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Discovery of Potent and Brain-Penetrable Tubulin Inhibitors that Effectively Suppress Breast Cancer Brain Metastasis
Raisa I Krutilina1,2, Kelli L Adeleye3,4, Hilaire C Playa1,2
1Department of Pathology, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee.
Abstract:
Breast cancer brain metastasis (BCBM) remains a clinical challenge marked by limited therapeutic options and poor survival rates. Approximately 30% of all patients with metastatic breast cancer develop BCBM, with the highest incidence in patients with aggressive molecular subtypes, including triple-negative breast cancer (TNBC). Patients with TNBC with brain metastasis experience rapid disease progression and significantly reduced survival times due to a lack of targeted treatments that can penetrate the blood-brain barrier (BBB) and effectively control metastatic expansion. Current treatment options, such as whole-brain radiotherapy and chemotherapy, offer limited efficacy and are associated with significant toxicities, underscoring the urgent need for novel therapeutics that can target BCBM directly. We developed innovative colchicine binding site inhibitors (CBSI) targeting tubulin, SB-216 and SP-1-39, that show potent preclinical efficacy against brain and extracranial metastases in BCBM models. Both CBSIs cross the BBB, inhibit cell growth and migration, and induce apoptosis with low nanomolar potencies, similar to Azixa (MPC-6827), another CBSI previously evaluated in clinical trials. SB-216 reduced brain and concurrent extracranial metastases in a preventive dosing paradigm, extending overall survival. SB-216 also suppressed the expansion of preestablished brain lesions. In a taxane-refractory patient-derived TNBC model, SP-1-39 therapy markedly reduced brain and extracranial tumor burden. Together, these results highlight the promising therapeutic potential of SB-216 and SP-1-39 in treating taxane-sensitive or -resistant BCBM, filling a critical gap in TNBC management by offering targeted treatments that can cross the BBB and combat chemorefractory disease.
Insights
New colchicine binding site inhibitors (CBSIs), SB-216 and SP-1-39, show promise for treating breast cancer brain metastasis (BCBM). These drugs effectively cross the blood-brain barrier, inhibit tumor growth, and improve survival in preclinical models.
Area of Science:
- Oncology
- Neuro-oncology
- Pharmacology
Background:
- Breast cancer brain metastasis (BCBM) presents a significant clinical challenge with poor outcomes, especially in triple-negative breast cancer (TNBC).
- Existing treatments for BCBM, including radiotherapy and chemotherapy, have limited efficacy and substantial toxicity.
- There is a critical unmet need for novel therapeutics that can penetrate the blood-brain barrier (BBB) and effectively treat BCBM.
Purpose of the Study:
- To develop and evaluate novel colchicine binding site inhibitors (CBSIs) targeting tubulin for the treatment of BCBM.
- To assess the ability of these CBSIs to cross the BBB and inhibit tumor growth, migration, and induce apoptosis in BCBM models.
- To determine the therapeutic potential of SB-216 and SP-1-39 in both preventive and treatment settings for BCBM, including taxane-resistant TNBC.
Main Methods:
- Development of novel CBSIs, SB-216 and SP-1-39, targeting tubulin.
- Evaluation of BBB penetration, in vitro cytotoxicity, cell migration inhibition, and apoptosis induction.
- Preclinical testing in BCBM models, including assessment of preventive and therapeutic efficacy on brain and extracranial metastases, and overall survival.
- Testing in a taxane-refractory TNBC patient-derived xenograft (PDX) model.
Main Results:
- SB-216 and SP-1-39 demonstrated potent preclinical efficacy against BCBM, crossing the BBB with low nM potencies.
- Both agents inhibited cell growth and migration while inducing apoptosis, comparable to Azixa (MPC-6827).
- SB-216 reduced brain and extracranial metastases and extended survival in preventive models, also suppressing established lesions.
- SP-1-39 significantly reduced tumor burden in a taxane-refractory TNBC PDX model.
Conclusions:
- SB-216 and SP-1-39 represent promising therapeutic candidates for BCBM, including TNBC.
- These CBSIs possess the ability to cross the BBB and combat both taxane-sensitive and -resistant disease.
- The findings highlight a potential new strategy for managing aggressive BCBM and addressing therapeutic gaps in TNBC treatment.
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