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.