Brain metastases (BM) are a devastating complication of lung cancer, and occur in approximately 30-40% of all lung cancer cases. Prognosis for lung cancer patients with untreated brain metastases is grim, with a median survival of 4-6 months. Whole brain radiation therapy (WBRT) has historically been used as a palliative method to treat patients with BM, but comes at the cost of increased cognitive decline. Targeted agents for the treatment of metastatic lung cancers harboring ?driver? kinase mutations have also recently been developed, but have proven ineffective owing to variable responses and the emergence of drug resistance. Thus, the development of new therapeutic strategies for the treatment of metastatic lung cancer remains an unmet clinical need. Recently, our lab discovered that inhibition of the ABL family of tyrosine kinases (ABL1, ABL2) dramatically impairs lung cancer metastasis to multi-organ sites including the brain. Unexpectedly, we found that re-expression of an active form of the TAZ transcriptional co-activator (a target of ABL signaling) rescues the metastatic potential of ABL- deficient lung cancer cells and re-directs metastasis specifically to the brain. Intriguingly, our preliminary data revealed that the ABL kinases regulate activity of the receptor tyrosine kinase AXL, a known driver of lung cancer metastasis and therapy resistance. Based on these exciting observations, my central hypothesis is that ABL kinases are required for lung cancer brain metastasis by integrating signaling networks downstream of metastatic drivers including AXL, and that an ABL-TAZ signaling network promotes the expression of target genes which confer brain-specific metastasis in lung cancer. I will examine this hypothesis through the following two aims: 1) Identify ABL-dependent signaling pathways required for lung cancer brain metastasis, and 2) Identify the ABL/TAZ-regulated transcriptional target genes required for lung cancer brain metastasis.

Public Health Relevance

Brain metastases are a devastating complication of lung cancer, and occur in approximately 30-40% of all lung cancer patients. Currently, no effective therapeutic options exist for lung cancer patients with metastatic disease to the brain. Based on preliminary in vitro and in vivo data, this proposal seeks to identify novel pharmacological strategies for the treatment and prevention of lung cancer brain metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA224960-02
Application #
9638425
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Korczak, Jeannette F
Project Start
2018-02-01
Project End
2021-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705