
Targeting VEGF-mediated Tumor Angiogenesis in Cancer Therapy
Thursday, June 19, 2014 - Friday, June 20, 2014
Presented By
A decade after the first cancer drug targeting VEGF signaling in tumor blood vessel formation received approval by the US Food and Drug Administration (FDA), significant effort has been dedicated toward progressing the research, development, and clinical application of anti-angiogenic cancer therapies. Drawing on lessons learned from successes and failures, this conference will examine ways to improve cancer therapy by addressing urgent issues such as:
- inherent /acquired resistance,
- immunomodulation,
- enhanced invasiveness / metastasis, and
- lack of validated predictive and prognostic biomarkers.
Presentations, including a keynote lecture by Harold F. Dvorak, MD, will explore VEGF-dependent and alternative mechanisms of angiogenesis. "Point–Counterpoint" debates between leading experts will aim to resolve controversies regarding the function of vascular normalization, treatment-induced metastasis, and the validity of hypertension as a physiological biomarker.
Registration Pricing
By 04/25/2014 | After 04/25/2014 | Onsite | |
Member | $230 | $280 | $305 |
Student/Postdoc Member | $125 | $175 | $200 |
Nonmember (Academia) | $295 | $350 | $375 |
Nonmember (Corporate) | $360 | $420 | $445 |
Nonmember (Non-profit) | $295 | $350 | $375 |
Nonmember (Student / Postdoc / Fellow) | $155 | $205 | $230 |
Registration includes a complimentary, one-year membership to the New York Academy of Sciences. Complimentary memberships are provided to non-members only and cannot be used to renew or extend existing or expiring memberships. A welcome email will be sent upon registration which will include your membership credentials.
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Presented by
Agenda
* Presentation titles and times are subject to change.
Day 1 — Thursday, June 19, 2014 | |
8:00 AM | Breakfast and Registration |
8:45 AM | Opening Remarks |
9:00 AM | Keynote Lecture |
Session I: Mechanisms of Tumor AngiogenesisSession Chair: Gabriele Bergers, PhD, University of California, San Francisco | |
9:45 AM | From the Isolation and Cloning of VEGF-A to FDA Approval of Multiple VEGF Inhibitors for Cancer and Intraocular Diseases |
10:15 AM | Effects of Extracellular Matrix Binding on the Biology of VEGF and VEGF-Therapy |
10:45 AM | Coffee Break |
11:15 AM | HOT TOPIC TALK (selected from submitted abstracts) |
11:30 AM | HOT TOPIC TALK (selected from submitted abstracts) |
11:45 AM | Interacting Signaling Pathways in Tumor Angiogenesis: VEGF, Delta/Notch, and Angiopoetin-1/Tie-2 |
12:15 PM | Instructive Angiocrine Contribution of Vascular Niche to Tumor Progression |
12:45 PM | Networking Lunch and Poster Viewing |
Session II: Immunomodulation in AngiogenesisShahin Rafii, MD, Weill Cornell Medical College | |
2:00 PM | HOT TOPIC TALK (selected from submitted abstracts) |
2:15 PM | Novel Immunotherapeutic Approaches for Cancer Therapy |
2:45 PM | Tackling Resistance to Anti-angiogenic Therapy: a Tumor-Immune Cell Dialogue |
3:15 PM | Coffee Break |
3:45 PM | Overcoming Tumor Resistance to VEGFA Signaling Blockade by Co-targeting ANG2-TIE2 Signaling and Macrophages |
4:15 PM | Imaging Immune Cells in the Context of Tumor Angiogenesis |
Session III: Vascular Normalization in Angiogenesis | |
4:45 PM | Point – Counter Point Debate Does Vascular Normalization Improve Delivery of Cancer Therapeutics? Each debater will be given 15 minutes for a short slide presentation. These presentations will be followed by a moderated debate. |
5:30 PM | Poster Session and Networking Reception |
7:00 PM | Conclusion of Day 1 |
Day 2 — Friday, June 20, 2014 | |
8:00 AM | Breakfast and Registration |
8:00 AM | Early Career Investigator Mentoring Workshop (concurrent) Editor's Guide to Writing and Publishing Your Paper In this 45-minute workshop participants will gain an inside look into the editorial review process and how to best present the results of their work for publication. |
Session IV: Challenges to Anti-angiogenic Therapy — Learning from Successes and FailuresSession Chair: Gavin Thurston, PhD, Regeneron Pharmaceuticals | |
9:00 AM | Synergy of Chemotherapy and anti-VEGF Treatment (Mechanisms of Action of Targeting VEGF) |
9:30 AM | Optimal Strategies for Resistance Avoidance and Long-Term Treatment with Anti-angiogenic Therapy |
10:00 AM | HOT TOPIC TALK (selected from submitted abstracts) |
10:15 AM | HOT TOPIC TALK (selected from submitted abstracts) |
10:30 AM | Coffee Break |
11:00 AM | Understanding VEGFR2 Targeting for Cancer Therapy |
11:30 PM | Anti-angiogenic Therapy: Impact on Invasion and Metastatic Disease Outcomes |
12:00 PM | Point – Counter Point Debate Does Anti-angiogenic Therapy Induce Invasion and Metastasis? Each debater will be given 15 minutes for a short slide presentation. These presentations will be followed by a moderated debate. |
12:45 PM | Networking Lunch and Poster Viewing |
Session V: Biomarkers for Anti-angiogenic Cancer TreatmentSession Chair: Dan Gabriel Duda, DMD, PhD, Massachusetts General Hospital Center | |
2:00 PM | Genetic and Circulating Markers Associated with Response to Anti-VEGF Therapy |
2:30 PM | Novel Biomarkers that Are of Prognostic Value and Can Predict Response or Resistance to Anti-angiogenic Therapy |
3:00 PM | HOT TOPIC TALK (selected from submitted abstracts) |
3:15 PM | HOT TOPIC TALK (selected from submitted abstracts) |
3:30 PM | Coffee Break |
4:00 PM | Identification and Analysis of In Vivo VEGF Downstream Markers Link VEGF Pathway Activity with Efficacy of Anti-VEGF Therapies |
4:30 PM | Point – Counter Point Debate Is Hypertension a Valid Biomarker for Anti-angiogenic Tumor Therapy? Each debater will be given 15 minutes for a short slide presentation. These presentations will be followed by a moderated debate. |
5:15 PM | Closing Remarks |
5:30 PM | Adjourn |
Speakers
Organizers
Gabriele Bergers, PhD
University of California, San Francisco
website
Melanie Brickman Stynes, PhD, MSc
The New York Academy of Sciences
Michele de Palma, PhD
EPFL School of Life Sciences, Lausanne
website
Brooke Grindlinger, PhD
The New York Academy of Sciences
Kerstin Hofmeyer, PhD
The New York Academy of Sciences
Luisa Iruela Arispe, PhD
University of California, Los Angeles
website
Robert Kerbel, PhD
Sunnybrook Research Institute
website
Gregory Plowman, MD, PhD
ImClone Systems / Eli Lilly and Company
Gavin Thurston, PhD
Regeneron Pharmaceuticals
Keynote Speaker
Harold F. Dvorak, MD
Beth Israel Deaconess Medical Center
website
Speakers
Carlos Bais, PhD
Genentech, Inc.
Laura E. Benjamin, PhD
ImClone Systems
Oriol Casanovas, PhD
Catalan Institute of Oncology - IDIBELL
John S. Condeelis, PhD
Albert Einstein College of Medicine
website
Elisabeth G.E. de Vries, MD, PhD
University Medical Center Groningen, the Netherlands
Dan Gabriel Duda, PhD, DMD
Massachusetts General Hospital
website
Lee M. Ellis, MD
The University of Texas MD Anderson Cancer Center
website
Napoleone Ferrara, MD
University of California, San Diego
website
Axel Grothey, MD
Mayo Clinic College of Medicine
website
John V. Heymach, MD, PhD
MD Anderson Cancer Center
website
Herbert I. Hurwitz, MD
Duke Department of Medicine
website
David F. McDermott, MD
Beth Israel Deaconess Medical Center
website
Thomas Powles, MBBS, MRCP, MD
Barts Cancer Institute
website
Shahin Rafii, MD
Weill Cornell Medical College
website
Brian Rini, MD
Cleveland Clinic
website
Sponsors
For sponsorship opportunities please contact Kerstin Hofmeyer, PhD at khofmeyer@nyas.org or 212.298.8610.
Silver Sponsors
Bronze Sponsor
Regeneron Pharmaceuticals, Inc.
Grant Support
This program is supported by grants from AbbVie and Genentech.
Funding for this conference was made possible (in part) by CA186652-01 from the National Cancer Institute. The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. Government.
Promotional Partners
American Association of Immunologists
American Society of Clinical Oncology
American Society of Hematology
Elsevier's Global Events List: Science & Medicine
The Journal of Clinical Investigation
North American Vascular Biology Organization (NAVBO)
Oncogene or Nature Medicine (Nature Publishing Group)
Vascular Pharmacology - Elsevier
Presented by
Abstracts, Day 1: Monday, April 28, 2014
Keynote Lecture
Heterogeneity of the Tumor Vasculature: Why Doesn't Anti-VEGF / VEGF Receptor Therapy Work Better?
Harold F. Dvorak, MD, The Center for Vascular Biology Research and the Department of Pathology, Beth Israel Deaconess Medical Center, Boston; and Harvard Medical School, Boston
Session I: Mechanisms of Tumor Angiogenesis
From Isolation and Cloning of VEGF-A to FDA Approval of Multiple VEGF Inhibitors for Cancer and Intraocular Diseases
Napoleone Ferrara, MD, University of California, San Diego
We have recently been studying the mechanisms of resistance to anti-VEGF therapies in various tumor models. These studies indicate that multiple pro- angiogenic mechanisms may be implicated. We identified factors produced by myeloid cells and by fibroblasts. In recent studies, we identified Interleukin 17, a key product of Th17 Helper T cells as a factor mediating angiogenic escape and resistance to VEGF inhibitors. Efforts are ongoing to determine the translational and clinical significance of such findings.
Effects of Extracellular Matrix Binding on the Biology of VEGF and VEGF-Therapy
M. Luisa Iruela-Arispe, PhD, University of California, Los Angeles
Co-authors: Christiana Ruhrberg, PhD, Carmen M. Warren, PhD, Tom Chen, PhD, University of California, Los Angeles
The miR-126–VEGFR2 Axis Controls the Innate Response to Pathogen-associated Nucleic Acids
Judith Agudo, PhD, Icahn School of Medicine at Mount Sinai, New York
Deletion of the gene encoding VEGFR2 specifically in DCs resulted in impaired pDC development and reduced type I interferon production; indicating that VEGFR2 signaling is also important for pDC function, and suggesting that miR-126 regulates pDCs, at least in part, through its control of VEGFR2 expression. These studies indicate that the miR-126–VEGFR2 axis is an important regulator of the innate response to pathogen infection, which operates through multiscale control of pDCs, and assigns an important new function to the clinically targeted receptor VEGFR2 and its ligand VEGF-A.
Co-authors: Albert Ruzo, Navpreet Tung, Hélène Salmon, Marylène Leboeuf, Daigo Hashimoto, Christian Becker, Alessia Baccarini, Miriam Merad, and Brian D. Brown,Icahn School of Medicine at Mount Sinai, New York; Lee-Ann Garrett-Sinha, State University of New York at Buffalo.
Overcoming Resistance to VEGF-Blockade by Combinatorial Targeting of the Angiopoietin/Tie2 Axis
Alexander Scholz, PhD, University Cancer Center & Institute of Neurology, Goethe University Medical School, Frankfurt; and Laboratory of Immunology and Vascular Biology, Stanford University
To define new therapeutic options for anti-angiogenic therapy in GBM, we addressed the role of the Angiopoietin(Ang)/Tie signaling pathway. We found Ang-2 to be upregulated in vessels of malignant human brain tumors while being absent in normal brain. Furthermore, Ang-2 expression correlated with WHO grade and the amount of infiltrating myeloid cells. In a mouse model with endothelial cell-specific overexpression of Ang-2, we observed significantly increased numbers of myeloid cells in an orthotopic, syngeneic glioblastoma model, thus corroborating our findings in the human system. Interfering with Ang-2/Tie2 signaling by either blockade of Ang-2 or overactivation of the receptor lead to increased overall survival, vessel normalization, and reduced infiltration of myeloid cells in the Gl261 glioma model. Combining anti-Ang-2 and anti-VEGF treatment showed synergistic effects with regard to survival and myeloid cell infiltration.
Thus, targeting Ang-2 and VEGF in glioblastoma represents a promising approach for future therapy by targeting two major components of solid tumors, angiogenesis, and inflammation.
Co-authors: Sebastian Cremer1, Patrick N. Harter1, Michel Mittelbronn1, Karl H. Plate1, Yvonne Reiss1, Paul van Slyke2, and Daniel J. Dumont2
1. University Cancer Center & Institute of Neurology, Goethe University Medical School, Frankfurt
2. Sunnybrook Health Center, Toronto
Overcoming Resistance to VEGF-Blockade by Combinatorial Targeting of the Angiopoietin/Tie2 Axis
Alexander Scholz, PhD, University Cancer Center & Institute of Neurology, Goethe University Medical School, Frankfurt; and Laboratory of Immunology and Vascular Biology, Stanford University
Interacting Signaling Pathways in Tumor Angiogenesis: VEGF, Delta/Notch, and Angiopoetin/Tie-2
Gavin Thurston, PhD, Regeneron Pharmaceuticals
Instructive Angiocrine Contribution of Vascular Niche to Tumor Progression
Shahin Rafii, MD, Weill Cornell Medical College
Session II: Immunemodulation in Angiogenesis
Mechanisms of Macrophage Promotion of Tumor Angiogenesis
Evelyn Aranda, PhD, Albert Einstein College of Medicine
Co-authors: Bin-Zhi Qian, Jeffrey W. Pollard, PhD, Albert Einstein College of Medicine
Novel Immunotherapeutic Approaches for Cancer Therapy
David F. McDermott, MD, Beth Israel Deaconess Medical Center, Boston
Tackling Resistance to Anti-angiogenic Therapy: a Tumor-Immune Cell Dialogue
Gabriele Bergers, PhD, Helen Diller Family Comprehensive Cancer Center and Brain Tumor Research Center, University of California, San Francisco
Co-authors: Lee B. Rivera1, Kan Lu1, David Meyronet2, and Judy Varner3.
1. Helen Diller Family Comprehensive Cancer Center, UCSF
2. Hospices Civils de Lyon
3. Moores Cancer Center, UCSD
Overcoming Tumor Resistance to VEGFA Signaling Blockade by Co-targeting ANG2-TIE2 Signaling and Macrophages
Michele De Palma, PhD, The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland
Imaging Immune Cells in the Context of Tumor Angiogenesis
John S. Condeelis, PhD, Albert Einstein College of Medicine
TMEM functions as a dedicated site of tumor cell transendothelial migration for intravasation and extravasation [Roh-Johnson et al, Oncogene, 2013]. The gene expression profile of the tumor cells involved in TMEM function has been determined and has supplied prognostic markers for predicting tumor cell dissemination in breast tumors [Robinson et al, Clin. Cancer Res., 2009; Rohan et al, JNCI, 2014 in Press; Agarwal et al, Breast Cancer Res., 2012]. The micro-pharmacology of the signaling between cells within TMEM suggest that TMEM is similar in function to an angiogenic sprout suggesting that re-tasking of drugs directed toward inhibition of angiogenesis, but at much lower concentrations, may block tumor cell dissemination.
Session III: Vascular Normalization in Angiogenesis
Point – Counter Point Debate: Does Vascular Normalization Improve Delivery of Cancer Therapeutics?
Pro-Debater: Dan G. Duda, DMD, PhD, Massachusetts General Hospital and Harvard Medical School, Boston
Co-authors: Kyrre E. Emblem, Marek Ancukiewicz, Christine Lu-Emerson, Elizabeth R. Gerstner, Tracy T. Batchelor, A. Greg Sorensen, and Rakesh K. Jain, Massachusetts General Hospital and Harvard Medical School, Boston.
Contra-Debater: Elisabeth G.E. de Vries, MD, PhD, The University Medical Center Groningen, the Netherlands.
Abstracts, Day 2: Friday, June 20, 2014
Editor's Guide to Writing and Publishing Your Paper
Brooke Grindlinger, PhD, The New York Academy of Sciences
Session IV: Challenges to Anti-angiogenic Therapy — Learning from Successes and Failures
Synergy of Chemotherapy and Anti-VEGF Treatment (Mechanisms of Action of Targeting VEGF)
Lee M. Ellis, MD, The University of Texas MD Anderson Cancer Center, Houston
The mechanisms of action of VEGF targeted therapies are diverse and probably cannot be attributed primarily to any single effect. This is more complicated by the fact that multi-kinase inhibitors affect numerous pathways in addition to VEGF signaling. With rare exception, the addition of VEGF-Receptor (VEGFR) targeted tyrosine kinase inhibitors (TKIs) to chemotherapy has not led to meaningful improvements in survival in patients with solid malignancies. In fact, in recent meta- analysis of VEGFR TKIs and chemotherapy (Funakoshi et al, Cancer Treatment Reviews, 2014), the relative risk of a fatal adverse event was increased by nearly 50%. Antibodies to VEGF (Bevacizumab) and more recently VEGFR2 (Ramucirumab) have led to improvements in survival in some, but not all clinical trials where these combinations have been studied. The same holds true for VEGF-Trap (Aflibercept). This presentation will discuss various mechanisms of action of VEGF targeted therapies.
Optimal Strategies for Resistance Avoidance and Long-Term Treatment with Anti-angiogenic Therapy
Axel Grothey, MD, Mayo Clinic College of Medicine
Vessel Architectural Imaging Reveals Early Vascular Response to Anti-angiogenic Therapy
Kyrre E. Emblem, PhD, Oslo University Hospital; and Massachusetts General Hospital and Harvard Medical School, Boston
VAI combines perfusion MRI from small (<10µm) and large vessels in one exam for in vivo assessment of vessel caliber, vessel type (arterioles/capillaries/venules), and relative oxygen saturation levels (ΔSO2). As early as day one of therapy, 21/40 newly diagnosed glioblastoma patients treated with cediranib+chemoradiation [Batchelor et al, PNAS, 2013] and 10/30 patients with recurrent glioblastomas treated with cediranib only [Emblem et al, Nature Medicine, 2013] responded to therapy by increased perfusion, normalization of arterio-venous ratios and ΔSO2 levels, and reduction of abnormal vessel calibers. Compared to non-responding patients, newly diagnosed glioblastoma responders had a survival of 696 versus 381 days (+10 months) and recurrent glioblastoma responders had 341 versus 146 days (+6 months). These effects were not observed in newly diagnosed glioblastoma patients receiving chemoradiation only (NCT00756106).
Collectively, our results indicate that vascular normalization may be a mechanism of survival benefit in selected glioblastoma patients, and that VAI enables early identification of patients most likely to benefit from anti-angiogenic therapy.
Co-authors: Elizabeth R. Gerstner2, Tracy T. Batchelor2, Dan G. Duda2, Bruce Rosen2, Rakesh K. Jain2, Marco C. Pinho2,3, A. Greg Sorensen2,4, Patrick Y. Wen5.
1. Oslo University Hospital
2. Massachusetts General Hospital and Harvard Medical School, Boston
3. University of Texas Southwestern Medical Center, Dallas
4. Siemens Healthcare Health Services, Malvern, Pennsylvania
5. Dana-Farber Cancer Center and Harvard Medical School, Boston
Population Pharmacodynamics: Mechanism-based Modeling of the Angiogenesis Receptor Kinome in Cancer
Feilim Mac Gabhann, PhD, Johns Hopkins University, Baltimore
We have previously used these models to simulate treatment of 'average' tumors of particular types, and compared the results to ensemble experimental data. However, tumors are highly diverse, exhibiting significant variability of gene expression between individuals and heterogeneity within an individual. In our current work, we incorporate patient-specific gene expression data sets into multiple instances of our mechanistic pharmacodynamic models. We simulate the impact of multiple drug and dosing regimens on a population of in silico individuals ('virtual patients') based on real patient data, allowing us to run thousands of 'virtual clinical trials.' We use these patient-specific computational models to predict the efficacy of multiple anti- angiogenic drugs—anti-ligand antibodies, receptor-blocking peptides, and tyrosine kinase inhibitors—and compare the predictions to the outcomes of clinical trials. We also compare the predicted responsiveness of primary tumors to those at metastatic sites to design optimal therapeutic approaches.
Co-author: R. Joseph Bender, MSc, Johns Hopkins University, Baltimore.
Understanding VEGFR2 Targeting for Cancer Therapy
Laura E. Benjamin, PhD, ImClone Systems, a wholly owned subsidiary of Eli Lilly
Anti-angiogenic Therapy: Impact on Invasion and Metastatic Disease Outcomes
Robert S. Kerbel, PhD, Sunnybrook Research Institute, University of Toronto
Point – Counter Point Debate: Does Anti-angiogenic Therapy Induce Invasion and Metastasis?
Pro-Debater: Oriol Casanovas, PhD, Translational Research Laboratory, Catalan Institute of Oncology (IDIBELL), Barcelona
Contra-Debater: Napoleone Ferrara, MD, University of California, San Diego.
Session V: Biomarkers
Genetic and Circulating Markers Associated with Response to Anti-VEGF Therapy
John V. Heymach, MD, PhD, MD Anderson Cancer Center
Novel Biomarkers that are of Prognostic Value and can Predict Response or Resistance to Anti-angiogenic Therapy
Thomas Powles, MBBS, MRCP, MD, Barts Cancer Institute, London
Direct Evidence of Targeted Inhibition by Anti-angiogenic Agents from a Wound-healing Model in Patients with Advance Solid Tumors
Jingquan Jia, MD, PhD, Duke University Medical Center, Durham, North Carolina
Co-authors: Andrew Dellinger1, Eric S. Weiss2, Anuradha Bulusu1, Haiyan Li3, Leigh Howard1, Neal Kaplan1, Herbert Pang4, Herbert I. Hurwitz1, and Andrew B. Nixon1.
1. Duke University Medical Center, Durham, North Carolina
2. Temple University School of Medicine, Philadelphia
3. Department of Medicine, Center for Musculoskeletal Research, University of Rochester Medical Center
4. School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Metabolic PET Imaging Approaches as Early Biomarkers of Cardiac Toxicity Following Treatment with the Tyrosine Kinase Inhibitor Sunitinib
Ian S. Miller, PhD, Royal College of Surgeons in Ireland, Dublin
Mice or rats were treated with sunitinib [40 or 20 mg/kg respectively, p.o.]. Blood pressure was measured weekly. Cardiovascular function was assessed using echocardiography. Positron emission tomography (PET) tracers 18F-FDG (Fluoro- deoxyglucose), 18F-FTHA (Fluoro-6-thia-heptadecanoic acid), and 11C-acetate (myocardial perfusion) were used to interrogate changes in myocardial metabolism and blood flow. Immunohistochemistry, histology, and electron microscopy were carried out on rodent cardiac tissue to interrogate sub-cellular off-target effects.
Treated animals displayed a significant increase in blood pressure after 5 days of treatment, a decline in left ventricular perfusion, indicated by lower 11C-acetate PET signal, and perturbation in cardiac function over the course of the study.
Importantly, changes in FTHA /FDG-PET signal and accumulation of lipid vesicles in cardiomyocytes indicated metabolic adjustments. Proteomic analyses of cardiac tissue from treated animals indicated major metabolic aberrations (mitochondrial dysfunction, increase in glycolytic enzymes, and increase in lipid storage). Metabolic PET imaging approaches may represent early cardiotoxicity biomarkers in patients treated with sunitinib.
Co-authors: Alice C. O'Farrell1, Rhys Evans1, Johanna M.U. Silvola2, Emer Conroy3, Monika Jarzabek1,5, David W. Murray1,4, Liam Shiels1, Marina Alamanou4, Sue Hector1, Antti Saraste2, Heidi Liljenbäck2, Sami Mahrus5, Axel Ducret6, P. Cutler6, William Gallagher3,4, Maurice Cary7, Juhani Knuuti2, Anne Roivainen2, and Annette T. Byrne1.
1. Royal College of Surgeons in Ireland, Dublin
2. Turku PET Centre, Turku, Finland
3. University College Dublin, Dublin
4. Oncomark Ltd., Dublin
5. Genentech, San Francisco
6. Roche, Basel, Switzerland
7. Pathology Experts GmbH, Therwil, Switzerland
Acknowledgments: AngioTox is funded by a European Commission FP7 Industry Academia Pathways and Partnerships Marie Curie Award. The authors would like to thank M2i Limited Blackrock clinic for supplying 18F-FDG and the EuroBioimaging initiative and BACR for work carried out at the Turku PET Centre, Finland.
Identification and Analysis of In Vivo VEGF Downstream Markers Link VEGF Pathway Activity with Efficacy of Anti-VEGF Therapies
Carlos Bais, PhD, Genentech, Inc.
Experimental Design: Surrogate markers of VEGF inhibition [VEGF-dependent genes or VEGF-dependent vasculature (VDV)] were identified by profiling gene expression changes induced in response to VEGF blockade in preclinical tumor models and in human biopsies from patients treated with anti-VEGF monoclonal antibodies. The potential value of VDV genes as candidate predictive biomarkers was tested by correlating high or low VDV gene expression levels in pretreatment clinical samples with the subsequent clinical efficacy of bevacizumab (anti-VEGF)-containing therapy.
Results: We show that VDV genes, including direct and more distal VEGF downstream endothelial targets, enable detection of VEGF signaling inhibition in mouse tumor models and human tumor biopsies. Retrospective analyses of clinical trial data indicate that patients with higher VDV expression in pretreatment tumor samples exhibited improved clinical outcome when treated with bevacizumab- containing therapies.
Conclusions: In this work, we identified surrogate markers (VDV genes) for in vivo VEGF signaling in tumors and showed clinical data supporting a correlation between pretreatment VEGF bioactivity and the subsequent efficacy of anti-VEGF therapy. We propose that VDV genes are candidate biomarkers with the potential to aid the selection of novel indications as well as patients likely to respond to anti- VEGF therapy. The data presented here define a diagnostic biomarker hypothesis based on translational research that warrants further evaluation in additional retrospective and prospective trials.
Co-authors: Matthew J. Brauer1, Guanglei Zhuang1, Maike Schmidt1, Jenny Yao1, Xiumin Wu11, Joshua S. Kaminker1, Stefanie S. Jurinka1, Ganesh Kolumam1, Alicia S. Chung1, Adrian Jubb1, Zora Modrusan1, Tomoko Ozawa2, C. David James2, Heidi Phillips1, Benjamin Haley1, Rachel N.W. Tam1, Anne C. Clermont1, Jason H. Cheng1, Sherry X. Yang4, Sandra M. Swain5, Daniel Chen1, Stefan J. Scherer1, Hartmut Koeppen1, Ru-Fang Yeh1, Peng Yue1, Jean-Philippe Stephan1, Priti Hegde1, Napoleone Ferrara1, and Mallika Singh3.
1. Genentech, Inc., South San Francisco
2. University of California at San Francisco
3. Novartis Institutes for Biomedical Research, Emeryville, California
4. National Cancer Institute, NIH, Bethesda, Maryland
5. Washington Cancer Institute, Medstar Washington Hospital, Washington, DC
Point – Counter Point Debate: Hypertension is a Valid Biomarker for Anti-angiogenic Therapy
Pro-Debater: Brian I. Rini, MD, FACP, Cleveland Clinic Taussig Cancer Institute; and Glickman Urological Institute, Cleveland
Contra-Debater: Herbert I. Hurwitz, MD, Duke University School of Medicine, Durham, North Carolina.
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