Brain metastases pose a significant problem for women with advanced metastatic diseases. The rate of brain metastasis has increased significantly in the last 10 years, approaching or exceeding 35% in subpopulations of metastatic breast cancer patients, particularly those with Her2+ or triple-negative tumors. After diagnosis of multiple metastatic lesions, patients typically die within one to two years. Gap: Treatment of brain metastases is primarily palliative due to limited curative effectiveness of radiation, surger, and poor delivery of chemotherapy across the blood-brain barrier (BBB). This proposal focuses on preventing metastasis seeding and initial growth in brain using preclinical models. Hypothesis: By reducing the efficiency of metastatic cancer cell penetration into brain and increasing drug delivery and efficacy in early micrometastatic lesions, we will decrease large metastases development and improve both neurological function and overall survival.
Aim 1 : Demonstrate that brain invasion of metastatic breast cancer cells can be inhibited at the level of the BBB: Preliminary data indicate TGF- inhibition reduces brain invasion, at the level of the BBB, of triple negative human metastatic breast cancer cells in vivo ~70-80%. This work is extended to characterize mechanisms of how TGF- inhibition reduces BBB cell invasion and the role Her2+ plays in BBB invasion.
Aim 2 : Elucidate the causal relationship between blood-tumor barrier permeability changes and chemotherapeutic uptake and effect in brain micrometastases of breast cancer: Preliminary data suggest that, contrary to common assumptions, most micrometastatic lesions (<500 m diameter) of breast cancer in brain show marked changes in metastatic vasculature structure and function, including vessel co- option, reduced vascular density, enhanced permeability, and elevated VEGF expression. In this Aim, work will be completed to characterize BBB changes in micrometastases, with the goal of identifying selective difference in micrometastases, such as VEGF and Notch, which can be used for targeted therapeutic benefit.
Aim 3 : Develop novel strategies to modulate blood-brain barrier permeability to improve therapeutic efficacy for brain micrometastases treatment: Preliminary data demonstrate that inhibition of vascular endothelial Notch signaling in both large and small brain metastases in the presence of VEGF results in targeted increases in BBB permeability. In this Aim, the targeted increases in permeability are exploited to improve chemotherapy delivery, cytotoxic effect and overall survival in three preclinical tumor models. Impact: The goal of this proposal is to develop novel approaches to reduce breast cancer cell invasion to brain, to modulate BBB permeability and improve chemotherapy uptake into CNS metastases, with an overall purpose to reduce brain metastases related death. The work requires state-of-the-art cell targeting, BBB permeability, and drug distribution methods to link barrier changes in selected small tumors with overall brain metastasis invasion and growth.

Public Health Relevance

The proposed research is relevant to public health because brain metastases are becoming increasingly common in women with advanced metastatic breast cancer. Unfortunately, once brain metastases are established and clinically detectable with an MRI, few treatment options are available and patients die within one to two years. Consequently, we are studying ways to prevent metastasis occurrence in brain, and ways to kill metastatic lesions in brain while they are very small, before they become untreatable.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA166067-03
Application #
8638904
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Forry, Suzanne L
Project Start
2013-12-18
Project End
2018-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
3
Fiscal Year
2015
Total Cost
$307,100
Indirect Cost
$99,600
Name
West Virginia University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26505
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Shah, Neal; Mohammad, Afroz S; Saralkar, Pushkar et al. (2018) Investigational chemotherapy and novel pharmacokinetic mechanisms for the treatment of breast cancer brain metastases. Pharmacol Res 132:47-68
Bohn, Kaci A; Adkins, Chris E; Nounou, Mohamed I et al. (2017) Inhibition of VEGF and Angiopoietin-2 to Reduce Brain Metastases of Breast Cancer Burden. Front Pharmacol 8:193
Mittapalli, Rajendar K; Adkins, Chris E; Bohn, Kaci A et al. (2017) Quantitative Fluorescence Microscopy Measures Vascular Pore Size in Primary and Metastatic Brain Tumors. Cancer Res 77:238-246
Terrell-Hall, Tori B; Ammer, Amanda G; Griffith, Jessica I G et al. (2017) Permeability across a novel microfluidic blood-tumor barrier model. Fluids Barriers CNS 14:3
Venishetty, Vinay K; Geldenhuys, Werner J; Terell-Hall, Tori B et al. (2017) Identification of Novel Agents for the Treatment of Brain Metastases of Breast Cancer. Curr Cancer Drug Targets 17:479-485
Logsdon, Aric F; Lucke-Wold, Brandon P; Turner, Ryan C et al. (2017) A mouse Model of Focal Vascular Injury Induces Astrocyte Reactivity, Tau Oligomers, and Aberrant Behavior. Arch Neurosci 4:
Terrell-Hall, Tori B; Nounou, Mohamed Ismail; El-Amrawy, Fatema et al. (2017) Trastuzumab distribution in an in-vivo and in-vitro model of brain metastases of breast cancer. Oncotarget 8:83734-83744
Nounou, Mohamed Ismail; Adkins, Chris E; Rubinchik, Evelina et al. (2016) Anti-cancer Antibody Trastuzumab-Melanotransferrin Conjugate (BT2111) for the Treatment of Metastatic HER2+ Breast Cancer Tumors in the Brain: an In-Vivo Study. Pharm Res 33:2930-2942
Adkins, Chris E; Mohammad, Afroz S; Terrell-Hall, Tori B et al. (2016) Characterization of passive permeability at the blood-tumor barrier in five preclinical models of brain metastases of breast cancer. Clin Exp Metastasis 33:373-83

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