Project Summary
Metastatic lesions encompass approximately 80% of all CNS tumors. Of that, breast cancer brain metastasis
comprises a third of all brain metastases. Treatment options are few and often only offer palliative support, but
include surgery, chemotherapy, and radiation therapy. Ionizing radiation is observed to disrupt the BTB,
however the mechanism and time course of molecular events following radiation exposure remains poorly
understood. Gap: There is currently no consensus on the sequence of events following radiation therapy for
patients with brain metastases, and whether or not chemotherapy can be effectively timed with windows of
greatest disruption of the BTB. My goal during the F99 phase is to elucidate the time line, at a range of
clinically relevant doses, of radiation-induced BTB openings and determine if two approved therapeutics, when
given at windows of greatest disruption, lead to increased cytotoxicity when timed competently rather than at
random. The training plan set forth in this application employs a wide variety of experimental techniques
including animal modeling of metastatic brain cancer, multiple imaging modalities, use of radiation in small
animals, design of clinically translatable experiments, and conducting science with integrity in a rigorous and
competitive field. This project uses an innovative approach combining our novel brain tropic breast cancer cell
lines with small animal radiation techniques. Herein, we will use our unique multimodal fluorescence and
phosphorescent imaging techniques to monitor changes in BTB permeability. I will complete this research
under the mentorship of Dr. Paul R. Lockman, whose lab boasts a strong publication record with excellent
funding in the field of brain metastases of breast cancer. The F99 phase of this award aligns with the remaining
2 years I have of my time in the Pharmaceutical and Pharmacological Sciences graduate program at West
Virginia University. Our institutional environment is more than adequately positioned to conduct the research
and training described in this proposal, which more than demonstrates the quality and strength offered by the
faculty at our university. In the K00 phase of this award, I will identify a postdoctoral mentor at an institution
with a strong cancer center allowing me to pursue further the cellular and molecular foundation of BBB/BTB
regulation in brain metastases from a different, but complementary avenue. Combined together, the two
phases of this award will provide me with the means to establish myself as a successful cancer researcher
and enable me to lay the foundation for my own independent cancer research laboratory predicated on
the study of the molecular interworking of the BTB in CNS metastatic lesions and novel treatment strategies.