Combined vascular endothelial growth factor-targeted therapy and radiotherapy for rectal cancer: theory and clinical practice.
ABSTRACT: Despite the routine use of adjuvant and neoadjuvant chemoradiotherapy, patients with advanced rectal tumors experience significant rates of treatment failure and disease recurrence. Resistance to radiation is a particular problem. Adding a vascular endothelial growth factor (VEGF)-targeted therapy may improve outcomes in these patients. Epidemiologic studies have shown that tumor expression of VEGF predicts disease recurrence and lower overall survival in patients treated with radiation. In tumor xenograft models in mice, VEGF-targeted agents increase the response to radiation, with a greater probability of tumor control and a greater delay in tumor growth. In addition to killing cancer cells indirectly by damaging tumor blood vessels (antivascular effect), VEGF-targeted therapy may sensitize tumors to radiation through two mechanisms: by normalizing the tumor vasculature, leading to greater tumor oxygenation, and thereby increasing the cytotoxicity of radiation to cancer cells, and by increasing the radiosensitivity of tumor-associated endothelial cells. In addition, anti-VEGF agents may inhibit the regrowth of tumors after radiation by decreasing the number of circulating endothelial cells and endothelial progenitor cells. A phase I dose-escalation study has shown the safety of bevacizumab at a dose of 5 mg/kg in combination with 5-fluorouracil and radiation in patients with rectal carcinoma, and has provided evidence of both vascular normalization and antivascular mechanisms. Phase II evaluation of bevacizumab in this setting is under way.
Project description:The effects of vascular endothelial growth factor (VEGF) blockade on the vascular biology of human tumors are not known. Here we show here that a single infusion of the VEGF-specific antibody bevacizumab decreases tumor perfusion, vascular volume, microvascular density, interstitial fluid pressure and the number of viable, circulating endothelial and progenitor cells, and increases the fraction of vessels with pericyte coverage in rectal carcinoma patients. These data indicate that VEGF blockade has a direct and rapid antivascular effect in human tumors.
Project description:Tumors escape antiangiogenic therapy by activation of proangiogenic signaling pathways. Bevacizumab is approved for the treatment of recurrent glioblastoma, but patients inevitably develop resistance to this angiogenic inhibitor. We previously investigated targeted ?-particle therapy with 225Ac-E4G10 as an antivascular approach and showed increased survival and tumor control in a high-grade transgenic orthotopic glioblastoma model. Here, we investigated changes in tumor vascular morphology and functionality caused by 225Ac-E4G10.We investigated remodeling of the tumor microenvironment in transgenic Ntva glioblastoma mice using a therapeutic 7.4-kBq dose of 225Ac-E4G10. Immunofluorescence and immunohistochemical analyses imaged morphologic changes in the tumor blood-brain barrier microenvironment. Multicolor flow cytometry quantified the endothelial progenitor cell population in the bone marrow. Diffusion-weighted MR imaged functional changes in the tumor vascular network.The mechanism of drug action is a combination of remodeling of the glioblastoma vascular microenvironment, relief of edema, and depletion of regulatory T and endothelial progenitor cells. The primary remodeling event is the reduction of both endothelial and perivascular cell populations. Tumor-associated edema and necrosis were lessened, resulting in increased perfusion and reduced diffusion. Pharmacologic uptake of dasatinib into tumor was enhanced after ?-particle therapy.Targeted antivascular ?-particle radiation remodels the glioblastoma vascular microenvironment via a multimodal mechanism of action and provides insight into the vascular architecture of platelet-derived growth factor-driven glioblastoma.
Project description:Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the treatment strategy for EGFR-mutant lung cancers; however, resistance usually occurs due to a secondary mutation, T790M, in EGFR. Combination therapy using afatinib and cetuximab has had good results in lung tumors harboring EGFRT790M mutations in clinical trials. The effect of bevacizumab, an antivascular endothelial growth factor (VEGF) antibody, combined with EGFR-TKIs has also been investigated. We hypothesized that the dose of afatinib and cetuximab could be reduced by combination with bevacizumab and that the triplet therapy may result in better tumor inhibition with tolerable toxicity. Using a xenograft mouse model with H1975-harboring EGFRL858R+T790M and RPC-9-harboring EGFR19DEL+T790M , we tested the efficacy of the triplet therapy with a modified dose of afatinib, cetuximab, and bevacizumab, and compared this therapy to single and double therapies. Triplet therapy with afatinib, cetuximab, and bevacizumab induced pathological complete remission in xenograft tumors with H1975 and RPC-9 cells versus tumors treated with single or double therapies. We saw no body weight loss in the mice. The triple therapy induced a significant reduction in CD31-positive vascular endothelial cells and increased cleaved caspase-3-positive cells in the tumors. This suggests that one mechanism underlying the deep remission could be suppression of neovascularization and induction of apoptosis by intensive inhibition of driver oncoproteins and VEGF. These results highlight the potential of afatinib, cetuximab, and bevacizumab to induce deep remission in tumors harboring EGFRT790M mutations. Therefore, clinical trials of this combination therapy are warranted.
Project description:Significant progression has been achieved in the treatment of metastatic colorectal cancer (mCRC) in recent years. This has been partly attributed to successfully incorporating new drugs into combination chemotherapy. In addition to the traditional cytotoxic chemotherapeutic agents, molecularly targeted agents began to play an important role in the treatment of advanced solid tumors. To date, two classes of molecularly targeted agents have been approved for treatment of patients with mCRC: (1) antivascular endothelial growth factor (anti-VEGF) agents (such as bevacizumab and aflibercept) and (2) antiendothelial cell growth factor receptor (anti-EGFR) agents (such as cetuximab and panitumumab). Aflibercept is a new member of anti-VEGF agents which has demonstrated efficacy for treatment of mCRC. With the commencement of clinical trials and basic research into aflibercept, more data from the bedside and the bench have been obtained. This review will outline the application of anti-VEGF agents by reviewing clinic experiences of bevacizumab and aflibercept, and try to add perspectives on the use of anti-VEGF agents in mCRC.
Project description:We explored plasma and urinary concentrations of two members of the vascular endothelial growth factor (VEGF) family and their receptors as potential response and toxicity biomarkers of bevacizumab with neoadjuvant chemoradiation in patients with localized rectal cancer. The concentrations of VEGF, placental growth factor (PlGF), soluble VEGF receptor 1 (sVEGFR-1), and sVEGFR-2 were measured in plasma and urine at baseline and during treatment. Pretreatment values and changes over time were analyzed as potential biomarkers of pathological response to treatment as well as for acute toxicity in patients with locally advanced rectal cancer treated prospectively in 2002-2008 with neoadjuvant bevacizumab, 5-fluorouracil, radiation therapy, and surgery in a phase I/II trial. Of all biomarkers, pretreatment plasma sVEGFR-1-an endogenous blocker of VEGF and PlGF, and a factor linked with "vascular normalization"-was associated with both primary tumor regression and the development of adverse events after neoadjuvant bevacizumab and chemoradiation. Based on the findings in this exploratory study, we propose that plasma sVEGFR-1 should be further studied as a potential biomarker to stratify patients in future studies of bevacizumab and/or cytotoxics in the neoadjuvant setting.
Project description:Angiogenesis has a clear and definite role in the breast cancer progression process, making antivascular endothelial growth factor (VEGF) therapies an attractive option for the treatment of metastatic breast cancer (MBC). Bevacizumab is a potent humanized monoclonal antibody to VEGF, which has shown regression of breast cancer in preclinical and clinical setting, either alone or in combination with cytotoxic treatment. Additionally, bevacizumab potentially increases the effectiveness of other anticancer therapies through the normalization of tumor vasculature, reduction of intratumoral pressure and improved tumor oxygenation. Phase 1/2 trials showed significant antitumor effects of bevacizumab in MBC, in particular in tumors not expressing HER2 receptor. A first phase 3 trial in pre-treated MBC patients showed better response rates but no survival benefit from the addition of bevacizumab to capecitabine. However, in two phase 2 trial in first-line setting in patients with MBC, bevacizumab improved progression-free survival in combination with weekly paclitaxel in comparison to paclitaxel alone or in combination with 3-weekly docetaxel in comparison with docetaxel alone, respectively. Bevacizumab in combination with taxanes seems to be a highly effective first-line treatment for MBC patients. Future research will investigate bevacizumab in the neoadjuvant or adjuvant setting, where even more potential may exist for these patients.
Project description:Emerging evidence suggests that the Notch/Delta-like ligand 4 (Dll4) pathway may offer important new targets for antiangiogenesis approaches. In this study, we investigated the clinical and biological significance of Dll4 in ovarian cancer. Dll4 was overexpressed in 72% of tumors examined in which it was an independent predictor of poor survival. Patients with tumors responding to anti-VEGF therapy had lower levels of Dll4 than patients with stable or progressive disease. Under hypoxic conditions, VEGF increased Dll4 expression in the tumor vasculature. Immobilized Dll4 also downregulated VEGFR2 expression in endothelial cells directly through methylation of the VEGFR2 promoter. RNAi-mediated silencing of Dll4 in ovarian tumor cells and tumor-associated endothelial cells inhibited cell growth and angiogenesis, accompanied by induction of hypoxia in the tumor microenvironment. Combining Dll4-targeted siRNA with bevacizumab resulted in greater inhibition of tumor growth, compared with control or treatment with bevacizumab alone. Together, our findings establish that Dll4 plays a functionally important role in both the tumor and endothelial compartments of ovarian cancer and that targeting Dll4 in combination with anti-VEGF treatment might improve outcomes of ovarian cancer treatment.
Project description:Preclinical data have demonstrated that the combination of antihuman epidermal growth factor receptor-2 (anti-HER2) and antivascular endothelial growth factor (anti-VEGF)--targeted agents has antitumor activity; these data indicate certain patients with HER2-overexpressing breast cancer may derive clinical benefit from this combination. The purpose of this single-arm phase II study was to determine the efficacy and safety of the dual-targeting combination of lapatinib and bevacizumab. Women with HER2-overexpressing advanced breast cancer received 1,500 mg oral lapatinib daily plus 10 mg/kg IV bevacizumab every 2 weeks. The primary endpoint was progression-free survival (PFS) at week 12; secondary endpoints included overall tumor response rate (ORR), clinical benefit rate (CBR), duration of response, time-to-response, PFS, and safety. Circulating tumor cells (CTC) and circulating endothelial cells (CEC) were measured at baseline and during study treatment as potential response markers. Fifty-two patients with stage IV disease were enrolled. The 12-week investigator-assessed PFS rate was 69.2% (95% confidence interval [CI]: 54.9, 81.3). Median PFS was 24.7 weeks (95% CI: 20.4, 35.1), and the CBR was 30.8% (95% CI: 18.7, 45.1). Of 45 patients with measurable disease, 6 were determined to have a partial response per Response Evaluation Criteria in Solid Tumors (ORR: 13.3%; 95% CI: 5.1, 26.8). The most common adverse events (AEs) included diarrhea, rash, and fatigue; most of these were either grade 1 or 2. Clinical responses were correlated with decreases in CTC and CEC. Lapatinib plus bevacizumab was active in patients with HER2-overexpressing breast cancer. The AE profile of the combination was consistent with the known profiles for these agents.
Project description:Clinical studies converge on the observation that circulating cytokines are elevated in most cancer patients by anti-vascular endothelial growth factor (VEGF) therapy. However, the source of these molecules and their relevance in tumor escape remain unknown. We examined the gene expression profiles of cancer cells and tumor-associated macrophages in tumor biopsies before and 12 days after monotherapy with the anti-VEGF antibody bevacizumab in patients with rectal carcinoma. Bevacizumab up-regulated stromal cell-derived factor 1alpha (SDF1alpha), its receptor CXCR4, and CXCL6, and down-regulated PlGF, Ang1, and Ang2 in cancer cells. In addition, bevacizumab decreased Ang1 and induced neuropilin 1 (NRP1) expression in tumor-associated macrophages. Higher SDF1alpha plasma levels during bevacizumab treatment significantly associated with distant metastasis at three years. These data show that VEGF blockade up-regulates inflammatory pathways and NRP1, which should be evaluated as potential targets for improving anti-VEGF therapy.
Project description:Vascular endothelial growth factor (VEGF) plays a pivotal role in the cascade of development and progression of cancers. Targeting this cancer hallmark is a logical strategy for imaging based cancer detection and monitoring the anti-angiogenesis treatment. Using Bevacizumab (Avastin®), which is a recombinant humanized monoclonal antibody directly against VEGF and an angiogenesis inhibitor, as a targeting ligand, a multimodal VEGF targeted molecular imaging probe was developed by conjugating near infrared dye (NIR830) labeled bevacizumab to magnetic iron oxide nanoparticles (IONP) for optical and magnetic resonance (MR) imaging of cancers over-expressing VEGF. The targeting effect of NIR830-bevacizumab-IONPs on VEGF over-expressing cells was investigated by receptor mediated cell uptake experiments and a blocking assay using VEGF over-expressing 4T1 breast cancer cells. Systemic administration of VEGF-targeted NIR830-bevacizumab-IONPs into mice bearing 4T1 breast tumors resulted in higher accumulation of targeting IONPs in tumors compared to non-targeted IONPs. Quantitative analysis of T2-weighted MRI at 48 h post-injection revealed that the averaged percentage of signal intensity change in tumors treated with NIR830-bevacizumab-IONPs was 52.4 ± 11.0% compared to 26.9 ± 12.4% in controls treated with non-targeted IONPs. The results demonstrated the feasibility and efficacy of NIR830-bevacizumab-IONPs as a VEGF targeting dual-modality molecular imaging probe that can be potentially used for imaging of cancers with VEGF over-expression and delivery of bevacizumab for imaging guided anti-cancer treatment.