Targeting Neuronal-like Metabolism of Metastatic Tumor Cells as a Novel Therapy for Breast Cancer Brain Metastasis
Abstract
Background -- The Challenge: Every single breast cancer survivor fears relapse. While being free of the primary breast tumor after treatment is encouraging, it is emotionally devastating to step out of the clinic after a yearly checkup with a diagnosis of metastatic disease. Metastasis is responsible for 90% of cancer-related mortality. In order to the prevent deaths from breast cancer by 2020, we strongly believe that the solution is ending metastasis-related mortality. Therefore, in this proposal, we aim to tackle two interrelated overarching challenges: (1) Eliminate the mortality associated with metastatic breast cancer. (2) Determine why/how breast cancer cells lay dormant for years and then re-emerge (recurrence) and determine how to prevent recurrence. Despite the clinical advances in early tumor detection and treatment regimens for primary breast tumors, the overall mortality of patients who have relapsed with metastatic breast cancer in the United States has not changed in 20 years! Notably, brain metastasis incidence is increasing. Unfortunately, treatment options for brain metastasis are lacking given our limited understanding of brain metastasis, further hindering the design and development of novel adjuvant treatments for this relapsed disease. Brain metastases are different from primary tumors and should be viewed and treated differently! First, brain metastasis is an evolutionary process. Not every disseminated tumor cell will develop into brain metastasis; yet, those rare breast cancer cells that do thrive in the brain display different behavior from the primary tumor. After a long period of dormancy and consequent adaptation to the brain microenvironment, brain metastases are reprogramed to utilize a neuron-like signaling pathway (glutamate receptors) to survive. Therefore, current therapy designed based on the primary tumor is rarely effective to prevent brain relapse. Second, the unique structure of blood-brain barrier (BBB) is largely impermeable to most anti-cancer therapies, representing a major challenge for delivery of many investigational and Food and Drug Administration (FDA)-approved anti-cancer drugs. The Breakthrough Ideas in This Proposal: In order to the prevent deaths from breast cancer brain metastasis by 2020, we need to take creative approaches to design novel treatments for this group of patients. Based on our preliminary study, we propose a bold hypothesis that the evolutionary changes of brain metastases during the first metastatic seeding event to aggressive growth at the brain microenvironment can be capitalized as intriguing therapeutic targets. As all investigational and FDA-approved neurological drugs targeting neuron-specific receptors readily penetrate the BBB, we reason that clinically available neurological drugs could be repurposed as a novel therapy for treating brain metastasis. Therefore, our overall objective is to explore the functional importance of key neuronal-like changes during metastatic evolution and target metastatic colonization of the brain with BBB-permeable neurological drugs. Coupled with our unmatched imaging approaches, we aim to understand how brain metastasis recurrence occurs in an intact metastatic microenvironment. We also aim to preclinically examine the therapeutic efficacy of co-targeting neuronal-specific receptors (e.g., glutamate receptors) and breast cancer driver genes in brain metastasis animal models. The Pathway to Clinical Translation: The mechanistic and functional study in this proposal will reveal the importance of neuron-like receptors during the brain metastasis colonization. Preclinical combinatorial study of neurological drugs with current breast cancer therapy will provide critical preclinical rationale for the concept of metastatic specific drug repurposing. Our study will provide important rationale to develop a completely different category of therapies targeting brain metastasis-specific evolutionary c
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510021
Entities
People
- Siyuan Zhang
Organizations
- United States Army
- University of Notre Dame