Synergistic Targeting of the JAK2-STAT3 and SMO-GLI1 Pathways in Triple-Negative and HER2-Enriched Breast Cancers
Abstract
The Goals: There is an unmet urgent need to identify effective treatments for patients with triple-negative breast cancer and for those with HER2-positive breast cancer that has lost the responsiveness to Herceptin/trastuzumab. Approximately 30%-50% of the invasive breast cancer belongs to the triple-negative or the HER2-enriched subtypes that are associated more aggressive tumor characteristics and a higher likelihood for metastasis, the number one 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 the 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 drugs already approved by the Food and Drug Administration (FDA) for other diseases and/or being evaluated in clinical trials for the triple-negative and HER2-positive Herceptin-refractory breast cancers. Since the drugs to be combined in proposed studies have excellent safety profiles, the combinations with lower dosages for individual drugs will likely be safe. 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 110 active cancer-related clinical trials at various stages being conducted at our Cancer Center; 10 of them are for breast cancer patients. The Molecular Targets: Our pilot studies have uncovered that two druggable cellular pathways are concurrently hyperactivated in over 60% of triple-negative and HER2-positive breast cancer specimens, namely, the JAK2-STAT3 and SMO-GLI1 pathways. The co-activation is associated with an increased potential to develop metastasis and more malignant clinical progression. (1) Janus-activated kinase 2 (JAK2) is a non-receptor tyrosine kinase that is frequently overexpressed and hyperactive in triple-negative and HER2-positive breast cancers. JAK2 serves as a signaling hub that connects oncogenic receptor tyrosine kinase (EGFR and HER2) to STAT3 oncogenic transcription factor. Dysregulated JAK2-STAT3 pathway is associated with poor clinical outcomes and is a breast cancer therapeutic target. (2) Like the JAK2-STAT3 pathway, the SMOGLI1 pathway is also a therapeutic target in triple-negative breast cancer. Smoothened (SMO) is an oncogenic 7-transmembrane receptor that activates the glioma-associated oncogene homolog 1 (GLI1) oncogenic transcription factors, contributing to poor survival of breast cancer patients. The Combination Treatments: Our preclinical studies showed exciting synergistic therapeutic effects from combined uses of JAK2- and SMO-targeted inhibitors that are FDA-approved for other conditions and/or undergoing clinical evaluations for triple-negative and HER2-positive/Herceptin-resistant breast cancers. The JAK2 inhibitors that we will investigate are orally active ruxolitinib and pacritinib. Ruxolitinib (Jakafi; Novartis) is the only FDA-approved JAK2 inhibitor and was approved in 2011 for treating psoriasis and myelofibrosis. Ruxolitinib in combination with paclitaxel is in a Phase I/II trial for triple-negative inflammatory breast cancer (NCT02041429). Ruxolitinib with capecitabine is being evaluated in a Phase II trial for advanced or metastatic HER2-negative breast cancer (NCT02120417). For metastatic HER2-positive breast cancer, ruxolitinib in combination with Herceptin is being evaluated in a Phase I/II clinical trial (NCT02066532). Pacritinib (CTI and Baxter International) is being tested clinically for leukemias and lung and colon cancers. There is currently no clinical trial with pacritinib for breast cancer. The SMO inhibitors that we will investigate are orally active vismodegib, sonidegib, glasdegib, taladeg
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710044
Entities
People
- Hui-Wen Lo
Organizations
- United States Army
- Wake Forest University