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Principal Investigator: Bulent Ozpolat
Organization: METHODIST HOSPITAL RESEARCH INSTITUTE
Fiscal Year: 2024
Award: $378,124
Funding agency: National Cancer Institute
Project Summary
Triple-negative breast cancer (TNBC) has the highest patient death rate of all breast cancer subtypes. Several
molecular targets have been identified for breast cancer treatment, but currently, there is no approved,
broadly applicable targeted therapy for TNBC. Through 10 years of research, we found that elongation factor
2-kinase (EF2K) expression is a critical driver of TNBC tumorigenesis and progression. We also found that
microRNA-22 (miR-22) expression is broadly repressed in TNBC patients, and is inversely correlated with EF2K
expression. Further analysis revealed that miR-22 suppresses tumors by specifically binding to EF2K, which
inhibits EF2K expression and reduces tumor growth in multiple TNBC models. Considering the clinical
significance and potential therapeutic value of EF2K in TNBC, we have thus developed an AXL receptor-targeted
AXL aptamer-coated SLNP-miR-22 nanoparticle system that can specifically deliver miR-22 to TNBC tumors in
vivo (but does not lead to miR-22 accumulation in normal tissues).
On the basis of this preliminary work, we hypothesize that EF2K is an effective therapeutic target in TNBC, and
that targeting EF2K using our AXL-aptamer-SLNP-miR-22 nanotherapeutics can provide significant therapeutic
efficacy in TNBC treatment. However, understandably, this therapeutic system is complex, and it has been
difficult to further understand the underlying biological and physical processes that significantly impact
treatment outcome, and to identify the optimal doses and dosing schedules for maximizing treatment
efficacy. Therefore, in this project, we propose to overcome this challenge by integrating biological experiments
with mathematical modeling based on the underlying biological and physical mechanisms that are involved in
cancer invasion, drug penetration, and drug-cancer cell interactions in the EF2K-targeted miR-22
nanotherapeutics for TNBC treatment. Our hypothesis will be tested by achieving the following two specific aims:
1) experimental testing of the EF2K-targeted miR-22 nanotherapy (Aim 1), and 2) mathematical modeling (Aim
2). In Aim 1, we will focus on characterizing and determining the in vivo therapeutic efficacy of EF2K-targeted
miR-22 mediated therapies in orthotopic mouse models. In Aim 2, we will focus on developing, testing, and
validating a mathematical model of EF2K-targeted, miR-22 based nanotherapy, using a logically integrated
statistical and multiscale mechanistic modeling approach. Experimental data from Aim 1 will be supplied to Aim
2 for developing and validating the mathematical model, and experiments in Aim 1 will be guided by discoveries
obtained from computational investigations in Aim 2. Through this iteration-based feedback approach, the
mathematical model will be used to predict and determine the effects of various parameters, including siRNA
dose and dosing schedules, on tumor response to EF2K-targeted miR-22 mediated therapies (with or without
chemotherapy), and to determine the optimal drug doses and dosing schedules for optimizing therapeutic
efficacy. The long-term goal of this project is to demonstrate that this miR-22-based nanotherapy is safe and
effective, both alone and in combination with standard chemotherapeutic agents as a co-adjuvant therapy, and
to complete preclinical development for potential future clinical translation for TNBC patients.
Terms: <14-Hydroxydaunomycin><AXL Protein><Accounting><Acute><Adriamycine><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Binding><Biological><Biological Function><Biological Markers><Biological Process><Biology><Breast Cancer><Breast Cancer Cell><Breast Cancer Model><Breast Cancer Patient><Breast Cancer Treatment><Breast Tumor Patient><Breast tumor model><CAM kinase III><Cam PK III><Cancer Drug><Cancer Treatment><Cancers><Cell Body><Cell Communication><Cell Interaction><Cell Line><Cell-to-Cell Interaction><CellLine><Cells><Chronic><Clinical><Complex><Coupling><Data><Data Bases><Databases><Death Rate><Diffusion><Dose><Doxorubicin><Doxorubicina><Drug Transport><Drug resistance><Drugs><E-2 kinase><EF-2 kinase><Feedback><Fostering><Future><Goals><Health><Hydroxyl Daunorubicin><Hydroxyldaunorubicin><Immune><Immunes><In Vitro><Invaded><Investigation><Malignant Breast Neoplasm><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Math Models><Maximal Tolerated Dose><Maximally Tolerated Dose><Maximum Tolerated Dose><Mediating><Medication><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methodology><Micro RNA><MicroRNAs><Mission><Modeling><Molecular Interaction><Molecular Target><NIH><National Institutes of Health><Neoplasm Metastasis><Neoplastic Disease Chemotherapeutic Agents><Normal Tissue><Normal tissue morphology><Oncogenesis><Organ><PK/PD><Pancreas Cancer><Pancreatic Cancer><Patients><Penetration><Pharmaceutical Preparations><Physical Phenomena or Properties><Physics><Pre-Clinical Model><Preclinical Models><Process><Prognosis><Receptor Protein><Relapse><Repression><Research><Safety><Schedule><Secondary Neoplasm><Secondary Tumor><Short interfering RNA><Small Interfering RNA><Strains Cell Lines><System><T-Stage><TCGA><TNBC><Testing><The Cancer Genome Atlas><Therapeutic><Time><Toxic effect><Toxicities><Treatment Efficacy><Treatment outcome><Tumor stage><Tumor-Specific Treatment Agents><Tyrosine-Protein Kinase Receptor UFO><UFO oncogene protein><United States National Institutes of Health><Work><anti-cancer drug><anti-cancer therapy><appropriate dose><aptamer><axl receptor tyrosine kinase><bio-markers><biologic><biologic marker><biomarker><breast tumor cell><calmodulin-dependent protein kinase III><cancer metastasis><cancer microenvironment><cancer sub-types><cancer subtypes><cancer therapy><cancer-directed therapy><chemotherapeutic agent><chemotherapy><clinical practice><clinical significance><clinical translation><clinically significant><clinically translatable><computer based prediction><cultured cell line><data base><diffused><diffuses><diffusing><diffusions><dosage><drug resistant><drug/agent><eEF-2-specific Ca and calmodulin-dependent protein kinase III><elongation factor 2 kinase><experiment><experimental research><experimental study><experiments><guided discovery><guided inquiry><improved><in vivo><innovate><innovation><innovative><intervention efficacy><lipid based nanoparticle><lipid nanoparticle><malignancy><malignant breast tumor><mammary cancer model><mammary tumor model><mathematic model><mathematical model><mathematical modeling><miR therapy><miR-based therapeutic><miR-based therapy><miRNA><miRNA delivery><miRNA therapy><miRNA-based therapeutic><miRNA-based therapy><miRNAs><microRNA delivery><microRNA therapy><microRNA-based therapeutic><microRNA-based therapy><model development><model developments><mortality rate><mortality ratio><mouse model><murine model><nano particle><nano particle delivery><nano therapy><nano-sized particle><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><nanotherapeutic><nanotherapy><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><optimal drug dosage><optimal drug dose><pancreatic malignancy><pharmacokinetics and pharmacodynamics><pharmacologic><physical process><pre-clinical development><preclinical development><predictive modeling><protein kinase CPK3><receptor><resistance to Drug><resistant to Drug><response><siRNA><site targeted delivery><targeted delivery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapeutic miRNA><therapeutic miRs><therapeutic microRNA><therapeutic target><therapeutically effective><therapy efficacy><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor cell metastasis><tumor growth><tumor microenvironment><tumorigenesis><ufo receptor>