Wednesday, April 2, 2025
4/2/2025
Circadian Rhythms in Blood Brain Barrier Permeability and Increased Efficacy of Chemotherapy for Brain Metastases - Project Summary Breast cancer is a devastating disease that affects large numbers of women annually; it is estimated that 1 in 8 women in the United States will be diagnosed with this disease during their lifetime. The five-year survival rate for women diagnosed with localized or regional breast cancer is greater than 90 percent. However, the presence of brain metastases reduces five-year survival rates to less than 10 percent. Chemotherapy treatment of brain metastases is challenging and has yielded inferior results compared to tumors in the periphery, likely reflecting the inability of chemotherapy to cross the blood brain barrier (BBB) and/or blood tumor barrier (BTB) at efficacious rates. Recent studies demonstrate circadian regulation of BBB permeability; however no study has examined whether temporal alterations in chemotherapy administration can improve the efficacy of treatment of brain metastases. This project aims to take advantage of circadian control of BBB permeability by optimally timing chemotherapy administration to increase anti-tumor efficacy and reduce adverse side effects of brain metastases. Specifically, I hypothesize that circadian control of efflux transporter expression at the BBB underlies the fluctuations in BBB/BTB permeability to chemotherapeutic agents. Permeability of two of the most commonly prescribed chemotherapeutic drugs for breast cancer, doxorubicin (A) and paclitaxel (P), will be assessed via phosphor autoradiography imaging by using 14C labeled chemotherapeutic drugs. Additionally, pharmacological inhibition and genetic approaches (CRISPR) will be utilized to determine both the type and location (BBB or BTB) of efflux transporters that underlie altered permeability. Mice harboring brain metastases of breast cancer will receive intravenous injections of doxorubicin/cyclophosphamide cocktail or paclitaxel every 2 weeks during either the peak or trough of BBB permeability. Anti-tumor efficacy will be assessed via bioluminescence and immunohistochemistry. Adverse behavioral effects of chemotherapy will be assessed via multiple behavioral tasks and sleep assessment. I predict that optimal timing of chemotherapy administration will increase anti-tumor efficacy and minimizes adverse side effects. Indeed, preliminary data demonstrate that altering only the timing of injection increased the amount of chemotherapy within brain metastases of breast cancer by approximately 50%. Thus, chrono-chemotherapy represents a viable and novel treatment strategy. Together, these studies will provide essential information with a high potential for clinical relevance to better treat patients with breast cancer. This career development training award will enable me to become an independent investigator by allowing training in emerging techniques (i.e., CRISPR and blood-brain barrier/blood-tumor barrier biology), professional development, grant writing, guest lab training, mentor training, and highly focused research support. To help accomplish my goals, I have assembled a multidisciplinary mentoring team that has extensive expertise in the fields of circadian biology, cancer, and neuroscience.
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