Breast cancer is the most frequently diagnosed cancer in women in the United States. Triple-negative breast cancer (TNBC) represents ~15% of breast cancer, so-called because the tumor cells lack expression of the targetable proteins estrogen receptor, progesterone receptor and epidermal growth factor receptor HER2. There are currently no molecularly targeted therapies approved for TNBC. As a result, TNBC is the leading cause of breast cancer death and in most cases is considered as an incurable malignancy. To eliminate the mortality associated with TNBC, there is an urgent need to discover novel surface targets for TNBC and develop corresponding targeted therapy for TNBC. We hypothesize that tissue factor (TF) is a novel, surface protein receptor target in TNBC and that targeting TF represents an innovative therapeutic approach for TNBC. The rationale behind the hypothesis is that (i) our preliminary and published studies demonstrate that TF is over-expressed on TNBC cancer cells (60-85%, n=171) and on tumor vascular endothelial cells (64%, n=14) from TNBC patients as well as on cancer stem cells (CSCs) isolated from TNBC lines, xenografts and breast cancer patients. Importantly, TF is not expressed on normal breast gland and quiescent endothelial cells of normal vasculature. Thus, TF is a novel surface target in TNBC and targeting TF may constitute a novel targeted therapy with ability to target three major tumor compartments (TNBC cells, CSCs and tumor neovasculature) for a majority of TNBC patients. (ii) Dr. Hu?s prior work demonstrated that TF-targeted therapies are effective and safe in preclinical animal studies and clinical studies. He has co-invented and patented the first TF-targeting Immuno-Conjugate agent named ICON that consists of factor VII (fVII, the natural ligand to TF) fused to the Fc region of human IgG1. As a neovascular- targeting agent, ICON has shown therapeutic efficacy and safety in preclinical animal models against solid cancers, wet macular degeneration (AMD) and endometriosis and in a competed Phase I trial for AMD patients. ICON is currently being tested in a Phase I trial in ocular melanoma patients (NCT02771340) and in a Phase II trial in AMD patients (NCT02358889). (iii) We have improved ICON to achieve better efficacy and safety, as a second-generation TF-targeting immunotherapy agent, named L-ICON (for lighter or light chain ICON). The major goal and specific aims of this proposal are to evaluate the novel TF-targeting L-ICON (via systemic delivery of recombinant protein) as single agent therapy and combination therapy with current immune modulatory agents (immune checkpoint inhibitors and cytokines) and natural killer (NK) cells for TNBC in humanized, patient-derived xenograft (PDX) mouse models, in which human immune cells and human tumors are both present to better translate and predict clinical outcome. To ultimately translate the findings into clinic, we are collaborating with breast cancer expert and clinical trialist, GMP manufacturing NK cell expert, pathologist and biostatistician on this proposal. If successful, the significance and clinical impact of this project is that it will provide novel targeted approaches for the treatment of TNBC and hopefully to reduce the mortality associated with this malignancy.
These translational preclinical studies are relevant to public health for three reasons. First, this project is to address triple-negative breast cancer (TNBC), which is considered as incurable malignancy and is the leading cause of breast cancer death in the USA as well as globally. Second, they may discover a new and common surface oncotarget for cancer cells, cancer stem cells and tumor neovasculature in TNBC. Third, they may provide a novel targeted immunotherapy and combination therapy for TNBC patients.