Precision Genetic RNAi Medicines to Treat Metastatic Triple-Negative Breast Cancer (TNBC)

点击翻译按钮获取中文摘要

ABSTRACT Metastatic Triple-Negative Breast Cancer (TNBC) is the most aggressive and devastating form of breast cancer, predominantly affecting younger women and women of color. Unfortunately, standard of care chemotherapeutic and surgery have done little to impact TNBC patient survival. TNBC has a dismal 40% survival rate at 5 years and accounts for 30% of all breast cancer deaths in the US. A recent immunotherapy combination (atezolizumab [anti-PD-L1] plus nab-paclitaxel) was FDA approved; however, it only increased progression-free survival by 2 months at the 1-year mark. Alternative approaches of Antibody-Drug Conjugates (ADCs) to treat TNBC are unfeasible because of the lack of an exclusive cell surface marker to target, leading to the inescapable deficit of killing normal cells expressing the targeted receptor. Thus, there is a great unmet clinical need to develop new precision genetic medicines capable of targeting and killing TNBC tumor cells. TNBC is driven by the amplification, overexpression and deregulation of the cMYC master oncogene transcription factor that drives cellular metabolism, growth, proliferation, survival, epithelial-mesenchymal transition (EMT), immortalization, transformation, drug resistance, angiogenesis and metastasis. Transcription factors, including cMYC, are highly recalcitrant to small molecule inhibitors. However, cMYC can be targeted by precision genetic RNAi medicines. Despite RNAi's promising therapeutic features to treat liver disorders, due to their ~40 negatively charged phosphates, siRNA RNAi therapeutics cannot enter most cell types, including cancer cells and size (14 kDa), on their own and require a delivery agent. Although current extra-hepatic siRNA delivery approaches using lipid and synthetic nanoparticles show merit to address the delivery problem, their overall size (100 Mega-Daltons) results in an inescapably poor (low) diffusion coefficient that diminishes their potential to treat TNBC. Consequently, while RNAi has great potential to target cMYC, there is currently no viable approach to deliver RNAi therapeutics to treat TNBC. Our project will develop next-generation Antibody RNAi conjugate (ARC) precision genetic medicines that target the otherwise undruggable cMYC oncogene in TNBC and incorporate our novel Universal Endosomal Escape Domains (uEEDs). Endosomal escape is the rate-limiting step for delivery of siRNAs and uEEDs directly address this problem in a non-toxic manner. We will test this approach using mouse models from patient-derived xenografts (PDX) from TNBC patients. We hypothesize that targeting the cMYC master oncogene using Antibody-RNAi Conjugates (ARCs) will induce a lethal RNAi response that selectively kills TNBC tumor cells based on their cMYC oncogene addiction, while leaving normal cells unharmed.