The Expanding Role of Angiogenesis in Cancer Therapeutics: Folkman Legacy

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The Expanding Role of Angiogenesis in Cancer Therapeutics: Folkman Legacy

Tuesday, May 26, 2009

The New York Academy of Sciences

Presented By

Presented by the Biochemical Pharmacology Discussion Group and held jointly with the American Chemical Society's New York Section.

 

The concept of anti-angiogenesis as a therapeutic strategy for solid tumors was brought forth several decades ago when it was demonstrated that progressive tumor growth is contingent upon formation of new vessels that support proliferation (Folkman, 1972, 1975). Subsequent studies demonstrated that inhibition of angiogenesis, either via direct or indirect means, presents a viable target in anticancer therapy.

After many efforts to develop angiogenesis inhibitors, the breakthrough came in 2004, when the FDA approved bevacizumab (Avastatin; Genentech) and pegaptanib (Macugen; Eyetech Pharmaceuticals). Clinical trials have since proven and indicate that anti-angiogenic therapy will be a mainstay of cancer treatment – a fourth arm with surgery, radiation, and chemotherapy.

Now that the importance of angiogenesis in cancer has been clinically validated, a second generation of questions must be answered. These include the following issues: (1) resistance to angiogenic therapy, (2) the role of endothelial progenitors in angiogenesis, (3) the role of vascular recruitment, (4) surrogate markers for clinical studies, (5) optimal combination strategies, and (6) new targets. The purpose of this symposium is to discuss emerging new data that enables scientists to better utilize and to better identify angiogenic therapies for treating cancer.

The BPDG at the New York Academy of Sciences represents a diverse group of scientists and others with an interest in biochemistry, molecular biology, biomedical research, and related areas. Members are from pharmaceutical and biotechnology companies, and university and medical center research facilities across the Eastern United States. The group also serves as the Biochemical Topical Group for the American Chemical Society's New York Section. The purpose of the BPDG is to bring together diverse institutions and communities, industrial and academic, to share new and relevant information at the frontiers of research and development.

Agenda


8:30 AM

Continental Breakfast

9:00 AM

Welcome Remarks & Session Introduction
Guy Lagaud, PTC Therapeutics, Inc.

9:20 AM

Keynote Talk: Achieving Cancer Control: New Directions for the Antiangiogenesis Paradigm
William Li, The Angiogenesis Foundation

10:05 AM

Antiangiogenesis: Emerging Paradigms and Biomarkers
Rakesh Jain, Massachusetts General Hospital and Harvard Medical School

10:40 AM

Coffee Break

11:10 AM

Mechanisms and Consequences of Therapeutically Inhibiting Tumor Angiogenesis
Robert Kerbel, University of Toronto

11:45 AM

PTC299 – A Novel, Post-transcriptional Inhibitor of Tumor VEGF Production: Preclinical and Clinical Studies in Cancer
Stuart Peltz, PTC Therapeutics, Inc.

12:20 PM

Luncheon

1:20 PM

Session Introduction
Dan Hicklin, Schering-Plough Research Institute

1:30 PM

Endogenous Anti-angiogenics from the VEGF Family
David Bates, Bristol Heart Institute

2:05 PM

Beyond VEGF: Targets in the Setting of Anti-VEGF Resistance
George Yancopoulos, Regeneron Pharmaceuticals, Inc.

2:40 PM

Notch Signaling in Tumor Angiogenesis
Jan Kitajewski, Columbia University

3:15 PM

Coffee Break

3:45 PM

Understanding Evasive Resistance to Antiangiogenic Therapy
Gabriele Bergers, University of California, San Francisco

4:20 PM

Inhibition of Angiogenesis in Cancer; Another Arrow for the Quiver
Rick Kendall, Amgen Inc.

4:55 PM

Closing Remarks
Dan Hicklin, Schering-Plough Research Institute

Organizers

Guy Lagaud

PTC Therapeutics, Inc.

Dr. Lagaud is senior scientist in the metabolism and pharmacology profiling team at PTC Therapeutics Inc. His current research projects include new target identifications for cancer on signaling molecules in angiogenesis, in addition to investigating the role of PTC299 (in phase 1b/2 studies in patients with cancer; a novel small-molecule, orally bioavailable that inhibits the production of the protein vascular endothelial growth factor (VEGF) within tumors) in various xenograft models of human cancer. Lagaud received his doctorate degree from University Louis Pasteur in Strasbourg (France), while working on the relationship between the endothelial and smooth muscle calcium signaling. He was a Vancouver Vascular Biology Research Postdoctoral Special Fellow at University of British Columbia (Canada), where he studied the pivotal role of the endothelium in the regulation of cardiovascular diseases such as atherosclerosis, diabetes and hypertension. He continued his work at Albert Einstein College of Medicine of Yeshiva University in New York (USA) where he investigated the use of potassium channels modulators and gene therapy to ameliorate bladder hyperactivity and erectile dysfunction. Following his post doctorate work he joined Johnson and Johnson Pharmaceuticals Research & Development in the physiological system department.

Dan Hicklin

Schering-Plough Research Institute

Dr. Hicklin currently works in Oncology Discovery at the Schering-Plough Research Institute, Kenilworth, USA. Before joining Schering-Plough in 2007, he held several senior Research and Development positions at ImClone Systems, Inc., New York, most recently as Vice President of Experimental Therapeutics. While at ImClone, he worked for over 20 years on the development of targeted oncology therapeutics, including the anti-epidermal growth factor receptor antibody cetuximab and several other targeted therapies that are currently in clinical development. He has an established reputation in the areas of angiogenesis, tumour biology and drug development of targeted oncology therapeutics. He has authored over 180 publications in peer-reviewed scientific journals.

Keynote Speaker

William Li

The Angiogenesis Foundation

Speakers

David Bates

Bristol Heart Institute

David Bates completed his PhD in 1992 at St George's Hospital Medical School, on the microvascular parameters affecting post mastectomy lymphoedema in patients. After a year learning molecular biology at Glasgow University in Drosophila genetics, he spent three years as a postdoctoral researcher at the University of California at Davis, where he developed the existing single capillary cannulation technique to examine chronic regulation of permeability by growth factors, and started investigating VEGF signalling. He continued these studies as a lecturer at the University of Leicester, investigating the mechanism by which VEGF increases permeability using novel tyrosine kinase inhibitors. During that time he developed angiogenesis protocols to investigate VEGF signalling during blood vessel growth and moved to the University of Bristol as a BHF research fellow. In 2001 he was awarded a BHF lectureship, and in collaboration with Dr Steven Harper, a consultant nephrologist at Southmead Hospital, established the Microvascular Research Laboratories within the School of Veterinary Sciences. In that year he discovered the anti-angiogenic class of VEGF splice variants, and now investigates the potential of VEGF splice variants, tyrosine kinase inhibitors, and VEGF activated ion channels for anti-VEGF therapy. He was appointed Professor of Microvascular Biology and Medicine in the Department of Physiology and Pharmacology in Bristol in 2007.

Gabriele Bergers

University of California San Francisco

Gabriele Bergers PhD is an Associate Professor of Neurological Surgery, a PI of the Brain Tumor Research Center and is affiliated with the Diller Family Comprehensive Cancer Center at UCSF. She is an internationally recognized expert in the field of tumor angiogenesis. Dr. Bergers studies the multifaceted interactions of tumor cells with the vasculature in a variety of mouse tumor models including pancreatic islet tumors, glioblastomas and mammary carcinomas. She was the first to publish that angiogenesis inhibitors have different efficacies depending on the stage of carcinogenesis being targeted (Science 1999). She identified that the angiogenic factor VEGF is critical for the angiogenic switch and is regulated posttranscriptionally, via proteolytic release from the extracellular matrix by the metalloproteinase MMP-9 that is expressed by bone marrow-derived monocytic cells (Nature Cell Biology 2000, Cancer Cell In revision). Dr. Bergers further revealed that VEGF can directly and negatively control perivascular tumor cell invasion of GBM in which tumor cells migrate on the outside of blood vessels deep into normal tissues, an adaptive phenotype that occurs when GBM are unable to induce angiogenesis (Cancer Cell 2003 and In revision). She discovered bone marrow-derived pericyte progenitors in tumors and established their functional significance in maintaining and protecting tumor vessels (Nature Cell Biology 2005, J, Clin. Invest. 2003). Dr. Bergers translates these findings into experimental therapeutic approaches to help guide clinical trials and co-organizes with Dr. Douglas Hanahan the experimental therapeutic group at UCSF that includes various clinical oncologists and basic scientists. Dr. Bergers is a former Kimmel Scholar, an award given to selected promising scientists engaged in cancer research who are at an early stage of their career. She further received a V Foundation Scholar and a Goldhirsh Foundation Award and currently holds the Neill H. and Linda S. Brownstein Endowed Chair in Brain Tumor Research. She is supported by various NIH RO1 grants. Dr. Bergers is an Associate Editor for the Journal of Cancer Research and serves as an external advisor for Emory University and the Children’s Hospital of Los Angeles (Pediatric Brain Tumors). She has chaired and organized angiogenesis sessions at various AACR, Gordon and Keystone Conferences. Dr. Bergers received her graduate degree from the University of Vienna (and the Institute of Molecular Pathology, Vienna) and completed her postdoctoral training under Douglas Hanahan, PhD (UCSF).

Rakesh Jain

Massachusetts General Hospital and Harvard Medical School

Rakesh K. Jain, PhD, is the Andrew Werk Cook Professor of Tumor Biology in the Department of Radiation Oncology at Harvard Medical School, and the Director of the Edwin L. Steele Laboratory of Tumor Biology at the Massachusetts General Hospital. Dr. Jain is regarded as a pioneer in the fields of tumor biology, drug delivery, in vivo imaging and bioengineering. He is known for discovering the physiological barriers to delivery and efficacy of anticancer drugs, for proposing strategies to overcome these barriers and for translating these strategies from bench to bedside. His work has fundamentally changed the thinking of scientists and clinicians about how molecularly targeted therapeutics, especially antiangiogenic agents, actually work in animal models and cancer patients, and how to combine them optimally with cytotoxic therapies to improve survival rates in cancer patients. A mentor to more than 100 doctoral and postdoctoral students from multiple disciplines, and a collaborator of over 100 clinicians and scientists worldwide, Dr. Jain’s findings are summarized in more than 460 publications, including three in Scientific American. He serves on advisory panels to government, industry and academia, and is a member of editorial boards of ten journals, including Nature Reviews Cancer and Nature Reviews Clinical Oncology. He received more than 30 major awards and lectureships, including a Guggenheim Fellowship (1983-1984), an NCI-Research Career Development Award (1980-1985) and an NCI-Outstanding Investigator Grant (1993-2000). He is a member of all three US National Academies - the Institute of Medicine, the National Academy of Engineering and the National Academy of Sciences – and the American Academy of Arts and Sciences.

Rick Kendall

Amgen Inc.

Dr. Kendall is an Executive Director of the Hematology and Oncology department at Amgen Inc. He is currently Head of the Biochemistry and Cellular Biology Departments in the oncology therapeutic area at the Thousand Oaks, CA and Cambridge, MA research sites. Dr. Kendall joined Amgen Inc. in 1999 and has since recruited and built a state-of-the-art Department for research that supports over 30 on going projects including programs in all phases of clinical testing. Dr. Kendall’s Department is directly responsible for the research and discovery leading to 9 clinical candidate molecules including AMG 706, AMG 386, AMG 479, AMG 102 and AMG 208. Prior to joining Amgen Inc. Dr. Kendall was a Senior Scientist at Merck and Company. He holds a Ph.D. in Biological Chemistry from the University of California at Irvine and a Bachelors of Science Degree in Biochemistry from the University of California at Los Angeles. He is a member of number of societies including The American Association for Cancer Research, the American Society for Biochemistry and Molecular Biology and the American Association for the Advancement of Science. He is an Editorial Member and Ad Hoc reviewer for >10 scientific Journal and an Adjunct Associate Professor in the Department of Molecular Cellular and Developmental Biology at the University of California at Santa Barbara.

Robert Kerbel

University of Toronto

Dr. Robert Kerbel, an internationally recognized cancer biologist, is a Senior Scientist in the Molecular and Cellular Biology Research Program in the Sunnybrook Research Institute, Sunnybrook Health Sciences Centre in Toronto. He is also a Professor in the Department of Medical Biophysics, and Department of Laboratory Medicine & Pathobiology, University of Toronto. He also holds a Canada Research Chair in Tumor Biology, Angiogenesis and Antiangiogenic Therapy. Dr. Kerbel has worked in several related areas of tumor biology research since beginning his career as an independent investigator in 1975. These include tumor immunology, biology of metastasis and tumor progression, drug resistance mechanisms in cancer and experimental therapeutics. Since 1990 the main focus of his research has been to understand the basis of tumor angiogenesis, and the design of new therapeutic strategies for cancer based on vascular targeting and inhibition of tumor angiogenesis. His most noteworthy contributions include pioneering the concept of metronomic low-dose chemotherapy, development of biomarker strategies for antiangiogenic drugs, elucidating mechanism of action of VEGF-pathway targeting drugs in fostering the anti-tumor effects of chemotherapy, and developing new models in mice of advanced metastatic disease for drug therapy testing. He has served or currently serves on the editorial boards of numerous journals as well as advisory boards in academia and industry and is the author or co-author of over 330 papers and has given 650 invited lectures on his work around the world since 1976. Dr. Kerbel is also a recipient of a number of research awards including the Robert Noble Prize for Excellence in Cancer Research from the National Cancer Institute of Canada/Canadian Cancer Society in 2004.

Jan Kitajewski

Columbia University

Jan Kitajewski, Ph.D. is Professor of Pathology and Ob/Gyn at Columbia University. He directs the Division of Reproductive Sciences in Ob/Gyn and is Director of the Cancer Signaling Networks program of the Herbert Irving Comprehensive Cancer Center. Dr. Kitajewski obtained a B.S. in Biochemistry from the University of California Berkeley and a Ph.D. in 1987 from Princeton University, conducting thesis work on translational control with Dr. Thomas Shenk. He then conducted postdoctoral work on mammary tumorigenesis with Dr. Harold Varmus at University of California San Francisco. In 1992, he joined the faculty of Columbia University and his laboratory is based in the Irving Cancer Research Center. His research has been funded by the NIH, American Cancer Society, American Heart Association, Department of Defense Breast Cancer Program and Avon Breast Cancer Program. He currently serves as a Charter Member of the Cardiovascular Differentiation and Development NIH Study section and is Co-Editor in Chief of a new BioMed Central open-access journal, Journal of Angiogenesis Research.

Stuart Peltz

PTC Therapeutics, Inc.

Dr. Peltz, President and CEO of PTC Therapeutics, is a leader in the investigation of mRNA turnover and translation and has been involved in developing the first biochemical assays to investigate the regulation of mRNA turnover as well as in demonstrating the strong connection between the processes of translation and mRNA turnover. Dr. Peltz is widely published and serves on National Institutes of Health and American Cancer Society review committees. A recognized scientific leader in the area of post-transcriptional control processes, Dr. Peltz's work was instrumental in identifying and characterizing components of the nonsense-mediated mRNA decay pathway. His laboratory has established the notion that factors involved in nonsense-mediated mRNA turnover are also involved in modulating the processes of translation termination and programmed -1 ribosomal frameshifting. Dr. Peltz received his Ph.D. at the McArdle Laboratory for Cancer Research at the University of Wisconsin.

George Yancopoulos

Regeneron Pharmaceuticals Inc.

After graduating as valedictorian of both the Bronx High School of Science and Columbia College, Dr. Yancopoulos received his MD and PhD degrees in 1987 from Columbia University’s College of Physicians & Surgeons. Following widely-recognized work in the field of molecular immunology at Columbia University with Dr. Fred Alt, for which he received the Lucille P. Markey Scholar Award, Dr. Yancopoulos left academia in 1989 as a founding scientist for Regeneron Pharmaceuticals, where he is now the Chief Scientific Officer and President of Regeneron Laboratories. Dr. Yancopoulos is also an Adjunct Full Professor at Columbia University, and was recently awarded Columbia University’s Stevens Triennial Prize for Research and its University Medal of Excellence for Distinguished Achievement. According to a study by the Institute for Scientific Information, Dr. Yancopoulos was the eleventh most highly cited scientist in the world during the 1990's (citation rates reflect how often a scientist’s work is referred to by other scientists, and is widely regarded as the best way to rank scientists), and the only scientist from the biotechnology industry on the list. Dr. Yancopoulos’ scientific contributions were recently recognized by his election in 2004 to both the National Academy of Sciences and the American Academy of Sciences.

Abstracts

Keynote Presentation

Achieving Cancer Control: New Directions for the Antiangiogenesis Paradigm

William Li
The Angiogenesis Foundation

"Anti-angiogenesis", envisioned by the late Dr. Judah Folkman in the early 1970s, has now become a mainstream approach to treating some forms of cancer and blindness. The still ongoing journey from the discovery of angiogenesis regulatory processes to clinical trials to practical therapies has been characterized by pitfalls and failures, successes and breakthroughs, and unexpected findings. Across this timeline, new biological pathways and interactions at the level of tumor microvascuature have been established, posing new opportunities and challenges for designing therapies that improve outcomes in conquering and controlling cancer. This presentation will discuss how certain core elements of Folkman's pioneering hypothesis have held true, while other elements have evolved to reflect the new biology of angiogenesis and the clinical learnings from today's oncology practice. The future directions of antiangiogenic therapy will be forecast, including the potential for preventing cancer using pharmacological and even dietary approaches.

Antiangiogenesis: Emerging Paradigms and Biomarkers

Rakesh Jain
Massachusetts General Hospital and Harvard Medical School

The seminal hypothesis put forward by the late Dr. Judah Folkman in 1971 has resulted in antiangiogenesis as the fourth modality of cancer treatment. The approval of bevacizumab, an anti-VEGF antibody, in combination with chemotherapy, as well as the approval of oral multi-receptor tyrosine kinase inhibitors that include VEGF receptors as one of their targets have changed the practice of oncology for metastatic colorectal, lung, breast, renal cell and hepatocellular carcinomas.

The approval of these agents has also raised many questions: How do these therapies work in patients? Is their mechanism of action in patients the same as originally envisioned for antiangiogenic agents? Is it the same as demonstrated in animal models? Why is the overall survival benefit so modest? Why do some patients benefit from these therapies and others not? How do we select the former? Why do tumors stop responding? What new pathways should be targeted to prolong the duration of response and survival without increasing toxicities? How do we tailor these new therapies to individual patients? How do we schedule them with existing conventional therapies or other Food and Drug Administration (FDA) approved molecular therapeutics? The answers to these very basic questions are not known for most approved agents and would require sophisticated multi-disciplinary clinical trials tightly integrated with equally sophisticated preclinical studies.

In this presentation, Dr. Jain will attempt to answer these questions with preclinical and clinical data, present emerging paradigms and biomarkers, and speculate where this nascent field is heading in the next several decades for the treatment of cancer and other diseases.

Contrasting Effects of Antiangiogenic Therapy on Tumor Growth, Progression & Metastasis

Robert Kerbel
University of Toronto

Encouraging results obtained in preclinical studies were critical in the decision to evaluate antiangiogenic drugs in clinical trials. Very few of the preclinical studies, however, evaluated therapeutic outcomes in the neoadjuvant, adjuvant, or even advanced metastatic treatment settings. Recent preclinical studies from the Kerbel lab have shown the possibility that antiangiogenic drugs may actually accelerate the growth of early stage micrometastatic disease while inhibiting large established tumors. In this regard, the recently reported results of the C-08 randomized phase III trial of adjuvant bevacizumab and chemotherapy (and then bevacizumab maintenance therapy) in colorectal cancer suggest this type of potential growth–promoting effect must be taken seriously, at least as a matter for future study. Our results also suggest clear strategies to enhance the efficacy of antiangiogenic drugs by minimizing or blocking such potential malignancy promoting effects while amplifying their intrinsic and beneficial growth suppressive properties, e.g. combination with metronomic chemotherapy or 'anti-invasive' agents.

PTC299 – A Novel, Post-transcriptional Inhibitor of Tumor VEGF Production: Preclinical and Clinical Studies in Cancer

Stuart Peltz
PTC Therapeutics, Inc.

PTC Therapeutics, Inc., a biopharmaceutical company located in South Plainfield, NJ, has developed an investigational drug called PTC299. This is a novel, orally administered small-molecule compound that inhibits the production of the protein vascular endothelial growth factor (VEGF) in tumors. PTC Therapeutics discovered PTC299 through the company's proprietary GEMS (Gene Expression Modulation by Small-Molecules) technology by targeting the post-transcriptional processes that regulate VEGF formation. Unlike currently available agents that disrupt VEGF signaling at endothelial cells, PTC299 is designed to inhibit VEGF production within tumors while sparing physiological VEGF homeostasis. Preclinical characterization reveals that PTC299 blocks VEGF synthesis in multiple tumor types, reduces VEGF concentrations in tumors and in plasma, reduces tumor microvessel density, and induces tumor growth delay or regression in a variety of xenograft models of human cancer. PTC299 has been well tolerated in nonclinical safety pharmacology and toxicology studies. Data from completed Phase 1 single and multiple dose studies in healthy volunteers support the compound's favorable clinical safety and pharmacokinetic profiles. Phase 1b/2 studies in patients with cancer are ongoing.

Endogenous Anti-Angiogenics from the VEGF Family

David Bates
Bristol Heart Institute

Much of Judah Folkman's work was focused on endogenous anti-angiogenic agents produced by proteolytic cleavage of extracellular proteins. Proteloytic cleavage is one method of generating alternate forms of proteins post-transcriptionally. Another major source of posttranscriptional proteomic diversity is alternative splicing (AS). The most widely studied anti-angiogenic agent, VEGF is generated from AS of 8 exons, with exons 6 and 7 being subject to AS generating isoforms with altered heparin and neuropilin binding affinities. Use of an additional alternate splice site in exon 8 results in a more distal splice site selection in this final exon. This results in a sister family of isoforms termed VEGFxxxb, which differ only in their terminal 6 amino acids from conventional VEGF isoforms. Using antibodies generated to the unique c-terminal protein sequence, we found that the VEGFxxxb isoforms are widely expressed at the protein level in normal human tissues, varying from 96% of total VEGF being VEGFxxxb (colonic mucosa), to 1.5% in the placenta, an angiogenic tissue. These isoforms are downregulated in cancers and other pathologies associated with abnormal angiogenesis (diabetic retinopathy, retinal vein occlusion, Denys Drash syndrome (DDS), and pre-eclampsia). Using human recombinant VEGF165b, we and others have shown that this AS causes these isoforms to gain anti-angiogenic activity in the rabbit corneal eyepocket, the rat mesentery and the mouse retina and choroid. Furthermore these isoforms inhibit growth of colorectal carcinoma, renal cell carcinoma, prostate cancer, malignant melanoma and Ewing's sarcoma. Recombinant VEGF121b also inhibits migration of endothelial cells, angiogenesis in vivo and tumour growth. We have identified some of the proteins that regulate VEGF AS. Cells can switch from anti-angiogenic VEGFxxxb to pro-angiogenic VEGFxxx when treated by IGF1, TNF-α and PDGF-AB, or the reverse switch by TGF-β1 and that this occurs through the use of specific splice factors. Moreover, we have now identified how AS occurs in a genetic disease of the kidney (DDS), due to the effect of WT1 mutations on these splice factor regulators. The VEGFxxxb isoforms are recognized by most VEGF antibodies including bevacizumab, and over-expression of VEGF165b inhibits the anti-angiogenic action of bevacizumab in mouse models of human cancers. In summary, C terminal distal splicing is a key component of VEGF biology, providing endogenous anti-angiogenics by alternative splicing.

Beyond VEGF: Targets in the Setting of Anti-VEGF Resistance

George Yancopoulos
Regeneron Pharmaceuticals, Inc.

The notion that tumors can be controlled by directly targeting their vascular supply has finally come of age, with the demonstration that therapies targeting VEGF can extend life in cancer patients. Anti-VEGF therapies can also improve and maintain vision in vascular eye diseases that can otherwise lead to blindness. However, data suggests that these current regimens may not provide for complete VEGF inhibition, and thus that the maximum therapeutic potential of VEGF blockade has not yet been achieved. We have engineered a very potent, high affinity VEGF blocker, termed the "VEGF Trap" (Holash et al., PNAS 2002, 99:11393), that may provide for the opportunity to explore the potential of more complete VEGF blockade in cancer, as well as for more complete and longer term dosing regimens in eye diseases.
Despite the critical role for VEGF in tumor angiogenesis, it is also clear that in some cases tumor growth and angiogenesis can proceed even in the face of potent VEGF blockade. Thus, additional angiogenesis-targeted therapies are necessary for tumors resistant to VEGF blockade. We developed models of such resistance so as to explore the involved pathways. Moreover, we have exploited our high-throughput mouse genetics approaches, VelociGene (Valenzuela et al., Nature Biotechnology 2003, 21:652) and VelociMouse (Poueymirou et al., Nature Biotechnology 2007, 25:91), to define new targets in the field of angiogenesis. One such target, termed Delta-like ligand 4 (Dll4), is induced by VEGF as a negative feedback regulator, and blockade of this feedback system results in uncontrolled excessive tumor angiogenesis which cannot support tumor growth, and instead results in tumor inhibition (Noguera et al., Nature 2006, 444:1032). We now report that Dll4-blockade is effective in several tumor models resistant to anti-VEGF therapies, and further that Dll4-blockade can also be effectively combined with anti-VEGF therapies for superior tumor control. We will also report that we have utilized our new VelocImmune platform, in which our VelociGene and VelociMouse technologies were used to genetically "humanize" over 6 Megabases of mouse immune genes so as to create a new mouse system for rapidly and efficiently generating fully human monoclonal antibodies against a target of interest, to generate high-affinity fully human antibody therapeutic candidates that block Dll4 and that will soon be entering into human trials.

Notch Regulates Tumor Angiogenesis by Diverse Mechanisms

Jan Kitajewski
Columbia University

The concept that blood vessel recruitment is essential for tumor growth, proposed by Dr. Judah Folkman, helped initiate a new field of study in tumor biology. From that initial concept to the present day, an appreciation of the diverse and complex mechanisms of tumor angiogenesis has evolved. This complexity if evident from studies of the Notch signaling pathway and recent findings show that Notch regulates tumor angiogenesis by diverse mechanisms.
Notch is fundamental to proper cardiovascular development and at least two key Notch ligands, Delta-like 4 and Jagged1, have been implicated in tumor angiogenesis. Inhibition of Dll4-mediated Notch signaling in tumors results in hyper-sprouting of non-functional vasculature. This Dll4 inhibition may paradoxically lead to increased angiogenesis but poor tumor growth because the newly growing vessels are not functional. In contrast, Jagged1 has been described as a Notch ligand expressed on tumor cells that can have a positive influence on tumor angiogenesis, possibly by activating Notch on tumor endothelium. To explore the potential for targeting Notch in tumors we discuss a Notch inhibitor, the Notch1 decoy, which blocks both Dll4 and Jagged1. The Notch1 decoy can disrupt tumor angiogenesis and growth in several murine tumor models and the activity of this inhibitor illustrates the utility of inhibiting several Notch ligands in the tumor microenvironment.

Evasive Adaptation Mechanisms to Anti-VEGF Therapy

Gabriele Bergers
University of California San Francisco

Dr. Judah Folkman's long-standing vision of angiogenesis as a therapeutic target has been increasingly validated both in mouse models of cancers as well as in the clinic resulting in the FDA approval of the three antiangiogenic drugs bevacizumab, sorafenib and sunitinib in certain tumors inhibiting the VEGFR pathways. However, in both preclinical and clinical settings, the benefits are transitory and are followed by a restitution of tumor growth and progression. Emerging data reveal that tumor relapse is caused by evasive resistance, an adaptation to circumvent the specific angiogenic blockade. In contrast to traditional concepts of drug resistance, evasive resistance induces alternative ways to sustain tumor growth while the specific therapeutic target of the anti-angiogenic drug remains inhibited. The currently experimental evidence, which is not yet definitive, suggests that there exist several distinct adaptive mechanisms that manifest evasive resistance to antiangiogenic therapies enabling the tumor to re-neovascularize and/or to finds means to propgate even in the absence of sufficient neovascularization. While the transitory efficacy of the VEGF pathway inhibitors might be considered as disappointing, the results must be evaluated in the context of the current standards of care for most of the major human cancers, which typically have transitory efficacy, inevitable resistance, and common toxicity and poor quality of life. Angiogenesis inhibitors, despite their evident limitations, still represent an important milestone in cancer therapeutics, where they are becoming components of standard-or-care therapy, for example for colorectal and renal cancers. The growing state of knowledge about their effects and efficacy, and about the existence and mechanistic basis for adaptive-evasive resistance presents an exciting future of opportunity for improving and sustaining the benefits of anti-angiogenic therapy.