Targeting Brain Metastasis with a Cell-based Approach
|Institution:||Scripps Research Institute|
Brunhilde Felding-Habermann , Ph.D. -
|Award Cycle:||2010 (Cycle 16)||Grant #: 16IB-0030||Award: $284,354|
|Innovative Treatments>Gene therapy and other treatments: new frontiers|
Initial Award Abstract (2010)
Breast cancer patients diagnosed with brain metastases have an extremely poor prognosis since no efficient therapies are available. Brain lesions are often shielded by the blood-brain barrier (BBB) which hinders drug penetration. Furthermore, the presence of multifocal brain lesions often hinders their complete removal by surgery due to neurotoxicities. Thus, novel therapeutic concepts tailored to overcome these current limitations in the treatment of brain lesions are urgently required.
In our mouse models of breast cancer brain metastasis we have observed a specific homing of activated microglia to cancer cells from the time point of their arrival in the brain and persisting throughout the development of macroscopic brain lesions. Microglia are the resident macrophages of the brain and spinal cord, and act as a form of immune defense in the central nervous system. Our preliminary work suggests that the majority of cancer cell-associated activated microglia originate from the inflammatory monocytes that are derived from the hematopoietic stem cells (HSC) in bone marrow. The infiltration of inflammatory monocytes into the brain is drastically increased upon the initiation of brain lesions.
For these studies, we have established mouse models of breast cancer brain metastases in which cancer cells are injected into the carotid artery to colonize the brain from the blood stream or implanted directly into the brain itself. Our first aim is to study the role of microglial activation in these models. For this we will administer minocycline, a BBB-permeable suppressor of microglial activation, and deplete bone marrow-derived microglia using clodronate-loaded liposomes. The suppression of microglial activation and their depletion will be confirmed by pathology staining and analyzed by FACS (fluorescence activated cell sorting) using markers for microglia and inflammatory monocytes. The quantification of tumor growth over time in treated animals vs. controls will be performed by bioluminescent imaging of cancer cells. Our second aim is to determine whether genetically engineered HSC will “home” to brain tumors from the blood stream. For this we will isolate HSC, introduce a fluorescent tracer, inject them into the circulation, and determine whether they migrate to sites of breast cancer metastasis in the brain. If this strategy proofs successful, we plan to use HSC as cellular vehicles to deliver therapeutic agents to malignant brain lesions.
Our microglia-based approaches could lead to novel therapies targeting brain metastases by overcoming the major therapeutic limitations imposed by the BBB, drug resistance, and the multifocal nature of brain lesions.
Final Report (2012)
This grant was originally proposed by and awarded to Dr. Mihaela Lorger, a Staff Scientist in my laboratory. During her time on this grant, Dr. Lorger focused on analyzing microglial cell population associated with breast cancer brain lesions in the mouse model, and on detection of evidence for recruitment of peripheral bone marrow derived stem cells into cerebral breast cancer metastases in experimental mice. A main approach of our studies is focused on human neural stem cells, the first stem cell type known to have extensive pathotropism (i.e. “homing” to the tumor site) in the brain. To explore alternative ways for utilizing host cells, eventually harnessed with oncocidal genes for targeted inhibition of brain metastatic growth, we focused here on direct clinical evidence for alternative host cell types that may populate breast cancer brain metastases from the periphery.
To this end, we analyzed a unique collection of breast cancer brain metastases from breast cancer patients and compared them to their matched primary breast tumors. The analyses focused on recruitment of peripheral host cell types into the microenvironment of breast cancer brain lesions. In contrast to the normal brain and primary brain tumors, we found strong evidence that brain metastatic breast cancer lesions induce a wound healing host response that leads to the generation of a tumor microenvironment within the brain that is clearly distinct from host responses in primary brain tumors. Within the microenvironment of breast cancer brain metastases, host cell types found and their matrix proteins and architecture of the tumor associated matrix very strongly indicate the recruitment of peripheral cell types resembling the peripheral wound healing response. These cell types characteristically include macrophage and fibroblasts like cells that apparently localize from the periphery to the tumor microenvironment of brain metastatic lesions. It is most likely that the host response cell types enter the brain from peripheral blood, attracted by breast cancer cells and permitted in by tumor modified vascular barrier functions.
Thus, it appears feasible that extracranial host cell types with oncotropism can be used for targeting breast cancer brain metastases. This information is highly relevant as it opens the possibility of using patient derived peripheral precursor cells to combat cerebral breast cancer lesions in novel, safe and effective therapies against breast cancer brain metastases.
Comparison of in vitro and in vivo approaches to studying brain colonization by breast cancer cells.
Periodical:Journal of Neurooncology
Index Medicus: J. Neoroonc.
Authors: Lorger M, Lee H, Forsyth JS, Felding-Habermann B
|Yr: 2011||Vol: 104||Nbr: 3||Abs:||Pg:689-96|