Truncated Glioma-Associated Oncogene Homolog 1 (tGLI1) Is a Novel Mediator and Target for Breast Cancer Brain Metastasis
Abstract
The Goals: There is an unmet urgent need to identify effective treatments for patients with metastatic triple-negative breast cancer and for those with HER2-positive breast cancer that has lost the responsiveness to Herceptin/trastuzumab. Thirty to fifty percent of the invasive breast cancer belongs to the triple-negative or the HER2-enriched subtypes; they are associated with more aggressive tumor characteristics and a higher likelihood for metastasis, the leading cause of breast cancer mortality. The goal of our study is therefore set to identify novel treatment strategies that can be used to effectively treat women with metastatic triple-negative and HER2-positive Herceptin-refractory breast cancers without unwanted toxicity and side effects. To achieve our study goal, we plan to generate preclinical evidence to support future clinical utility of several novel combination treatments consisting of radiation therapy, surgery, and ketoconazole (KCZ), an antifungal drug already approved by the Food and Drug Administration (FDA) for other diseases and/or being evaluated in multiple types of cancers including metastatic breast cancer. Based on cilinicaltrials.gov, there are 61 active clinical trials using KCZ for treating cancer patients, including a Phase II trial (NCT00212095; KCZ with docetaxel) for metastatic breast cancer. If proven effective in our preclinical studies, the treatment combinations can be moved to Phase I trials relatively quickly at the Wake Forest University Comprehensive Cancer Center. There are currently 107 active oncology clinical trials at various stages being conducted at our Cancer Center in which 19 of them are for breast cancer patients. The Molecular Target: The Principal Investigator’s (PI’s) laboratory made the discovery of a novel oncogenic transcription factor truncated glioma oncogene homolog 1 (tGLI1) as a tumor-specific, gain-of-function, master regulator of tumor growth, vascularity, and breast cancer brain metastasis (BCBM). Our published and pilot studies using >1,000 breast tumor and metastases samples and mouse models of breast cancer metastasis have established the following rationale to pharmacologically target tGLI1 for brain-metastatic HER2-enriched and triple-negative breast cancers. (a) tGLI1 strongly promotes breast cancer metastasis to the brain and shortens patients’ time to develop brain metastases. (b) tGLI1 is highly expressed in metastatic HER2 and triple-negative breast cancers (84%-91%) and brain metastases (86%). (c) tGLI1 expression is tumor-specific. (d) Datamining of over 1,200 patients showed tGLI1 is activated in the majority of triple-negative and HER2-enriched breast carcinoma samples, the two subtypes with high risks of brain metastasis. (e) Forced expression of tGLI1 renders radio-resistant BCBM cells more resistant to radiation therapy (the primary therapy for BCBM); radio-resistant brain metastases samples expressed higher levels of tGLI1 than radio-sensitive samples. Drug Screen and Preclinical Data: There is no available tGLI1 inhibitor. To identify inhibitors that selectively target tGLI1 that is only expressed in cancerous tissues but not normal tissues and strongly promotes BCBM, we conducted synthetic lethality screens of 1,520 compounds and subsequently identified an FDA-approved orally active, antifungal KCZ that selectively and strongly inhibits tGLI1(+) HER2-enriched and tGLI1(+) triple-negative breast cancer cells, particularly cancer stem cells that are known to be more metastatic and more resistant to therapies compared to the non-stem cell populations. tGLI1 is required for KCZ effects. Using preclinical mouse models of BCBM, we showed that KCZ crossed blood-brain and blood-tumor barriers, and selectively suppressed tGLI1-high BCBM without liver toxicity. A novel KCZ derivative KCZ-005 showed promising efficacy and no toxicity. KCZ strongly synergized with radiation therapy for treating radio-resistant HER2-enric
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910753
Entities
People
- Hui-Wen Lo
Organizations
- United States Army
- Wake Forest University