Clinical Trials Of Antiangiogenic Therapies Research Articles

Association of pathogenic germline variant KDR Q472H with angiogenesis and resistance to treatment in melanoma.

10060 Background: Preclinical data suggest that melanoma angiogenesis promotes resistance to MAPK-pathway (MAPKi) and immune checkpoint inhibitors (ICIs). However, phase II clinical trials of anti-angiogenic therapy in melanoma were disappointing. We previously identified a pathogenic germline variant Q472H in the kinase insert domain receptor [KDR Q472H; vascular endothelial growth factor receptor-2 (VEGFR-2)] in 35% of primary melanoma patients. We hypothesize that KDR Q472H promotes resistance to MAPKi or ICIs, and that combined MAPKi or ICI and VEGF pathway inhibition may improve outcomes in patients harboring the variant. Methods: Metastatic melanoma (MM) patient clinical data and biospecimens enrolled in the NYU Langone Medical Center Melanoma program were studied. KDR status was determined by TaqMan assays. Tumor microvessel density (MVD) was assessed by CD34 immunohistochemistry. The impact of KDR Q472H on the tumor microenvironment was determined by RNA-seq and Nanostring. Synergy between BRAF (dabrafenib) and VEGFR-2 (lenvatinib) inhibitors in KDR-genotyped MM cell lines was assessed using cell proliferation assays and the Chou-Talalay method. Synergy between ICIs and anti-VEGFR-2 was evaluated in vivo using a B16 melanoma model. Results: We studied 221 MM patients (38% KDR Q472H variants). KDR Q472H variant was significantly associated with higher tumor MVD (P = 0.002). Among the MAPKi-treated patients, KDR Q472H homozygotes had shorter median progression-free survival (PFS, 3.3 vs 9.7 months, P = 0.009) than KDR wild type (WT). In patients treated with anti-PD-1-based therapies, response rates were lower in KDR Q472H variant patients compared to WT (P = 0.012), with shorter median PFS (8.4 months vs not reached, P = 0.0443). Transcriptomic analyses identified an immunosuppressive phenotype in KDR Q472H tumors, with reduced expression of genes associated with chemotaxis, inflammation, T cell activity, and antigen presentation. Consistent with this finding, VEGFR-2 blockade in a KDR Q472H B16 mouse melanoma model augmented the anti-melanoma immune response. KDR Q472H cell lines displayed synergistic cytotoxicity with dabrafenib and lenvatinib, compared to KDR WT cells. Conclusions: Our data demonstrate that melanoma patients with pathogenic germline variant KDR Q472H may be more resistant to both ICIs and MAPKi. Anti-angiogenic therapy should be reconsidered within this specific subset of patients in prospective clinical trials.

Clinical trials of antiangiogenic therapy for hepatocellular carcinoma.

Angiogenesis is a promising therapeutic target to inhibit tumor growth. This review summarizes data from clinical trials of antiangiogenic agents in hepatocellular carcinoma. A systematic search of PubMed was performed to identify clinical trials of specific antiangiogenic agents in hepatocellular carcinoma treatment, particularly phase III trials involving treatment guidelines for advanced hepatocellular carcinoma. Sorafenib is the only systemic drug approved for the treatment of advanced hepatocellular carcinoma. Two large-scale, randomized phase III trials using sorafenib involving patients with unresectable HCC showed a significant survival benefit compared with placebo control groups. However, subsequent phase III trials of antiangiogenic agents in hepatocellular carcinoma have failed to improve survival compared with standard treatment protocols using sorafenib. The efficacy of antiangiogenic agents in combination with other drugs, transarterial chemoembolization, and surgical resection is currently being investigated. Future research is expected to optimize antiangiogenic therapies in combination with standard treatment with sorafenib.

Response Assessment Criteria for Glioblastoma: Practical Adaptation and Implementation in Clinical Trials of Antiangiogenic Therapy

Since 1990, the primary criteria used for assessing response to therapy in high-grade gliomas were those developed by Macdonald and colleagues, which incorporated 2-dimensional area measurements of contrast-enhancing tumor regions, corticosteroid dosing, and clinical assessment to arrive at a designation of response, stable disease, or progression. Recent advances in imaging technology and targeted therapeutics, however, have exposed limitations of the Macdonald criteria and have highlighted the need for reevaluation of response assessment criteria. In 2010, the Response Assessment in Neuro-Oncology (RANO) Working Group published updated criteria to address this need and to standardize response assessment for high-grade gliomas. In 2009, prior to the publication of the RANO criteria, the randomized, placebo-controlled, multicenter, phase 3 AVAglio trial was designed and initiated to investigate the effectiveness of radiotherapy and temozolomide with or without bevacizumab in newly diagnosed glioblastoma. The AVAglio protocol enacted specific measures to adapt the Macdonald criteria to the frontline treatment setting and to antiangiogenic agent evaluation, including the incorporation of a T2/fluid-attenuated inversion recovery component, qualitative assessment of irregularly shaped contrast-enhancing lesions, and a decision tree for confirming or ruling out pseudoprogression. Moreover, the protocol outlines practical means by which these adapted response criteria can be implemented in the clinic. This article describes the evolution of radiographic response criteria for high-grade gliomas and highlights the similarities and differences between those implemented in the AVAglio study and those subsequently published by RANO.

Biology of vascular endothelial growth factor and its receptors in head and neck cancer: Beyond angiogenesis

Angiogenesis is a necessary process for tumor progression and is driven through molecular interactions between cancer cells and neighboring vascular endothelial cells. The primary mediators of angiogenesis are the vascular endothelial growth factors and their respective receptors on endothelial cells. There are several U.S. Food and Drug Administration-approved anti-angiogenic agents in clinical use. In head and neck cancer there are clinical trials assessing the efficacy of anti-angiogenic agents in combination with chemoradiation therapy. Although the aforementioned growth factors and receptors have been traditionally viewed as anti-angiogenic targets, there are concomitant efforts to understand the role these molecules play within the tumor cells. In this review, we first discuss the biology of angiogenic proteins and the targeting of angiogenic molecules for cancer treatment. We summarize the current clinical trials of anti-angiogenic therapies in head and neck squamous cell carcinoma. Finally, the additional role these molecules play in tumor progression independent of angiogenesis is discussed.

PLASMA HEPARANASE AS A SIGNIFICANT MARKER OF TREATMENT RESPONSE IN CHILDREN WITH HODGKIN LYMPHOMA: Pilot Study

Introduction: The aim of this pilot study was to determine heparanase plasma levels (HP) at diagnosis and at restaging in children diagnosed with Hodgkin lymphoma and to investigate whether this parameter provides prognostic information for response to treatment after induction therapy. Patients and Methods: HP levels of 19 pediatric patients (mean age: 10.3 years (y) (range, 4–18 y), 9 girls, 10 boys) with Hodgkin lymphoma were assayed at diagnosis and at restaging. HP levels were determined using an ELISA anti-human heparanase immunoassay kit. According to diagnosis, CAT scan and/or FDG/ PET-CT fusion were performed to assess response to treatment after 2–3 courses of chemotherapy. Two patients received VAMP protocol (1 stage IA, 1 stage IIA), 1 received AV-PC (nonbulky stage IIA), 4 received COPP/ABV (3 stage IIA bulky, 1 stage IIIA nonbulky), 4 received ABVE-PC (2 stage IIB, 1 stage IIA bulky, 1 stage IIIA bulky), 2 received ABVD (1 stage IIA bulky, 1 stage IIIA), and 6 received escalated BEACOPP (1 stage IIIB, 3 stage IVA, 2 stage IVB). Results: Changes in HP levels were found to correlate with response to treatment for most of the children. At diagnosis, average HP level was 1019 pg/mL (range, 141–5733 pg/mL), decreasing at restaging to 588 pg/mL (range, 62–3267 pg/mL) (p =. 034). At diagnosis, the average HP of the 16 patients in CR or VGPR was 1104 pg/mL; it had decreased at restaging to 586 pg/mL (p =. 032). At diagnosis, the average HP level for the 3 patients with TP or PR was 1704 pg/mL; it had increased to 1938 pg/mL at restaging (p =. 166). Due to the small number of patients, no correlation was observed between HP levels at diagnosis, staging, or any other clinical prognostic factor. Conclusions: Changes in plasma HP levels correlated with response to treatment for children diagnosed with Hodgkin lymphoma. This provides a rationale for exploring clinical interest in plasma heparanase measurements of a larger group, using the test for clinical trials of antiangiogenic therapies.

Focal Gains of VEGFA and Molecular Classification of Hepatocellular Carcinoma

Hepatocellular carcinomas represent the third leading cause of cancer-related deaths worldwide. The vast majority of cases arise in the context of chronic liver injury due to hepatitis B virus or hepatitis C virus infection. To identify genetic mechanisms of hepatocarcinogenesis, we characterized copy number alterations and gene expression profiles from the same set of tumors associated with hepatitis C virus. Most tumors harbored 1q gain, 8q gain, or 8p loss, with occasional alterations in 13 additional chromosome arms. In addition to amplifications at 11q13 in 6 of 103 tumors, 4 tumors harbored focal gains at 6p21 incorporating vascular endothelial growth factor A (VEGFA). Fluorescence in situ hybridization on an independent validation set of 210 tumors found 6p21 high-level gains in 14 tumors, as well as 2 tumors with 6p21 amplifications. Strikingly, this locus overlapped with copy gains in 4 of 371 lung adenocarcinomas. Overexpression of VEGFA via 6p21 gain in hepatocellular carcinomas suggested a novel, non-cell-autonomous mechanism of oncogene activation. Hierarchical clustering of gene expression among 91 of these tumors identified five classes, including "CTNNB1", "proliferation", "IFN-related", a novel class defined by polysomy of chromosome 7, and an unannotated class. These class labels were further supported by molecular data; mutations in CTNNB1 were enriched in the "CTNNB1" class, whereas insulin-like growth factor I receptor and RPS6 phosphorylation were enriched in the "proliferation" class. The enrichment of signaling pathway alterations in gene expression classes provides insights on hepatocellular carcinoma pathogenesis. Furthermore, the prevalence of VEGFA high-level gains in multiple tumor types suggests indications for clinical trials of antiangiogenic therapies.

Rapidly acting antitumoral antiangiogenic therapies

We deal with a biophysical description of antitumor antiangiogenic therapies. In particular, by means of some simple models, we study the possible effects of the delay between the drug consumption by endothelial cells and their death on the outcome of the therapy. We have found that this time lag implies an increase in the minimal dose guaranteeing tumor eradication and, if the delay is greater than a meaningful threshold, it may preclude the total regression. These results might be of interest in better understanding the causes underlying the contradictory literature on the clinical trials of antiangiogenic therapies.

Plasma heparanase as a significant marker of treatment response in pediatric malignancies: Pilot study

9540 Introduction: The aim of this pilot study was to determine heparanase plasma levels (HP) at diagnosis and at restaging in children diagnosed with cancer, and to investigate whether this parameter provides prognostic information for remission after induction therapy and response to treatment. Patients and Methods: Heparanase plasma levels of 45 consecutive pediatric patients (pts) with various types of cancer were assayed at diagnosis and at restaging. Mean age: 10.3 years (y) (0.5y-21y), 20 females, 25 males. Levels of heparanase were determined using a commercially available ELISA anti-human heparanase immunoassay kit. According to diagnosis, bone marrow aspiration, CAT scan, MRI, technetium bone scan, PET-CT fusion were performed to assess response to treatment after the first month of induction for leukemia patients, 2 to 3 courses of chemotherapy for other malignancies. Results: Changes in HP levels were found to correlate with response to treatment for most of the children. At diagnosis, average HP level was 1,539 pg/mL (range, 55 pg/mL-6,567 pg/mL) and decreased at restaging to 943 pg/mL (range, 0 pg/mL -3,682 pg/mL) (p=0.0133). At diagnosis, the average HP of the 37 patients in CR or VGPR was 1,692 pg/mL and at restaging decreased to 928 pg/mL (p=0.0071). At diagnosis, the average HP level for the 5 pts with TP or PR was 1,873 pg/mL and increased to 2,633 pg/mL at restaging (p=0.4223). Due to the small number of patients we did not observe any correlation with diagnosis or any other clinical prognostic factor. Conclusions: Changes in plasma heparanase levels correlated with response to treatment for all of the children diagnosed with cancer. This provides a rationale for exploring clinical interest in plasma heparanase measurements of a larger group of children with malignancies, and using the test for clinical trials of antiangiogenic therapies. No significant financial relationships to disclose.

Risk of intracranial hemorrhage and cerebrovascular accidents in non-small cell lung cancer brain metastasis patients

7671 Background: Brain metastases confer significant morbidity and a poorer survival in non-small cell lung cancer (NSCLC). Vascular endothelial growth factor-targeted antiangiogenic therapies (AAT) have demonstrated benefit for patients with metastatic NSCLC and are expected to directly inhibit the pathophysiology and morbidity of brain metastases, yet patients with brain metastases have been excluded from most clinical trials of AAT for fear of intracranial hemorrhage (ICH). This is a low suspected risk, but needs to be quantitated to plan clinical trials of AAT for NSCLC brain metastases. Methods: Data from MD Anderson Cancer Center Tumor Registry and electronic medical records from January 1998 to March 2006 was interrogated. 2143 patients with metastatic NSCLC registering from Jan 1998 to Sept 2005 were followed till March 2006. 776 patients with and 1367 patients without brain metastases were followed till death, date of ICH, or last date of study, whichever occurred first. Results: The incidence of ICH seemed to be higher in those with brain metastasis compared to those without. However, the rates of symptomatic ICH were not significantly different. All ICH patients with brain metastasis had received radiation therapy for them and were not anticoagulated. Most of the brain metastasis-associated ICH's were asymptomatic, detected during radiologic surveillance. The rates of symptomatic ICH, or cerebrovascular accidents were similar and not significantly different between the two groups. The following table depicts the rates of CVA and/or ICH in metastatic NSCLC patients. Conclusions: In metastatic NSCLC patients, the incidence of spontaneous ICH appeared to be higher in those with brain metastases compared to those without, but was very low in both groups nonetheless without a statistically significant difference. These data suggest minimal risk of clinically significant ICH for NSCLC brain metastasis patients and justifies for them clinical trials of AAT. No significant financial relationships to disclose. [Table: see text]

SERUM VEGF AS A SIGNIFICANT MARKER OF TREATMENT RESPONSE IN HODGKIN LYMPHOMA

This pilot study aimed at determining serum VEGF levels (S-VEGF) at diagnosis and at restaging in children with Hodgkin lymphoma, and investigating whether this parameter provides prognostic information for remission after 2 courses of chemotherapy. PET-CT fusion was performed to assess response to treatment. Changes in S-VEGF levels were found to correlate with response to treatment for most of the children. This provides a rationale for exploring clinical interest in S-VEGF measurements in a larger group of children with Hodgkin lymphoma, and using the test for clinical trials of anti-angiogenic therapies.

Serum vascular endothelial growth factor as a significant marker of treatment response in Hodgkin disease

9033 Background: The aim of this pilot study was to determine VEGF serum levels (S-VEGF) at diagnosis and at restaging in children diagnosed with Hodgkin’s disease, and to investigate whether this parameter provides prognostic information for remission after 2 courses of chemotherapy Methods: S-VEGF levels of 9 consecutive pediatric patients (pts) with Hodgkin’s disease were assayed at diagnosis and at restaging. Levels of VEGF were determined using a commercially available ELISA anti-human VEGF immunoassay kit. PET-CT fusion was performed for each child at diagnosis and after 2 courses of chemotherapy in order to assess response to treatment. Results: 8 children went into complete remission or very good partial response after 2 courses of chemotherapy according to the protocol, one child developed tumor progression and respond to second line chemotherapy. At diagnosis average S-VEGF level was 655.7pg/ml (range, 1078.7–29.22 pg/ml) and at restaging decreased to 237.6 pg/ml (range, 0–453 pg/ml). (p=0.0039). One child with Hodgkin’s disease who had a higher level at first restaging and developed progressive disease responded to reinduction therapy and had a significantly lower level at the second restaging. The comparison between the levels of S-VEGF at diagnosis and at restaging showed a significant difference for the pts who responded to treatment with decreased S-VEGF and the pt who developed tumor progression with increased S-VEGF. Conclusions: Changes in S-VEGF levels correlated with response to treatment for most of the children diagnosed with Hodgkin’s disease. This provides a rationale for exploring clinical interest in S-VEGF measurements of a larger group of children with Hodgkin, and using the test for clinical trials of antiangiogenic therapies. No significant financial relationships to disclose.

Clinical trials of antiangiogenic therapy in non-small cell lung cancer: focus on bevacizumab and ZD6474

Lung cancer is the leading cause of cancer deaths in the USA. Despite the development of new chemotherapy regimens, the prognosis remains poor. Several studies comparing various platinum-based regimens failed to produce a significant impact in the outcomes for patients with non-small cell lung cancer and this therapeutic modality appears to be reaching a plateau. It has become clear that further advances will require the addition of agents with a different mechanism of action. Bevacizumab is the antiangiogenic agent at the most advanced stage of development in the treatment of cancer. Bevacizumab is synergistic with chemotherapy and usually well tolerated. The addition of bevacizumab to chemotherapy improved survival in patients with metastatic non-small cell lung cancer in a randomized clinical trial. Several small molecule antiangiogenic agents are in development. In this article, currently available data from clinical trials of antiangiogenic compounds in advanced non-small cell lung cancer are reviewed.

Current status and perspective of antiangiogenic therapy for cancer: urinary cancer

Angiogenesis is considered a prerequisite for solid tumor growth. Antiangiogenic therapy reduces tumor size and extends host survival in a number of preclinical animal models. However, in humans antiangiogenic therapy is a poor promoter of tumor regression and has shown minimal effect on patient survival. In urinary cancers, such as renal cell cancer, prostate cancer, and bladder cancer, advanced refractory disease is a good candidate for antiangiogenic therapy because of its resistance to ordinary chemotherapy, radiotherapy, and hormonal therapy. Unique characteristics of molecular mechanisms underlie the induction of angiogenesis in urinary cancers. In this review, we summarize these unique mechanisms and review the results of clinical trials of antiangiogenic therapy for these cancers, discussing prospects and problems relating to antiangiogenic therapy.

SERUM VASCULAR ENDOTHELIAL GROWTH FACTOR AS A SIGNIFICANT MARKER OF TREATMENT RESPONSE IN PEDIATRIC MALIGNANCIES

The aim of this pilot study was to determine VEGF serum levels (S-VEGF) at diagnosis and at restaging in children diagnosed with cancer, and to investigate whether this parameter provides prognostic information for remission after induction therapy and response to treatment. S-VEGF levels of 35 consecutive pediatric patients with various types of cancer were assayed at diagnosis and at restaging. Levels of VEGF were determined using a commercially available ELISA anti-human VEGF immunoassay kit. Thirty-one children went into complete remission or had a very good partial response to first-line therapy; 4 patients developed tumor progression. At diagnosis average S-VEGF level was 495 pg/mL (range, 0.89–2220 pg/mL) and at restaging it decreased to 118.36 pg/mL (range, 7.44–487 pg/mL). (p = .0039). The 4 patients with tumor progression had increased S-VEGF levels at restaging. The comparison between the levels of S-VEGF at diagnosis and at restaging showed a significant difference for the patients who responded to treatment with decreased S-VEGF and the patients who developed tumor progression with increased S-VEGF (p = .0019). One child with metastatic Ewing sarcoma developed progressive disease after several weeks, with significantly progressively higher S-VEGF levels. One child with Hodgkin disease, who had a higher level at first restaging and developed progressive disease, responded to reinduction therapy and had a significantly lower level at the second restaging. The child with metastatic hepatoblastoma responded to first-line chemotherapy with concomitant decrease in S-VEGF and α-fetoprotein levels, but developed local recurrence with elevation in both parameters. Changes in S-VEGF levels correlated with response to treatment for most of the children diagnosed with cancer. This provides a rationale for exploring clinical interest in S-VEGF measurements of a larger group of children with malignancies, and using the test for clinical trials of antiangiogenic therapies.

Progress Report on the Potential of Angiogenesis Inhibitors for Neuro-Oncology

New therapies for brain tumors are urgently needed. Brain tumors are highly vascularized, supporting the potential of anti-angiogenic therapies in their treatment. The promise of blocking tumor growth through inhibiting new blood vessel formation with anti-angiogenic agents has been heralded as a therapeutic breakthrough, and pre-clinical data supported this enthusiasm. However, early clinical trials in humans have been somewhat disappointing. Nonetheless, great optimism for these agents remains, and many new anti-angiogenic agents and strategies are being evaluated pre-clinically and in clinical trials. A number of issues need to be considered in the application of these agents to neuro-oncology. In this review, we discuss the biology of blood vessel formation in the brain and brain tumors as it relates to anti-angiogenic therapies. The difficulties inherent in performing clinical trials of anti-angiogenic therapies in patients with brain tumors are outlined. Finally, we consider numerous individual anti-angiogenic and antivascular therapies now in pre-clinical testing or in clinical trials.

Angiogenesis in endocrine tumors.

Angiogenesis is the process of new blood vessel development from preexisting vasculature. Although vascular endothelium is usually quiescent in the adult, active angiogenesis has been shown to be an important process for new vessel formation, tumor growth, progression, and spread. The angiogenic phenotype depends on the balance of proangiogenic growth factors such as vascular endothelial growth factor (VEGF) and inhibitors, as well as interactions with the extracellular matrix, allowing for endothelial migration. Endocrine glands are typically vascular organs, and their blood supply is essential for normal function and tight control of hormone feedback loops. In addition to metabolic factors such as hypoxia, the process of angiogenesis is also regulated by hormonal changes such as increased estrogen, IGF-I, and TSH levels. By measuring microvascular density, differences in angiogenesis have been related to differences in tumor behavior, and similar techniques have been applied to both benign and malignant endocrine tumors with the aim of identification of tumors that subsequently behave in an aggressive fashion. In contrast to other tumor types, pituitary tumors are less vascular than normal pituitary tissue, although the mechanism for this observation is not known. A relationship between angiogenesis and tumor size, tumor invasiveness, and aggressiveness has been shown in some pituitary tumor types, but not in others. There are few reports on the role of microvascular density or angiogenic factors in adrenal tumors. The mechanism of the vascular tumors, which include adrenomedullary tumors, found in patients with Von Hippel Lindau disease has been well characterized, and clinical trials of antiangiogenic therapy are currently being performed in patients with Von Hippel Lindau disease. Thyroid tumors are more vascular than normal thyroid tissue, and there is a clear correlation between increased VEGF expression and more aggressive thyroid tumor behavior and metastasis. Although parathyroid tissue induces angiogenesis when autotransplanted and PTH regulates both VEGF and MMP expression, there are few studies of angiogenesis and angiogenic factors in parathyroid tumors. An understanding of the balance of angiogenesis in these vascular tumors and mechanisms of vascular control may assist in therapeutic decisions and allow appropriately targeted treatment.

Angiogenesis in rheumatoid arthritis

Chapter SummaryThe expansion of the synovial lining of joints in rheumatoid arthritis (RA) and the subsequent invasion by the pannus of underlying cartilage and bone necessitate an increase in the vascular supply to the synovium, to cope with the increased requirement for oxygen and nutrients. The formation of new blood vessels – termed 'angiogenesis' – is now recognised as a key event in the formation and maintenance of the pannus in RA. This pannus is highly vascularised, suggesting that targeting blood vessels in RA may be an effective future therapeutic strategy. Disruption of the formation of new blood vessels would not only prevent delivery of nutrients to the inflammatory site, but could also lead to vessel regression and possibly reversal of disease. Although many proangiogenic factors are expressed in the synovium in RA, the potent proangiogenic cytokine vascular endothelial growth factor (VEGF) has been shown to a have a central involvement in the angiogenic process in RA. The additional activity of VEGF as a vascular permeability factor may also increase oedema and hence joint swelling in RA. Several studies have shown that targeting angiogenesis in animal models of arthritis ameliorates disease. Our own study showed that inhibition of VEGF activity in murine collagen-induced arthritis, using a soluble VEGF receptor, reduced disease severity, paw swelling, and joint destruction. Although no clinical trials of anti-angiogenic therapy in RA have been reported to date, the blockade of angiogenesis – and especially of VEGF – appears to be a promising avenue for the future treatment of RA.