Although initial response rates of breast cancer to surgery and mAb/chemotherapy are high, most patients will recur with treatment resistant disease, and maintaining complete remission has proven elusive. All of the current classical and experimental treatment options for ovarian cancer patients are focused on destroying the malignant cells. These genetically unstable and heterogeneous cells are a moving target for therapies. The tumor stroma contains genetically stable tumor-infiltrating myeloid cells, of which the tumor-associated macrophages (TAMs) are the dominant species. The central new idea of this proposal is to use the patho-physiological process of recruitment of hematopoietic stem cells (HSC) to the tumor stroma to deliver therapeutic genes into tumors. We propose a simple procedure involving G-CSF/AMD3100 mobilization and intravenous HD-Ad5/35++ vector injection to genetically engineer HSCs in cancer patients. These HSCs will provide a long-term source of genetically modified TAM progenitors that will be actively recruited by the tumor. Once differentiated into TAMs, a gene expression system will be activated that allows for the elimination of TAMs and neighboring tumor cells. Potentially our approach can also allow for the early detection of recurrent breast cancer based on the recruitment of TAMs and activation of TAM-specific reporter gene expression. The goals of this proposal are to increase the percentage of transgene-expressing TAMs and to test whether in vivo gene-engineered HSCs can be used for breast cancer detection and therapy.
The Specific Aims are:
Specific Aim 1. Test approaches that allow for the in vivo expansion of gene-engineered HSCs.
Specific Aim 2 : Track TAM differentiation and recruitment to tumor and test whether this can be used for early detection of breast cancer.
Specific Aim 3. Test whether the selective killing of TAMs and neighboring tumor cells stops tumor growth in mouse breast cancer models.
The main focus of our proposal is to detect and treat breast cancer using a hematopoietic stem cell-based gene transfer approach to express diagnostic and therapeutic genes from tumor- associated macrophages.
|Li, Chang; Psatha, Nikoletta; Wang, Hongjie et al. (2018) Integrating HDAd5/35++ Vectors as a New Platform for HSC Gene Therapy of Hemoglobinopathies. Mol Ther Methods Clin Dev 9:142-152|
|Li, Chang; Psatha, Nikoletta; Gil, Sucheol et al. (2018) HDAd5/35++ Adenovirus Vector Expressing Anti-CRISPR Peptides Decreases CRISPR/Cas9 Toxicity in Human Hematopoietic Stem Cells. Mol Ther Methods Clin Dev 9:390-401|
|Li, Chang; Psatha, Nikoletta; Sova, Pavel et al. (2018) Reactivation of ?-globin in adult ?-YAC mice after ex vivo and in vivo hematopoietic stem cell genome editing. Blood 131:2915-2928|
|Wang, Hongjie; Richter, Maximilian; Psatha, Nikoletta et al. (2018) A Combined In Vivo HSC Transduction/Selection Approach Results in Efficient and Stable Gene Expression in Peripheral Blood Cells in Mice. Mol Ther Methods Clin Dev 8:52-64|
|Richter, Maximilian; Saydaminova, Kamola; Yumul, Roma et al. (2016) In vivo transduction of primitive mobilized hematopoietic stem cells after intravenous injection of integrating adenovirus vectors. Blood 128:2206-2217|