Successful Antiangiogenic Therapy Research Articles

Stratification of 18F-Labeled PET Imaging Agents for the Assessment of Antiangiogenic Therapy Responses in Tumors

Successful antiangiogenic therapies have been developed for the treatment of various cancers, but not all patients respond. Therefore, the early determination of therapy efficacy is essential for patient management. This study was done to evaluate the utility of various PET imaging biomarkers for early determination of the response to therapy with the antiangiogenic agent axitinib, a multiple receptor tyrosine kinase inhibitor, in tumors with diverse biologic characteristics. Mice bearing U87-MG and MDA-MB-231 subcutaneous tumors were treated with axitinib (25 mg/kg intraperitoneally daily for 10 d), and tumor volumes were assessed with caliper measurements. The animals were concurrently imaged longitudinally with (18)F-FDG, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT), and 2-(18)F-fluoroethyl-triazolyl conjugated c(RGDyK) peptide ((18)F-FtRGD) to determine the optimal radiopharmaceutical for measuring the early treatment response in the 2 tumor types. Daily administration of axitinib successfully retarded the growth of both U87-MG and MDA-MB-231 subcutaneous tumors, with significant differences in tumor volumes being observed from day 7 after therapy on. (18)F-FDG revealed a treatment efficacy response only at day 10 after treatment in both U87-MG tumor-bearing and MDA-MB-231 tumor-bearing animals. (18)F-FLT afforded earlier detection of the therapy response, revealing a significant difference between drug- and vehicle-treated animals at day 3 for animals bearing U87-MG tumors and at day 7 for animals bearing the more slowly growing MDA-MB-231 tumors. (18)F-FtRGD showed a rapid change in tumor retention that reached significance by day 7 in U87-MG tumor-bearing animals; in contrast, no significant difference in tumor retention was observed in MDA-MB-231 tumor-bearing animals. Longitudinal imaging with different radiopharmaceuticals displays various characteristics in different tumor types, depending on their biologic characteristics. Such studies may provide clinically important information to guide patient management and monitor the response to antiangiogenic therapy with the optimum noninvasive imaging agent in the relevant cancer type.

Modulating the tumor immune microenvironment as an ovarian cancer treatment strategy

After more than 30 years of iterations of surgical debulking plus chemotherapy, the need for complementary ovarian cancer treatments has become clear. In the ovarian cancer microenvironment, myeloid immunosuppressive leukocytes, lymphocytes, fibroblasts and endothelial cells, as well as their secreted products, surface molecules and paracrine survival factors, all provide opportunities for novel interventions. The potential of targeting microenvironmental elements in ovarian cancer patients is underscored by recently successful anti-angiogenic therapies. The compartmentalized nature of ovarian cancer, its immunogenicity and its accessibility make it an ideal disease for targeting non-tumor host cells. This review discusses the 'state-of-the-art' of the field, with an emphasis on the potential of modulating the activity of abundant microenvironmental immune cells, which govern both angiogenesis and immunosuppression.

Tumor Angiogenesis 2012

It has been more than 40 years since the initial prospect emerged that tumor angiogenesis could be targeted for cancer therapy. This proposal was based on the very simple observation that tumors are capable of stimulating new vascularization. Later the concept of an angiogenic switch was proposed; where cancer cells evolve from a dormant state into angiogenic phenotype attracting blood vessels growth and invading neighboring and distant sites. Since Folkman's landmark observations [1] a more complex picture of angiogenesis has emerged replete with a complex tumor microenvironment and interactions with multiple cell types within the tumor. Numerous anti angiogenic agents were developed successfully for the treatment of renal cell carcinoma, lung cancer, breast cancer, brain tumors, and colorectal carcinoma, but resistance to these therapies soon emerged. This stimulated additional research that led to the better understanding of the very complex interaction of tumor angiogenesis and the tumor microenvironment responsible for the lack of lasting response to angiogenesis targeted therapy. In this issue of Tumor Angiogenesis, several review papers discuss the current status of our understanding of and therapy for ovarian carcinoma, head, and neck cancer, melanoma, glioma, and leukemia (papers by A. Amini et al., C. Carla et al., U. Adamcic et al., K. Shirai et al., S. R. Choudhury et al., and A. Trujillo et al.) The role of pericytes by E. Fakhrejahani and M. Toi T. Duong et al.'s contribution on the role of lymphangiogenesis enhance the spectrum of different cellular and structural components contributing to cancer progression and metastases. The most novel contribution emerges from the role of external stimuli in the promotion of angiogenesis. Diet as a modifier of tumor angiogenesis by W. W. Li et al. and I. Urits et al., substantiates the role of external control of microenvironment by diet, which is complemented by the observations of K. Luk et al. on pericyte-endothelial interaction influenced by morphine generally used to treat severe pain in patients with cancer. Insights into newer signaling pathways such as, PTEN (S. Rodriguez, and U. Huynh-Do), c-Kit (K. Rupertus et al.) and transcription factor FoxC2 (T. Kume) provide an understanding of yet to be conquered targets to efficiently treat cancer. Additionally, imaging techniques for tumor angiogenesis discussed by K. Tanaka et al. also offer novel approaches to understand tumor angiogenesis. The interaction between tumor vasculature and the microenvironment is reviewed by E. Fakhrejahani, M. Toi, K. Rupertus et al., and S. Niland et al., and inflammation and cancer is examined by J. I. Arias et al. These publications provide an up to date comprehensive state of research on tumor angiogenesis. We therefore hope that this issue will help the readers understand the underlying complex biology and challenges in developing successful antiangiogenic therapy. Arkadiusz Z. Dudek Kalpna Gupta Sundaram Ramakrishnan Debabrata Mukhopadhyay

Pulmonary Hypertension Presenting With Apnea, Cyanosis, and Failure to Thrive in a Young Child

Pulmonary Hypertension Presenting With Apnea, Cyanosis, and Failure to Thrive in a Young Child

Non-receptor protein-tyrosine kinases as molecular targets for antiangiogenic therapy (Review)

Antiangiogenic therapy, including blockade of vascular endothelial growth factor (VEGF) signaling, was highly anticipated to improve the prognosis for patients with advanced cancers following the success of preclinical animal models. However, antiangiogenic monotherapy with VEGF antagonists has produced disappointing results in clinical trials to date. One of the reasons for this poor outcome is that angiogenesis is not solely regulated by VEGF. Inhibition of VEGF signaling, therefore, may select for tumor cell populations that stimulate angiogenesis through VEGF-independent pathways. Successful antiangiogenic therapy, therefore, may require simultaneous blockade of signaling downstream from multiple proangiogenic factor receptors. Recently, we found that non-receptor protein-tyrosine kinases, including members of the Src and Fes families, play vital roles in the responses of cultured endothelial cells to several proangiogenic factors. In this review, we summarize the contributions of these kinase families to angiogenic pathways in endothelial cells, and discuss the potential of these kinases as new targets for antiangiogenic drug discovery.

Combinatorial Antiangiogenic Gene Therapy by Nonviral Gene Transfer Using the Sleeping Beauty Transposon Causes Tumor Regression and Improves Survival in Mice Bearing Intracranial Human Glioblastoma

Glioblastoma is a fatal brain tumor that becomes highly vascularized by secreting proangiogenic factors and depends on continued angiogenesis to increase in size. Consequently, a successful antiangiogenic therapy should provide long-term inhibition of tumor-induced angiogenesis, suggesting long-term gene transfer as a therapeutic strategy. In this study a soluble vascular endothelial growth factor receptor (sFlt-1) and an angiostatin–endostatin fusion gene (statin-AE) were codelivered to human glioblastoma xenografts by nonviral gene transfer using the Sleeping Beauty (SB) transposon. In subcutaneously implanted xenografts, co-injection of both transgenes showed marked anti-tumor activity as demonstrated by reduction of tumor vessel density, inhibition or abolition of glioma growth, and increase in animal survival (P = 0.003). Using luciferase-stable engrafted intracranial gliomas, the anti-tumor effect of convection-enhanced delivery of plasmid DNA into the tumor was assessed by luciferase in vivo imaging. Sustained tumor regression of intracranial gliomas was achieved only when statin-AE and sFlt-1 transposons were coadministered with SB-transposase-encoding DNA to facilitate long-term expression. We show that SB can be used to increase animal survival significantly (P = 0.008) by combinatorial antiangiogenic gene transfer in an intracranial glioma model.

A Comparison of Antiangiogenic Therapies for the Prevention of Liver Metastases

Angiogenesis is essential for solid tumor growth. Although successful antiangiogenic therapies have been demonstrated in animal models, a systematic comparison of the efficacy of different antiangiogenic factors has not been described in the hepatic environment. To address this issue, CT26 murine colon carcinoma cells were transfected with retroviral vectors encoding murine endostatin (mEndostatin), human angiostatin (hAngiostatin), murine-soluble vascular endothelial growth factor receptor-2, (msFlk-1), or murine-soluble Tie2 (msTie2). The transfected cells were then subjected to another round of transfection with a luciferase cDNA-encoding retroviral vector. Expression of these putative antiangiogenic proteins inhibited the proliferation of human umbilical vein endothelial cells in vitro but not tumor cells. To examine effects on tumor growth in vivo, modified cells were delivered via intrasplenic injection into BALB/c mice to induce liver metastases. Tumor burden was measured weekly by bioluminescence. Growth of hepatic metastases in vivo was significantly reduced in mice that were administered cells expressing msTie2 (76% reduction compared with control cells 21 days after intrasplenic inoculation; P < 0.05). Similar results were observed with cells that expressed msFlk-1 and hAngiostatin. However, expression of mEndostatin had no significant effect on the growth of liver metastases compared with control animals. These findings indicate that multiple antiangiogenic pathways are necessary for the growth of hepatic metastases, and each of these pathways is a potential clinically relevant antiangiogenic target for the treatment of this disease.

Pulmonary Capillary Hemangiomatosis With Atypical Endotheliomatosis : Successful Antiangiogenic Therapy With Doxycycline

We report here our experience in achieving remission in a 20-year-old man with pulmonary capillary hemangiomatosis (PCH) with atypical endotheliomatosis following therapy with doxycycline. PCH is a rare disorder characterized by proliferating capillaries that invade the pulmonary interstitium and alveolar septae, and occlude the pulmonary vasculature. The patient's symptoms, lung function, and radiographic findings had worsened despite treatment with both prednisone and alpha-interferon. He was considered to be a candidate for transplantation. Given the elevated levels of basic fibroblast growth factor (bFGF) in urine and the capillary proliferation noted on biopsy specimens, we elected to treat the patient with doxycycline, a matrix metalloproteinase and angiogenesis inhibitor. Following several weeks of therapy, a gradual resolution of symptoms was noted, with normalization of pulmonary function test results and urine bFGF levels. After 18 months of therapy, the patient remains in complete remission.

Local anti-angiogenic brain tumor therapies.

The critical role of angiogenesis in the growth of solid tumors, including neoplasms of the central nervous system, has provided the impetus for research leading to the discovery of inhibitors of tumor neovascularization. The therapeutic potential of systemically administered antiangiogenic drugs for brain tumors, however, is limited by a variety of anatomic and physiologic barriers to drug delivery. Implantable controlled-release polymers for local drug administration directly into the tumor parenchyma have therefore been developed to achieve therapeutic concentrations of these drugs within the brain while minimizing systemic toxicity. With use of these polymers, successful antiangiogenic therapy for treatment of experimental intracranial malignancies has been achieved. This has been demonstrated with a variety of otherwise unrelated drugs -- including the angiostatic steroids, tetracycline derivatives, and amiloride -- which modulate collagenase activity, and thus, basement membrane and interstitial matrix metabolism. Controlled-release polymers provide a clinically practicable method of achieving sustained antiangiogenic therapy which can be readily used in combination with other treatment modalities such as cytoreductive surgery, radiation, and cytotoxic chemotherapy.