eBriefing

Folkman's Legacy: Angiogenesis and Cancer Therapeutics

Folkman's Legacy
Reported by
Catherine Zandonella

Posted August 05, 2009

Overview

In a 1971 article published in The New England Journal of Medicine, Judah Folkman proposed that preventing new capillary formation could be a viable strategy for preventing and treating cancer. Today, eight anti-angiogenesis cancer therapies are on the market, and over 120 new anti-angiogenesis compounds are in various stages of preclinical study.

A May 26, 2009, full-day meeting of the Academy's Biochemical Pharmacology Discussion Group drew key researchers in the field to discuss the emerging understanding of angiogenesis, how anti-angiogenesis therapies fight cancer, and recent findings on how to improve these revolutionary therapeutics. Among the topics discussed were how normalizing vascularization with anti-angiogenic agents can benefit patients with some tumor types; how blocking vascular endothelial growth factor (VEGF) can promote tumor growth; ways in which VEGF inhibitors can serve as research tools, in addition to therapeutics; intersections between VEGF and the Notch signaling pathway that offer new targets for therapeutic intervention; other pro-angiogenic factors that could be targeted in addition to VEGF; and why boosting production of production of an endogenous, anti-angiogenic splice variant of VEGF could help diminish tumor cells.

Sample Media


William Li

Video Interview
Anti-Angiogenic Cancer Research


William Li, president of the Angiogenesis Foundation, provides an overview of the accomplishments and future of anti-antiogenic research against cancer.

Use the tabs above to view a meeting report and multimedia from the event.


Speakers discussed:

William Li (The Angiogenesis Foundation) *
Rakesh Jain (Massachusetts General Hospital, Harvard Medical School)
Robert Kerbel (University of Toronto) *
Stuart Peltz (PTC Therapeutics)
David Bates (Bristol Heart Institute)
George Yancopoulos (Regeneron Pharmaceuticals) *
Jan Kitajewski (Columbia University Medical Center) *
Gabriele Bergers (University of California, San Francisco) *
Richard Kendall (Amgen)

* slides and audio available

Web Sites

The Angiogenesis Foundation
A nonprofit organization dedicated to conquering disease using a new approach based on angiogenesis.

Cancer Warrior: a NOVA Television Documentary
This hour-long documentary about Judah Folkman and his lifelong work in angiogenesis is available to watch online.

The Folkman Laboratory at Children's Hospital of Boston
The Web site of Folkman's laboratory explains the rationale behind angiogenesis and contains a partial list of journal publications.

Understanding Cancer: Angiogenesis Tutorial
An online tutorial created by the National Cancer Institute.


Books

Figg WD, Folkman J. 2008. Angiogenesis: An Integrative Approach from Science to Medicine. Springer, New York.

Cooke R. 2001. Dr. Folkman's War: Angiogenesis and the Struggle to Defeat Cancer. Random House, New York.

Ferrara N. 2006. Angiogenesis: From Basic Science to Clinical Applications. CRC Press, Boca Raton, FL.


Articles

William Li

Abdollahi A, Schwager C, Kleeff J, et al. 2007. Transcriptional network governing the angiogenic switch in human pancreatic cancer. Proc. Natl. Acad. Sci. USA 104: 12890-12895. Full Text

Almog N, Ma L, Raychowdhury R, et al. 2009. Transcriptional switch of dormant tumors to fast-growing angiogenic phenotype. Cancer Res. 69: 836-844.

Folkman J. 1971. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285: 1182-1186.

Klement GL, Yip TT, Cassiola F, et al. 2009. Platelets actively sequester angiogenesis regulators. Blood 113: 2835-2842.

Li VW, Li WW. 2008. Antiangiogenesis in the treatment of skin cancer. J. Drugs Dermatol. 7(1 Suppl 1): s17-24.

Rakesh Jain

Chi AS, Sorensen AG, Jain RK, Batchelor TT. 2009. Angiogenesis as a therapeutic target in malignant gliomas. Oncologist. [Epub ahead of print]

Kamoun WS, Ley CD, Farrar CT, Duyverman AM, Lahdenranta J, Lacorre DA, Batchelor TT, di Tomaso E, Duda DG, Munn LL, Fukumura D, Sorensen AG, Jain RK. 2009. Edema control by cediranib, a vascular endothelial growth factor receptor-targeted kinase inhibitor, prolongs survival despite persistent brain tumor growth in mice. J. Clin. Oncol. 27: 2542-2552.

Jain RK. 2008. Taming vessels to treat cancer. Scientific American (November 10).

Jain RK. 2005. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307: 58-62.

Jain RK, Duda DG, Willett CG, et al. 2009. Biomarkers of response and resistance to antiangiogenic therapy. Nat. Rev. Clin. Oncol. 6: 327-338.

Willett CG, Duda DG, di Tomaso E, et al. 2009. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J. Clin. Oncol. [Epub ahead of print]

Zhu AX, Sahani DV, Duda DG, et al. 2009. Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J. Clin. Oncol. [Epub ahead of print]

Robert Kerbel

Bertolini F, Mancuso P, Braidotti P, et al. 2009. The multiple personality disorder phenotype(s) of circulating endothelial cells in cancer. Biochim. Biophys. Acta. [Epub ahead of print]

Ebos JM, Lee CR, Bogdanovic E, et al. 2008. Vascular endothelial growth factor-mediated decrease in plasma soluble vascular endothelial growth factor receptor-2 levels as a surrogate biomarker for tumor growth. Cancer Res. 68: 521-529.

Ebos JM, Lee CR, Christensen JG, et al. 2007. Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc. Natl. Acad. Sci. USA 104: 17069-17074. Full Text

Ebos JM, Lee CR, Cruz-Munoz W, et al. 2009. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15: 232-239.

Francia G, Emmenegger U, Kerbel RS. 2009. Tumor-associated fibroblasts as "Trojan Horse" mediators of resistance to anti-VEGF therapy. Cancer Cell 15: 3-5.

Kerbel RS. 2008. Tumor angiogenesis. N. Engl. J. Med. 358: 2039-2049.

Kerbel RS. 2006. Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Science 312: 1171-1175.

Shaked Y, Ciarrocchi A, Franco M, et al. 2006. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 313: 1785-1787.

Shaked Y, Henke E, Roodhart JM, et al. 2008. Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell 14: 263-273.

Stuart Peltz

Bhattacharyya A, Trotta CR, Peltz SW. 2007. Mining the GEMS—a novel platform technology targeting post-transcriptional control mechanisms. Drug Discov. Today 12: 553-560.

David Bates

Bevan HS, van den Akker NM, Qiu Y, et al. 2008. The alternatively spliced anti-angiogenic family of VEGF isoforms VEGFxxxb in human kidney development. Nephron. Physiol. 110: p57-67. Full Text

Harper SJ, Bates DO. 2008. VEGF-A splicing: the key to anti-angiogenic therapeutics? Nat. Rev. Cancer 8: 880-887. Full Text

Kawamura H, Li X, Harper SJ, et al. 2008. Vascular endothelial growth factor (VEGF)-A165b is a weak in vitro agonist for VEGF receptor-2 due to lack of coreceptor binding and deficient regulation of kinase activity. Cancer Res. 68: 4683-4692.

Nowak DG, Woolard J, Amin EM, et al. 2008. Expression of pro- and anti-angiogenic isoforms of VEGF is differentially regulated by splicing and growth factors. J. Cell Sci. 121: 3487-3495. Full Text

Rennel ES, Hamdollah-Zadeh MA, Wheatley ER, et al. 2008. Recombinant human VEGF165b protein is an effective anti-cancer agent in mice. Eur. J. Cancer 44: 1883-1894. Full Text

George Yancopoulos

Dechiara TM, Poueymirou WT, Auerbach W, et al. 2009. VelociMouse: fully ES cell-derived F0-generation mice obtained from the injection of ES cells into eight-cell-stage embryos. Methods Mol. Biol. 530: 311-324.

Gale NW, Dominguez MG, Noguera I, et al. 2004. Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc. Natl. Acad. Sci. USA 101: 15949-15954. Full Text

Huang J, Bae JO, Tsai JP, et al. Angiopoietin-1/Tie-2 activation contributes to vascular survival and tumor growth during VEGF blockade. Int. J. Oncol. 34: 79-87.

Noguera-Troise I, Daly C, Papadopoulos NJ, et al. 2007. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Novartis Found. Symp. 283: 106-120; discussion 121-125, 238-241.

Jan Kitajewski

Dufraine J, Funahashi Y, Kitajewski J. 2008. Notch signaling regulates tumor angiogenesis by diverse mechanisms. Oncogene 27: 5132-5137.

Funahashi Y, Hernandez SL, Das I, et al. 2008. A notch1 ectodomain construct inhibits endothelial notch signaling, tumor growth, and angiogenesis. Cancer Res. 68: 4727-4735.

Thurston G, Kitajewski J. 2008. VEGF and Delta-Notch: interacting signalling pathways in tumour angiogenesis. Br. J. Cancer 99: 1204-1209.

Zeng Q, Li S, Chepeha DB, et al. 2005. Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell 8: 13-23.

Gabriele Bergers

Bergers G, Hanahan D. 2008. Modes of resistance to anti-angiogenic therapy. Nat. Rev. Cancer 8: 592-603.

Du R, Lu KV, Petritsch C, et al. 2008. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13: 206-220. Full Text

Helton R, Cui J, Scheel JR, et al. Brain-specific knock-out of hypoxia-inducible factor-1alpha reduces rather than increases hypoxic-ischemic damage. J. Neurosci. 25: 4099-4107. Erratum in: J. Neurosci. 25: 1 p following 4888.

Pàez-Ribes M, Allen E, Hudock J, et al. 2009. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15: 220-231.

Rick Kendall

Oliner J, Min H, Leal J, et al. 2004. Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 6: 507-516.

Organizers

Guy Lagaud, PhD

PTC Therapeutics, Inc.
web site

Guy Lagaud is senior scientist in the metabolism and pharmacology profiling team at PTC Therapeutics, Inc. His current research projects include identifying new targets for cancer therapies, particularly signaling molecules in angiogenesis, and investigating the role of PTC299 (a novel small molecule that inhibits the production of VEGF within tumors) in various xenograft models of human cancer.

Lagaud received his doctorate from University Louis Pasteur in Strasbourg, France, where he worked on the relationship between endothelial and smooth muscle calcium signaling. He was a Vancouver Vascular Biology Research Postdoctoral Special Fellow at the University of British Columbia, 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, where he investigated the use of potassium channel modulators and gene therapy to ameliorate bladder hyperactivity and erectile dysfunction. Following his postdoctoral work he joined Johnson & Johnson Pharmaceuticals Research & Development in the physiological system department.

Daniel J. Hicklin, PhD

Schering-Plough Research Institute
web site | publications

Dr. Hicklin currently works in oncology discovery at the Schering-Plough Research Institute. Before joining the company, he held several senior research and development positions at ImClone Systems, 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, tumor biology and drug development of targeted oncology therapeutics. He has authored over 180 publications in peer-reviewed scientific journals.


Keynote Speaker

William W. Li

William W. Li, MD

The Angiogenesis Foundation
e-mail | web site | publications

William Li is president, medical director, and cofounder of the Angiogenesis Foundation. He trained in the laboratory of Dr. Judah Folkman, pioneer of the angiogenesis field, and has been actively engaged in angiogenesis research and clinical development for 22 years. Under Li's leadership, the Foundation has developed a unique social enterprise model based on national and international collaborations with academic medical centers, biopharmaceutical companies, and government agencies, including the National Institutes of Health, National Cancer Institute, and the Food and Drug Administration.

Dr. Li has testified before congressional and other government panels on the impact of angiogenesis in health care, and he lectures widely on angiogenesis-related topics before clinical, scientific, government, and industry audiences. He is involved in multiple research initiatives to advance angiogenesis-based therapeutics in diverse medical fields, ranging from oncology to cardiovascular to regenerative medicine and advanced wound care. He has been published in Science, The New England Journal of Medicine, The Lancet, and other leading peer-reviewed medical journals.

Dr. Li received his AB with honors in biochemistry from Harvard College, and his MD from the University of Pittsburgh School of Medicine. He completed his internship, residency, and fellowship training in general internal medicine at Massachusetts General Hospital. He has held appointments on the clinical faculties of Harvard Medical School and Tufts University School of Veterinary Medicine, and is currently a Visiting Assistant Professor of Medicine at Dartmouth Medical School. He is an Honorary Fellow of the American College of Wound Care Specialists, and has served as an advisor and consultant to global leaders in the oncology, ophthalmic, cardiovascular, wound care, and regenerative medicine industries.


Speakers

Rakesh K. Jain, PhD

Massachusetts General Hospital
Harvard Medical School
e-mail | web site | publications

Rakesh Jain 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 has 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 U.S. National Academies—the Institute of Medicine, the National Academy of Engineering, and the National Academy of Sciences—and of the American Academy of Arts and Sciences.

Robert Kerbel

Robert Kerbel, PhD

University of Toronto
e-mail | web site | publications

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 a professor in the Department of Medical Biophysics and Department of Laboratory Medicine & Pathobiology at the 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.

Kerbel 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 coauthor of over 330 papers and has given 650 invited lectures on his work around the world since 1976. He is 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.

Stuart Peltz, PhD

PTC Therapeutics, Inc.
e-mail | web site | publications

Stuart Peltz is president and CEO of PTC Therapeutics, Inc. He is a leader in the investigation of mRNA turnover and translation, having been involved in developing the first biochemical assays to investigate the regulation of mRNA turnover and 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, his 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.

Peltz received his PhD at the McArdle Laboratory for Cancer Research at the University of Wisconsin.

David Bates

David Bates, PhD

Bristol Heart Institute
e-mail | web site | publications

David Bates completed his PhD in 1992 at St George's Hospital Medical School, where he studied the microvascular parameters affecting post mastectomy lymphoedema in patients. After a year learning molecular biology and Drosophila genetics at Glasgow University, he spent three years as a postdoctoral researcher at the University of California, Davis, where he developed the existing single capillary cannulation technique to examine chronic regulation of permeability by growth factors, and started investigating VEGF signaling. 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 signaling 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.

George Yancopoulos, MD, PhD

Regeneron Pharmaceuticals, Inc.
web site | publications

After graduating as valedictorian of both the Bronx High School of Science and Columbia College, George 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, Yancopoulos left academia in 1989 as a founding scientist at Regeneron Pharmaceuticals, where he is now the chief scientific officer and president of Regeneron Laboratories.

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, he was the eleventh most highly cited scientist in the world during the 1990s, 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.

Jan Kitajewski

Jan Kitajewski, PhD

Columbia University Medical Center
e-mail | web site | publications

Jan Kitajewski 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.

Kitajewski obtained a BS in biochemistry from the University of California, Berkeley and a PhD 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 the 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.

Kitajewski's research has been funded by the NIH, the American Cancer Society, the American Heart Association, the Department of Defense Breast Cancer Program, and the Avon Breast Cancer Program. He currently serves as a Charter Member of the Cardiovascular Differentiation and Development NIH Study section and is coeditor-in-chief of a new BioMed Central open-access journal, Journal of Angiogenesis Research.

Gabriele Bergers

Gabriele Bergers, PhD

University of California, San Francisco
e-mail | web site | publications

Gabriele Bergers is an associate professor of neurological surgery and 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.

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 has made a number of important discoveries about VEGF and other factors in angiogenesis, and has translated these findings into experimental therapeutic approaches to help guide clinical trials. In collaboration with Douglas Hanahan, she also co-organizes the experimental therapeutic group at UCSF.

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 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.

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. 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 at UCSF.

Richard L. Kendall, PhD

Amgen, Inc.
e-mail | web site | publications

Richard Kendall is an executive director of the Hematology and Oncology Department at Amgen, Inc. He is head of the Biochemistry and Cellular Biology Departments in the oncology therapeutic area at Amgen's Thousand Oaks, CA and Cambridge, MA research sites. Kendall joined the company in 1999 and has since recruited and built a state-of-the-art department for research that supports over 30 ongoing projects, including programs in all phases of clinical testing. His department is directly responsible for the research and discovery leading to nine clinical candidate molecules.

Prior to joining Amgen, Kendall was a senior scientist at Merck. He holds a PhD in biological chemistry from the University of California, Irvine and a BS in biochemistry from the University of California, Los Angeles. He is a member of a 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 more than 10 scientific journals and an adjunct associate professor in the Department of Molecular Cellular and Developmental Biology at the University of California, Santa Barbara.


Catherine Zandonella

Catherine Zandonella is a science writer based in New York City, covering such topics as environmental science, public health, and applied technology. She has a master's degree in public health from the University of California, Berkeley. Zandonella has written for a number of publications, including New Scientist, The Scientist, and Nature.