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Combined treatment strategies for microtubule stabilizing agent-resistant tumors
Angela Broggini-Tenzer1, Ashish Sharma1, Katarzyna J Nytko1
1Laboratory for Molecular Radiobiology, Radiation Oncology, University Hospital Zurich, Zurich, Switzerland (ABT, AS, KJN, SB, VV, KO, DH, TOR, MP); Department of Dermatology, University Hospital Zurich, Zurich, Switzerland (DH); Clinical Research Priority Program Tumor Oxygenation, University Hospital Zurich, Zurich, Switzerland (KJN, MP).Current affiliation: Novartis Pharma Switzerland (KO).
Background:
Resistance to microtubule-stabilizing agents is a major hurdle for successful cancer therapy. We investigated combined treatment of microtubule-stabilizing agents (MSAs) with inhibitors of angiogenesis to overcome MSA resistance.
Methods:
Treatment regimens of clinically relevant MSAs (patupilone and paclitaxel) and antiangiogenic agents (everolimus and bevacizumab) were investigated in genetically defined MSA-resistant lung (A549EpoB40) and colon adenocarcinoma (SW480) tumor xenografts in nude mice (CD1-Foxn1
Results:
Inhibition of mTOR-kinase by everolimus only minimally reduced the proliferative activity of β tubulin-mutated lung adenocarcinoma cells alone and in combination with the MSA patupilone, but everolimus inhibited expression and secretion of vascular endothelial growth factor (VEGF) from these cells. mTOR-kinase inhibition strongly sensitized tumor xenografts derived from these otherwise MSA-resistant tumor cells to patupilone. Tumors treated with the combined modality of everolimus and patupilone had statistically significantly reduced tumor volume and stronger tumor growth delay (16.2 ± 1.01 days) than control- (7.7 ± 0.3 days, P = .004), patupilone- (10 ± 0.97 days, P = .009), and everolimus-treated (10.6 ± 1.4 days, P = .014) tumors. A combined treatment modality with bevacizumab also resensitized this MSA-refractory tumor model to patupilone. Treatment combination also strongly reduced microvessel density, corroborating the relevance of VEGF targeting for the known antivasculature-directed potency of MSA alone in MSA-sensitive tumor models. Resensitization to MSAs was also probed in P glycoprotein-overexpressing SW480-derived tumor xenografts. Different bevacizumab regimens also sensitized this otherwise-resistant tumor model to clinically relevant MSA paclitaxel.
Conclusions:
A treatment combination of MSAs with antiangiogenic agents is potent to overcome tumor cell-linked MSA resistance and should be considered as strategy for MSA-refractory tumor entities.
Insights
Combining microtubule-stabilizing agents (MSAs) with anti-angiogenic therapies overcomes resistance in cancer treatment. This strategy significantly delays tumor growth in resistant models, offering new hope for refractory tumors.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Microtubule-stabilizing agents (MSAs) are crucial in cancer therapy but face significant resistance.
- Overcoming MSA resistance is essential for improving patient outcomes.
Purpose of the Study:
- To investigate the efficacy of combining MSAs with anti-angiogenic agents to overcome MSA resistance.
- To evaluate this combination strategy in preclinical models of resistant lung and colon adenocarcinoma.
Main Methods:
- Used clinically relevant MSAs (patupilone, paclitaxel) and anti-angiogenic agents (everolimus, bevacizumab).
- Tested treatment regimens in genetically defined MSA-resistant lung (A549EpoB40) and colon adenocarcinoma (SW480) xenografts in mice.
- Assessed tumor growth delay using Kaplan-Meier analysis and statistical tests.
Main Results:
- Everolimus (mTOR inhibitor) sensitized MSA-resistant lung cancer cells to patupilone by reducing VEGF expression and secretion.
- Combined everolimus and patupilone significantly reduced tumor volume and prolonged tumor growth delay (16.2 days vs 7.7 days control).
- Bevacizumab also resensitized resistant lung and colon cancer models to MSAs (patupilone and paclitaxel), reducing microvessel density.
Conclusions:
- Combination therapy of MSAs with anti-angiogenic agents effectively overcomes tumor cell-linked MSA resistance.
- This strategy holds promise for treating MSA-refractory tumor entities.
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