Combined Vascular Endothelial Growth Factor–Targeted Therapy and Radiotherapy for Rectal Cancer: Theory and Clinical Practice
Section snippets
VEGF-Targeted Agents and Radiation in Experimental Tumor Models
Some of the early preclinical studies that used non–VEGF-targeted antiangiogenic agents combined with radiation found that the combination induced greater delays in the growth of tumors than did either modality alone.11, 12 Other studies showed that adding antiangiogenic agents could compromise the response to radiation.13 However, preclinical studies using selective inhibitors of VEGF combined with ionizing radiation have shown good tumor control. For example, the growth of various xenografted
Mechanisms of Action and Schedule Optimization of Anti-VEGF Therapy With Radiotherapy
The mechanisms of action by which anti-VEGF agents increase the efficacy of radiotherapy are not completely understood.20, 21 Three potential mechanisms have been reported.9, 10, 20 First, the inhibition of VEGF–VEGFR-2 signaling can radiosensitize tumor-associated endothelial cells, thereby reducing vascular density and inhibiting the formation of new vessels. Impaired vascular delivery of nutrients and oxygen may result in cancer cell death.22 Second, anti-VEGF agents can normalize the tumor
Multitargeted Agents That Target VEGF Receptors
In addition to antibodies that specifically inhibit VEGF or its main receptor, VEGFR-2, there are also a number of small molecules (receptor tyrosine kinase inhibitors) that inhibit VEGFR-2 in parallel with inhibition of other pathways.20 Some of these agents (eg, SU5416, PTK787/ZK 222584) inhibit primarily VEGF receptors, and others (eg, ZD6474, SU11248) inhibit the activity of several receptor tyrosine kinases in various stromal and cancer cells. Multitargeted inhibitors given as monotherapy
Clinical Trials
Chemoradiotherapy is a standard treatment for patients with locally advanced rectal cancer. To test the hypothesis that adding an anti-VEGF agent to a chemoradiotherapy protocol is safe, we conducted a phase I/II trial of neoadjuvant bevacizumab in combination with 5-FU and radiation therapy in patients with T3 or T4 rectal cancer (Fig 2).23, 24 Patients were given bevacizumab monotherapy in cycle 1 (2 weeks) and bevacizumab plus 5-FU and radiation therapy in cycles 2 to 4. Bevacizumab was
Summary
The successful clinical use of anti-VEGF agents, alone (multitargeted tyrosine kinase inhibitors) and in combination with chemotherapy (bevacizumab), raises important questions about their use in combination with radiation. VEGF plays an important role in the resistance of tumors to radiation. In tumor xenograft models, VEGF-targeted agents are known to sensitize tumors to radiation, increasing the delay of tumor growth and the probability of local control. The radiation-enhancing effects of
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Cited by (82)
Anti-angiogenic nano-delivery system promotes tumor vascular normalizing and micro-environment reprogramming in solid tumor
2022, Journal of Controlled ReleaseCitation Excerpt :Targeting VEGFA with blocking antibodies, or directly inhibiting the VEGF-receptor 2 is the first choice to downregulate angiogenesis [62]. Preclinical and clinical research have found temporarily increased recruitment of new pericytes of tumor vessels, but then extensive vascular pruning of vessels after treated with anti-VEGFA/VEGFR2 inhibitors [63]. The findings of transient vascular normalization effect gave rise to the idea that, rather than inhibiting angiogenesis altogether, controlling angiogenesis would be a preferable approach, thus proposing tumor vascular normalization as a new anti-cancer therapy.
The efficacy and safety of adding bevacizumab in neoadjuvant therapy for locally advanced rectal cancer patients: A systematic review and meta-analysis
2021, Translational OncologyCitation Excerpt :Substantial work has been made by oncologists to evaluate the efficacy of targeted agents as an addition to nCRT strategies for LARC patients in the past decade. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), has been reported to enhance the activity of radiotherapy (RT), based on phase II trials exploring whether bevacizumab facilitates the tumor downstaging-effect of nCRT [9–12]. A previous meta-analysis [13] critically reviewed and evaluated the efficacy of adding bevacizumab in the neoadjuvant setting for LARC patients and reported a promising pooled pCR rate of 27% in 23 bevacizumab-relevant cohorts.
Augmenting the therapeutic window of radiotherapy: A perspective on molecularly targeted therapies and nanomaterials
2020, Radiotherapy and OncologyHistidine-rich glycoprotein-induced vascular normalization improves EPR-mediated drug targeting to and into tumors
2018, Journal of Controlled ReleaseMetronomic chemotherapy
2023, Therapeutic Strategies in Veterinary Oncology
This work was supported by grants from the National Institutes of Health-National Cancer Institute (R21-CA 99237 to C.G.W. and P01-CA80124 and R01-CA115767 to R.K.J.), the National Foundation for Cancer Research (to R.K.J. and C.G.W.), and the American Association for Cancer Research (to D.G.D.).
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Dr Jain is a consultant to AstraZeneca Pharmaceuticals, GLG, Nektar Therapeutics, and ThromboGenics.