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Principal Investigator: Qingxin Mu
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2023
Award: $199,842
Funding agency: National Cancer Institute
Project Description
Triple negative breast cancer (TNBC) is the most challenging subtype to treat among all breast cancer cases
due to lack of cell surface receptors. Patients with metastatic TNBC have median overall survival of only 13.3
months with treatment. Newly approved immune checkpoint inhibitors such as PD-1 antibody only extend the
survival by 2-4 months when used with chemotherapy, and the efficacy highly relies on expression of targets
such as PD-L1 in tumors. Despite new treatment options, metastatic TNBC is predominantly treated by highly
potent chemotherapy, with combination therapy being advantageous over single agents regarding response rate
and overall survival. However, the drugs in combination chemotherapy have distinct physicochemical properties
that hinders formulation into single dosage; their distinct pharmacokinetic behavior hinders the in vivo synergism.
Furthermore, these drugs are non-specific to cancer cells and often show systemic toxicity. Our long-term goal
is to develop advanced and well-characterized drug delivery approaches to improve treatment outcomes of drugs
and drug combinations. In this project, we propose a dual-drug loaded dual-peptide ligand incorporated drug
combination nanoparticle (DCNP) approach for targeting and inhibition of metastatic TNBC. The lipid-based
DCNP leverage on effective gemcitabine and paclitaxel combination in clinic to deliver both drugs in prolonged
and synchronized manner. Through incorporation of two peptide ligands that targets TNBC cells (through ICAM-
1) and tumor vasculature (through endoglin), the DCNP could target both primary tumor and metastasis for
enhanced chemotherapy. Furthermore, both drugs are reported to upregulate PD-L1 and reduce population of
myeloid derived suppressor cells (MDSCs) in the tumor. These effects can sensitize TNBC cells for PD-1/PD-L1
therapy. The DCNPs that synchronize and co-deliver both drugs may further augment such effects thus generate
improved chemoimmuno therapeutic outcomes. The objectives of this project are to validate the concepts of
improved targeting and chemotherapy of metastatic TNBC with a dual-targeting DCNP approach and enhanced
combination therapy with immune checkpoint inhibitors. In Aim 1, we will prepare ligands-incorporated DCNPs
with high drug loading, proper size, and good stability, and test their cellular binding and efficacy, and effects on
cancer cell expression of PD-L1. In Aim 2, we will validate enhanced in vivo targeting efficiency with the dual-
ligand strategy and correlate it with expression levels of receptors and evaluate inhibition of primary tumor and
metastasis with monitoring of survival. In Aim 3, we will assess the upregulation of PD-L1 and reduction of
MDSCs by the DCNPs and carry out a pilot survival study with a chemoimmuno combination regimen. If
successful, this targeted drug combination strategy could substantially improve the treatment of metastatic TNBC.
Through tuning composition and targeting ligands, this highly translatable nanoformulation technology can be
potentially used for existing and future drug combinations to treat various metastatic cancers.
Terms: <Animal Model><Animal Models and Related Studies><Antibody-drug conjugates><Antimetabolites><Anzatax><Asotax><B7-H1><B7H1><Behavior><Binding><Biological Markers><Blood Plasma><Body Tissues><Breast Cancer><Breast Cancer Cell><Breast Cancer Model><Breast Cancer Treatment><Breast tumor model><Bristaxol><CD105><CD105 Antigen><CD105 Gene><CD274><CD54 Antigens><Cause of Death><Cell Body><Cell Surface Glycoproteins><Cell Surface Receptors><Cells><Checkpoint inhibitor><Clinic><Clinical><Combination Drug Therapy><Combined Modality Therapy><Development><Difluorodeoxycytidine><Disease><Disorder><Disseminated Malignant Neoplasm><Distant><Dose><Drug Combinations><Drug Compounding><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drug Preparation><Drug Synergism><Drug Targeting><Drugs><END Gene><ENG gene><Eligibility><Eligibility Determination><Endoglin><Endoglin Gene><Formulation><Future><Goals><Guidelines><HHT1><HHT1 Gene><Half-Life><Human><ICAM-1><Image><Immune checkpoint inhibitor><Immune mediated therapy><Immunocompetent><Immunologically Directed Therapy><Immunomodulation><Immunotherapeutic agent><Immunotherapy><In Vitro><Intercellular adhesion molecule 1><Keytruda><Life Extension><Ligands><Lipids><Lung><Lung Respiratory System><MICMET><Malignant Cell><Medication><Membrane Glycoproteins><Messenger RNA><Metastasis><Metastasis to the Lung><Metastasize><Metastatic Cancer><Metastatic Lesion><Metastatic Malignant Neoplasm><Metastatic Mass><Metastatic Neoplasm><Metastatic Neoplasm to the Lung><Metastatic Tumor><Metastatic Tumor to the Lung><Metastatic breast cancer><Mice><Mice Mammals><Micrometastasis><Micromets><Modeling><Modern Man><Molecular Interaction><Monitor><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Myeloid-derived suppressor cells><Neoplasm Metastasis><New Agents><ORW Gene><ORW1><ORW1 Gene><Outcome><PD-1 antibody><PD-1/PD-L1><PD-1/PDL1><PD-L1><PD-L1 inhibitors><PD-L1 therapy><PD-L1 treatment><PD1 antibody><PD1-PD-L1><PD1/PD-L1><PD1/PDL1><PDL-1><PDL1><PDL1 inhibitors><PDL1 therapy><PDL1 treatment><Paclitaxel><Paclitaxel (Taxol)><Patients><Peptide-based drug><Peptides><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacokinetics><Plasma><Plasma Serum><Polychemotherapy><Population><Praxel><Primary Neoplasm><Primary Tumor><Prognosis><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Property><Protocol Screening><Publishing><Receptor Protein><Regimen><Reporting><Reticuloendothelial System, Serum, Plasma><Secondary Neoplasm><Secondary Tumor><Site><Spleen><Spleen Reticuloendothelial System><Surface Glycoproteins><Survival Rate><TNBC><Taxol><Taxol A><Taxol Konzentrat><Technology><Testing><Therapeutic><Time><Tissues><Toxic effect><Toxicities><Transforming Growth Factor P Receptor III><Treatment Efficacy><Treatment outcome><Up-Regulation><Upregulation><Woman><Work><aPD-L1 therapy><aPD-L1 treatment><anti programmed cell death ligand 1 therapy><anti programmed cell death ligand 1 treatment><anti programmed cell death protein ligand 1 therapy><anti programmed cell death protein ligand 1 treatment><anti-PD-1 Ab><anti-PD-1 antibodies><anti-PD-1 monoclonal antibodies><anti-PD-L1 therapy><anti-PD-L1 treatment><anti-PD1 Ab><anti-PD1 antibodies><anti-PD1 monoclonal antibodies><anti-PDL1 therapy><anti-PDL1 treatment><anti-cancer immunotherapy><anti-programmed cell death protein 1 antibodies><anti-programmed death-1 antibody><anticancer immunotherapy><bio-markers><biologic marker><biomarker><breast tumor cell><cancer cell><cancer immunotherapy><cancer metastasis><cellular targeting><check point immunotherapy><check point inhibitor therapy><check point inhibitory therapy><check point therapy><checkpoint immunotherapy><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint therapy><chemotherapy><clinical translation><clinically translatable><combination chemotherapy><combination pharmacotherapy><combination therapy><combined drug therapy><combined modality treatment><combined treatment><dFdC><dFdCyd><developmental><dosage><drug/agent><gemcitabine><imaging><immune check point inhibitor><immune check point therapy><immune checkpoint therapy><immune competent><immune drugs><immune modulation><immune regulation><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapeutics><immune-based therapies><immune-based treatments><immuno therapy><immunologic reactivity control><immunologic therapeutics><immunomodulatory><immunoregulation><immunoregulatory><immunosuppressive myeloid cells><immunotherapeutics><immunotherapy agent><immunotherapy for cancer><immunotherapy of cancer><improved><improved outcome><in vivo><indexing><innovate><innovation><innovative><insight><intervention efficacy><lipid based nanoparticle><lipid nanoparticle><lung metastasis><mRNA><malignant breast neoplasm><malignant breast tumor><mammary cancer model><mammary tumor model><metastasize to the lung><model of animal><mortality><multi-modal therapy><multi-modal treatment><myeloid suppressor cells><myeloid-derived suppressive cells><nano formulation><nano particle><nano-sized particle><nanoformulation><nanoparticle><nanosized particle><new drug combination><new drug treatments><new drugs><new pharmacological therapeutic><new pharmacotherapy combination><new therapeutics><new therapy><next generation therapeutics><novel drug combination><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy combination><novel therapeutics><novel therapy><pembrolizumab><peptide drug><programmed cell death ligand 1><programmed cell death ligand 1 inhibitors><programmed cell death protein ligand 1><programmed cell death protein ligand 1 inhibitors><protein death-ligand 1><pulmonary><pulmonary metastasis><receptor><receptor expression><response><suppressive myeloid cells><synergism><systemic toxicity><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><taxane><therapeutic efficacy><therapeutic outcome><therapeutic peptide><therapeutic target><therapy efficacy><therapy outcome><treatment effect><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor cell metastasis><tumor growth><uptake><αPD-L1 therapy><αPD-L1 treatment>