><pyrimidine metabolism><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><resistant><risk-reducing><scaffold><scaffolding><secondary liver malignancy><secondary malignant liver neoplasm><ssDNA><standard of care><systemic toxicity><therapy failure><tumor><tumor specificity>