Patients with advanced breast cancer have a high propensity to metastasize to the brain with human epidermalgrowth factor receptor (EGFR) positive and triple-negative breast cancer (TNBC; estrogen receptor, progesteronereceptor and Her2 negative) subtypes showing the highest incidence of brain metastases. Most patients havemultiple metastatic lesions at the time of diagnosis making surgery an inadequate therapeutic option on its own.Furthermore, impaired cognitive decline induced by whole-brain radiation therapy (WBRT) and the tight blood brainbarrier (BBB) preventing the brain permeability of systemic therapies in the brain pose challenges for the success ofexisting therapies and result in failure to improve overall patient survival. To effectively treat multiple highlyaggressive breast metastatic foci in the brain, there is an urgent need to develop tumor specific multi-targetingagents that simultaneously target multiple aberrant signaling pathways in TNBC and utilize delivery vehicles whichspecifically seek metastatic foci in the brain. In our previously published and preliminary studies, we have 1)extensively demonstrated that engineered human and mouse neural stem cells (NSC) and mesenchymal stem cells(MSC) home extensively to primary and metastatic tumors in the brain and provide on-site means to deliver noveltumor specific agents; and 2) engineered EGFR-specific nanobodies (ENb) and their pro-apoptotic variant, bi-functional ENb-TRAIL and shown its potential to target both cell proliferation and death pathways in a mechanismbased manner in broad spectrum of tumor cells. The long term goal of this proposal is to test the mechanism basedtherapeutic efficacy of systemically delivered NSC-ENb-TRAIL in TNBC derived mouse models of breast to brainmetastasis that mimic the clinical scenario of breast metastatic tumor growth and progression. We will initiallyscreen established and patient derived TNBC lines for their response to EGFR and DR4/5 targeted therapies andassess their propensity to metastasize to brain. The mechanism based response of TNBC to NSC-ENb-TRAIL andthe fate and therapeutic efficacy of NSC-ENb-TRAIL in brain metastasis mouse models generated from brainseeking patient derived TNBC lines will be assessed. We hypothesize that simultaneous targeting of EGFR andDR4/5 will significantly influence epithelial-mesenchymal transition (EMT) and tumor growth and progression. Basedon our exciting preliminary data on the combined use BBB permeable histone deacetylase inhibitor (HDACi), CN147and ENb-TRAIL and the previous findings that concomitant use of HDACi with DR4/5 agonists and EGFR inhibitors,the combined therapeutic efficacy of NSC-ENb-TRAIL and CN147 will be assessed. We hypothesize that ENb-TRAIL and HDACi will have therapeutic efficacy in metastatic TNBC with a broader range of genetic backgroundsand with varying sensitivity to ENb-TRAIL in vivo. The proposed studies in this application are likely to unravel themechanism-based, targeted stem cell mediated therapies for metastatic breast tumors. We envision designing astrategy in which NSC-ENb-TRAIL will be injected intra-arterially to target the metastatic tumor deposits in the brainof metastatic breast cancer patients. This will have a major impact in saving the lives of many cancer patients.
In this proposal; we will create and characterize breast to brain metastatic tumor models andtest the mechanism based efficacy of stem cells (SC) delivered ENb-TRAIL in culture. Wewill also evaluate the therapeutic efficacy SC-ENb-TRAIL with and without HDAC inhibitors invivo in mouse model of breast to brain metastasis. The developed agents and strategies willbe designed to be clinically translatable and should have a major impact in translating stemcell based therapies for a broad spectrum of brain tumors.
|Bhere, Deepak; Khajuria, Rajiv Kumar; Hendriks, William T et al. (2018) Stem Cells Engineered During Different Stages of Reprogramming Reveal Varying Therapeutic Efficacies. Stem Cells 36:932-942|