Related Experiment Video
Updated: Jun 11, 2025
Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
Dual activity of Minnelide chemosensitize basal/triple negative breast cancer stem cells and reprograms
Fulya Koksalar Alkan1, Ahmet Burak Caglayan1, Hilmi Kaan Alkan1
1Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, HWCRC 723 4100 John R. Street, Detroit, MI, 48201, USA.
Abstract:
Triple negative breast cancer (TNBC) subtype is characterized with higher EMT/stemness properties and immune suppressive tumor microenvironment (TME). Women with advanced TNBC exhibit aggressive disease and have limited treatment options. Although immune suppressive TME is implicated in driving aggressive properties of basal/TNBC subtype and therapy resistance, effectively targeting it remains a challenge. Minnelide, a prodrug of triptolide currently being tested in clinical trials, has shown anti-tumorigenic activity in multiple malignancies via targeting super enhancers, Myc and anti-apoptotic pathways such as HSP70. Distinct super-enhancer landscape drives cancer stem cells (CSC) in TNBC subtype while inducing immune suppressive TME. We show that Minnelide selectively targets CSCs in human and murine TNBC cell lines compared to cell lines of luminal subtype by targeting Myc and HSP70. Minnelide in combination with cyclophosphamide significantly reduces the tumor growth and eliminates metastasis by reprogramming the tumor microenvironment and enhancing cytotoxic T cell infiltration in 4T1 tumor-bearing mice. Resection of residual tumors following the combination treatment leads to complete eradication of disseminated tumor cells as all mice are free of local and distant recurrences. All control mice showed recurrences within 3 weeks of post-resection while single Minnelide treatment delayed recurrence and one mouse was free of tumor. We provide evidence that Minnelide targets tumor intrinsic pathways and reprograms the immune suppressive microenvironment. Our studies also suggest that Minnelide in combination with cyclophosphamide may lead to durable responses in patients with basal/TNBC subtype warranting its clinical investigation.
Insights
Minnelide, a triptolide prodrug, effectively targets triple-negative breast cancer (TNBC) stem cells and reprograms the immune microenvironment. Combination therapy with cyclophosphamide eradicates tumors and prevents recurrence in preclinical models.
Area of Science:
- Oncology
- Immunology
- Cancer Stem Cell Biology
Background:
- Triple-negative breast cancer (TNBC) is aggressive, characterized by stemness and an immune-suppressive tumor microenvironment (TME), leading to limited treatment options.
- Current strategies struggle to effectively target the immune suppressive TME in TNBC.
- Minnelide, a triptolide prodrug, demonstrates anti-tumorigenic effects by targeting super enhancers, Myc, and HSP70.
Purpose of the Study:
- To investigate Minnelide's selective targeting of cancer stem cells (CSCs) in TNBC.
- To evaluate the efficacy of Minnelide in combination with cyclophosphamide in preclinical TNBC models.
- To determine the impact of this combination therapy on the TME and long-term tumor control.
Main Methods:
- Selective targeting of TNBC CSCs by Minnelide was assessed in vitro and in vivo.
- Combination therapy with Minnelide and cyclophosphamide was administered to 4T1 tumor-bearing mice.
- Tumor growth, metastasis, TME reprogramming, immune cell infiltration, and recurrence rates were analyzed post-treatment.
Main Results:
- Minnelide selectively targeted CSCs in TNBC cell lines by inhibiting Myc and HSP70.
- Combination therapy significantly reduced tumor growth and eliminated metastasis.
- Treatment led to TME reprogramming, enhanced cytotoxic T cell infiltration, and durable responses with no recurrence after tumor resection.
Conclusions:
- Minnelide targets tumor-intrinsic pathways and reprograms the immune suppressive TME in TNBC.
- Combination therapy with Minnelide and cyclophosphamide shows potential for durable responses in basal/TNBC patients.
- Further clinical investigation of this combination therapy for advanced TNBC is warranted.
Related Concept Videos
01:15Drugs that Stabilize Microtubules
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:10Drugs that Destabilize Microtubules
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...