Among 1.6 million women diagnosed with breast cancer every year, about 10-16% develop brain metastasis. Even with the most advanced clinical care, patients with brain metastasis have a devastating <20% one-year survival. At present, no effective drug treatment exists for patients with refractory breast cancer metastatic to the brain. Therefore, novel and effective therapies are urgently needed for this population. Unfortunately, developing effective therapies for brain metastasis is largely hampered by a lack of in-depth understanding of the basic mechanisms of brain metastasis, which could guide drug development and clinical trials. To surmount the challenge, we have performed an unprecedented in vivo screen of the human kinome to uncover novel kinases that promote breast cancer brain metastasis in mice, because kinases are at the central nodes of cancer cell signaling networks critical for cancer progression/metastasis and are druggable as therapeutic targets. Among the top candidate kinases associated with aggressive brain metastasis we identified, Mitogen- Activated Protein Kinase 12 (MAPK12, also known as p38?) was not previously known to play roles in brain metastasis but is overexpressed in highly aggressive human breast cancers, and patients with MAPK12 high- expressing breast cancers have higher incidences of brain metastasis later on. Therefore, we performed experimental brain metastasis assays using MAPK12-overexpressing breast cancer cells, and validated that MAPK12 indeed promotes brain metastasis in animals. MAPK12 is a member of the MAPK family and its overexpression increases cancer cell motility and invasion. Excitingly, we identified that MAPK12 is located at the hub of a signaling network of brain metastasis-enriched kinases that enhances brain metastatic cells? utilization of lactate as an energy source for outgrowth in the brain. Furthermore, MAPK12 is targetable with available inhibitors that are used in the clinic for other diseases. Here, we hypothesize that activation/ overexpression of MAPK12 coordinates signaling pathways in breast cancer cells to promote brain metastasis, and MAPK12 may be effectively inhibited by using clinically applicable kinase inhibitors. The major goals of this proposal are 1) Determine the functional roles of MAPK12 in spontaneous brain metastasis and in immune competent brain metastasis models, and further validating their clinical relevance; 2) Investigate novel mechanisms of MAPK12-mediated breast cancer brain metastasis by focusing on how MAPK12-activated brain metastatic cancer cells efficiently use lactate as an energy source for adaptation and outgrowth in the brain; 3) Explore the potential of MAPK12 as a therapeutic target for the treatment and/or prevention of breast cancer brain metastasis. The successful completion of these studies will bring about new understanding of breast cancer brain metastasis and the first generation of effective brain metastasis-targeted therapies. Ultimately, our findings will be smoothly translated to clinical trials, leading to new and better treatments for breast cancer brain metastasis patients in dire search of hope.

Public Health Relevance

This revised R01 application tackles one of the most challenging problems in the cancer field: no effective drug treatment exists for patients with brain metastatic breast cancer due to lack of basic understanding of the disease. The goal of this research is to determine whether and how MAPK12, identified from our in vivo kinome screen, promotes breast cancer brain metastasis, and whether inhibitors of MAPK12 may be developed as new therapeutic agents for brain metastasis. Our research findings will be smoothly translated to clinical trials, leading to new and better treatments for breast cancer brain metastasis to enhance the quality of life and prolong survival of patients suffering from brain metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA208213-03S1
Application #
9976243
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Snyderwine, Elizabeth G
Project Start
2017-06-01
Project End
2022-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Microbiology/Immun/Virology
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Wang, Xiao; Yao, Jun; Wang, Jinyang et al. (2017) Targeting Aberrant p70S6K Activation for Estrogen Receptor-Negative Breast Cancer Prevention. Cancer Prev Res (Phila) 10:641-650