Vascular Disruption Therapy as a New Strategy for Cancer Treatment
Abstract
1. Introduction
2. Vascular Development
2.1. Main Mechanisms of Tumor Vascularization
2.2. Normal Blood Vessels vs. Tumor Blood Vessels Characteristics
3. Strategies to Target Tumor Vasculature
3.1. Anti-Angiogenic Therapy
3.2. Vascular Normalization
3.3. Vascular Promotion
3.4. Vascular Disruption
4. Vascular Disrupting Agents
4.1. Microtubule-Destabilizing Agents
4.2. Flavonoids
4.3. Ligand-Directed Agents
5. Resistance to Vascular Disruption
5.1. Viable Tumor Rim
5.2. Hypoxia-Induced Adaptation
5.3. Cellular and Microenvironmental Factors
5.4. Strategies to Overcome Vascular Disruption Resistance
6. Current Status of Clinical Trial Studies of Vascular Disruption Agents
7. Conclusions and Future Challenges
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AAT | Anti-angiogenic therapy |
ASA404 | Vadimezan |
AVE8061 | Ombrabulin |
CA4P | Fosbretab |
DMXAA | Vadimezan |
EC | Endothelial cell |
EMT | Epithelial-to-mesenchymal transition |
EPCs | Endothelial progenitor cells |
HIF-1α | Hypoxia-inducible factor 1α |
HREs | Hypoxia response elements |
LLC | Lewis lung carcinoma |
LNPs | Nucleic acid-loaded nanoparticles |
MHC | Major histocompatibility complex |
NPI-2358 | Plinabulin |
NSCLC | Non-small cell lung cancer |
PDAC | Pancreatic ductal adenocarcinoma |
siRNA | Small interfering RNA |
TAMs | Tumor-associated macrophages |
TEMs | TIE2-expressing macrophages |
TGF-β | Transforming growth factor β |
TME | Tumor microenvironment |
TNF-α | Tumor necrosis factor α |
Treg | Regulatory T cells |
VCAM-1 | Vascular cell adhesion molecule 1 |
VEGF | Vascular endothelial growth factor |
VEGFR2 | Vascular endothelial growth factor receptor 2 |
VDAs | Vascular disruption agents |
VCO | Vessel co-option |
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Strategies | Mechanism | Advantages | Disadvantages |
---|---|---|---|
Anti-angiogenic therapy (AAT) | Inhibition of new blood vessel formation |
|
|
Vascular normalization | Reduced vessel density and improved structure and functionality |
|
|
Vascular promotion | Increased vessel density and improved structure and functionality |
|
|
Vascular disruption | Collapse of established angiogenic vessels |
|
|
VDAs | Compounds | Mechanism | Features | Enhancing Strategies | References |
---|---|---|---|---|---|
Microtubule-binding | CA4P, OXi4503 | Endothelial cytoskeleton collapse |
| Improved-selectivity analogs | Liu et al., 2017 [82] Wei et al., 2025 [78] Prieto et al., 2025 [79] |
Improved delivery systems | Su et al., 2025 [83] Li et al., 2025 [84] | ||||
Flavonoids | DMXAA | Cytokine induction, apoptosis |
| Cell-mediated delivery systems | Chu et al., 2025 [85] |
Ligand-directed | Antibodies, peptides | Targeted toxin/pro-coagulant delivery |
| Lipid nanoparticle-mediated ligand silencing | Endo et al., 2025 [86] |
Strategy | Mechanism of Action | Compound | Reported Benefits |
---|---|---|---|
Pericyte targeting | Selective ablation of pericyte-covered vessels | Z-GP-DAVLBH | Elimination of VDA-resistant tumor rim |
EPC inhibition | Blockage of post-treatment vascular repair | TKR inhibitors + CA4P/VEGFR2 inhibitors + CA4P | Reduced neovascularization |
Chemotherapy combination | Cytotoxic effect on surviving peripheral tumor cells | Conventional therapies (Carboplatin, Cisplatin, etc.) + VDAs | Enhanced tumor regression, including viable rim |
Immunotherapy combination | Increased immune infiltration and activation | Immune check-point inhibitors + VDAs | Improved immune-mediated tumor clearance |
Radiotherapy combination | Selective radiation of necrotic and hypoxic tumor regions | 131I-A5B7 + CA4P/131I-hypericin | Tumor necrosis targeting, imaging capability |
Anti-angiogenic therapy | Inhibition of neovascularization | VDAs + AAT | Dual targeting of existing and forming vasculature |
Nanoparticle co-delivery | Coordinated delivery of VDAs and cytotoxins | VDAs + drug-loaded nanoparticles | Improved penetration, reduced hypoxia-driven resistance |
Clinical Trial Code | Treatment (Drug) | VDA Target | Pathology Conditions | Start Year, Phase and Status |
---|---|---|---|---|
NCT00003768 | Fosbretabulin (CA4P) | Tubulin | Unspecified Adult Solid Resistant Tumor | 1998 Phase I Completed |
NCT00113438 | Fosbretabulin (CA4P) Paclitaxel Carboplatin | Tubulin | Advanced Imageable Malignancies | 2005 Phase II Completed |
NCT00395434 | Fosbretabulin (CA4P) Bevacizumab (Avastin) | Tubulin VEGF | Advanced solid tumors | 2006 Phase I Completed |
NCT00507429 | Fosbretabulin (CA4P) Carboplatin Paclitaxel | Tubulin | Anaplastic thyroid carcinoma | 2007 Phase II, III Terminated |
NCT00653939 | Fosbretabulin (CA4P) Carboplatin Paclitaxel Bevacizumab | Tubulin VEGF | NSCLC Lung Cancer | 2008 Phase II Completed |
NCT02279602 | Fosbretabulin (CA4P) | Tubulin | Neuroendocrine Tumors | 2014 Phase II Completed |
NCT02055690 | Fosbretabulin (CA4P) Pazopanib | Tubulin | Advanced Recurrent Ovarian Cancer | 2014 Phase Ib/II Terminated |
NCT03014297 | Everolimus Fosbretabulin (CA4P) | Tubulin | Neuroendocrine Tumors | 2017 Phase I Terminated |
NCT00322608 | Plinabulin (NPI-2358) | Tubulin | Advanced Solid Tumor Malignancies Lymphoma | 2006 Phase I Completed |
NCT00630110 | Plinabulin (NPI-2358) Docetaxel | Tubulin | Advanced NSCLC | 2008 Phase I, II Completed |
NCT02812667 | Plinabulin (NPI-2358) Nivolumab | Tubulin | NSCLC Metastatic | 2016 Phase I Active, not recruiting |
NCT02846792 | Plinabulin (NPI-2358) Nivolumab | Tubulin | Stage IIIB-IV NSCLC | 2017 Phase I, II Terminated |
NCT03575793 | Plinabulin (NPI-2358) Nivolumab Ipilimumab | Tubulin | Recurrent Small Cell Lung Cancer | 2018 Phase I, II Completed |
NCT05130827 | Plinabulin (NPI-2358) Pegfilgrastim | Tubulin | Multiple Myeloma | 2021 Phase II Active, not recruiting |
NCT00863733 | Vadimezan (DMXAA/ASA404) | Pro-inflammatory cytokine activation | Solid Tumors | 1996 Phase I Completed |
NCT00856336 | Vadimezan (DMXAA/ASA404) | Pro-inflammatory cytokine activation | Refractory Tumors | 2003 Phase I Completed |
NCT00832494 | Vadimezan (DMXAA/ASA404) Paclitaxel Carboplatin | Pro-inflammatory cytokine activation | NSCLC | 2004 Phase I, II Completed |
NCT00111618 | Vadimezan (DMXAA/ASA404) Docetaxel | Pro-inflammatory cytokine activation | Hormone Refractory Metastatic Prostate Cancer | 2005 Phase II Completed |
NCT00630110 | Vadimezan (DMXAA/ASA404) Docetaxel | Pro-inflammatory cytokine activation | Advanced or Recurrent Solid Tumors | 2009 Phase I Completed |
NCT01299415 | Vadimezan (DMXAA/ASA404) Fluvoxamine | Pro-inflammatory cytokine activation | Solid Tumors | 2009 Phase I Terminated |
NCT01240642 | Vadimezan (DMXAA/ASA404) Paclitaxel + Carboplatin Docetaxel | Pro-inflammatory cytokine activation | Metastatic Cancer With Impaired or Normal Renal Function | 2010 Phase I Terminated |
NCT01057342 | Vadimezan (DMXAA/ASA404) Carboplatin Paclitaxel | Pro-inflammatory cytokine activation | Extensive-Stage Small-Cell Lung Cancer | 2010 Phase II Completed |
NCT00699517 | Ombrabulin (AVE8062) | Tubulin | Advanced Soft Tissue Sarcoma | 2008 Phase III Completed |
NCT00968916 | Ombrabulin (AVE8062) | Tubulin | Advanced Solid Tumors | 2009 Phase I Completed |
NCT01293630 | Ombrabulin (AVE8062) Placlitaxel Carboplatin | Tubulin | Advanced Solid Tumors | 2011 Phase I Completed |
NCT01263886 | Ombrabulin (AVE8062) | Tubulin | NSCLC Metastatic | 2011 Phase II Completed |
NCT01332656 | Ombrabulin (AVE8062) Placlitaxel Carboplatin | Tubulin | Platinum-sensitive recurrent ovarian cancer | 2011 Phase II Completed |
NCT01034631 | BNC105P Everolimus | Tubulin | Renal Cell Carcinoma | 2010 Phase I, II Completed |
NCT03454165 | BNC105P Ibrutinib | Tubulin | Chronic Lymphocytic Leukemia | 2018 Phase I Completed |
NCT03647839 | BNC 105P Nivolumab BBI608 | Tubulin | Refractory Colorectal Cancer | 2018 Phase II Completed |
NCT00419328 | NGR-hTNF | CD13 (aminopeptidase N) | Advanced Solid Tumors | 2005 Phase I Completed |
NCT00483080 | NGR-hTNF | CD13 (aminopeptidase N) | Colorectal Cancer | 2006 Phase II Completed |
NCT00484211 | NGR-hTNF | CD13 (aminopeptidase N) | Advanced or Metastatic Hepatocellular Carcinoma | 2006 Phase II Completed |
NCT00483093 | NGR-hTNF Cisplatin | CD13 (aminopeptidase N) | Advanced or Metastatic Solid Tumor | 2007 Phase I Completed |
NCT00484276 | NGR-hTNF | CD13 (aminopeptidase N) | Advanced or Metastatic Malignant Pleural Mesothelioma | 2007 Phase II Completed |
NCT00675012 | NGR-hTNF Oxaliplatin Capecitabine | CD13 (aminopeptidase N) | Metastatic Colorectal Cancer | 2007 Phase II Completed |
NCT00484432 | NGR-hTNF Doxorubicin | CD13 (aminopeptidase N) | Advanced or Metastatic Ovarian Cancer | 2008 Phase II Completed |
NCT00994097 | NGR-hTNF Cisplatin Gemcitabine Pemetrexed | CD13 (aminopeptidase N) | Advanced NSCLC | 2009 Phase II Completed |
NCT00484341 | Low-dose NGR-hTNF High-dose NGR-hTNF Doxorubicin | CD13 (aminopeptidase N) | Advanced Soft Tissue Sarcoma | 2010 Phase II Completed |
NCT03804866 | NGR-hTNF Pegylated liposomal doxorubicin Doxorubicin | CD13 (aminopeptidase N) | Platinum-resistant Ovarian Cancer | 2013 Phase II Completed |
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Gómez-Escudero, J.; Berlana-Galán, P.; Guerra-Paes, E.; Torre-Cea, I.; Marcos-Zazo, L.; Carrera-Aguado, I.; Cáceres-Calle, D.; Sánchez-Juanes, F.; Muñoz-Félix, J.M. Vascular Disruption Therapy as a New Strategy for Cancer Treatment. Int. J. Mol. Sci. 2025, 26, 10085. https://doi.org/10.3390/ijms262010085
Gómez-Escudero J, Berlana-Galán P, Guerra-Paes E, Torre-Cea I, Marcos-Zazo L, Carrera-Aguado I, Cáceres-Calle D, Sánchez-Juanes F, Muñoz-Félix JM. Vascular Disruption Therapy as a New Strategy for Cancer Treatment. International Journal of Molecular Sciences. 2025; 26(20):10085. https://doi.org/10.3390/ijms262010085
Chicago/Turabian StyleGómez-Escudero, Jesús, Patricia Berlana-Galán, Elena Guerra-Paes, Irene Torre-Cea, Laura Marcos-Zazo, Iván Carrera-Aguado, Daniel Cáceres-Calle, Fernando Sánchez-Juanes, and José M. Muñoz-Félix. 2025. "Vascular Disruption Therapy as a New Strategy for Cancer Treatment" International Journal of Molecular Sciences 26, no. 20: 10085. https://doi.org/10.3390/ijms262010085
APA StyleGómez-Escudero, J., Berlana-Galán, P., Guerra-Paes, E., Torre-Cea, I., Marcos-Zazo, L., Carrera-Aguado, I., Cáceres-Calle, D., Sánchez-Juanes, F., & Muñoz-Félix, J. M. (2025). Vascular Disruption Therapy as a New Strategy for Cancer Treatment. International Journal of Molecular Sciences, 26(20), 10085. https://doi.org/10.3390/ijms262010085