The role of angiogenesis inhibitors in epithelial carcinoma of the ovary, fallopian tube, or peritoneum
- Michael J Birrer, MD, PhD
Michael J Birrer, MD, PhD
- Professor of Medicine
- Harvard Medical School
- Bradley J Monk, MD, FACS, FACOG
Bradley J Monk, MD, FACS, FACOG
- Division of Gynecologic Oncology
- Department of Obstetrics and Gynecology
- Creighton University School of Medicine
- St. Joseph’s Hospital and Medical Center
- Section Editors
- Barbara Goff, MD
Barbara Goff, MD
- Section Editor — Gynecologic Oncology
- Professor of Gynecologic Oncology
- University of Washington
- Don S Dizon, MD, FACP
Don S Dizon, MD, FACP
- Section Editor – Gynecologic Oncology
- Clinical Co-Director, Gynecologic Oncology
- Founder and Director, The Oncology Sexual Health Clinic
- Massachusetts General Hospital Cancer Center
- Associate Professor of Medicine
- Harvard Medical School
Epithelial cancers of ovarian, fallopian tubal, and peritoneal origin exhibit similar clinical characteristics and behavior. As such, these are often combined and define epithelial ovarian cancer (EOC) in clinical trials and clinical practice. This topic will consider all three histologies under the heading EOC. EOC is the most common cause of death among women with gynecologic malignancies and the fifth leading cause of cancer death in women in the United States. Treatment generally requires aggressive surgical evaluation and the use of adjuvant chemotherapy. For those with recurrence, chemotherapy is the mainstay of treatment, with surgery reserved for select situations.
The development of a blood supply is a necessary prerequisite for tumor growth. A dominant factor controlling tumor angiogenesis is vascular endothelial growth factor (VEGF). Angiogenesis plays a fundamental role in normal ovarian physiology and in the pathogenesis of EOC, progression through ascites formation, and metastatic spread [1-3]. VEGF and VEGF receptor (VEGFR) are expressed in EOC, and increased VEGF expression has been associated with the development of malignant ascites [2,4]. These data provide the rationale for targeting VEGF and VEGFR in the treatment of EOC.
This topic will review the role of angiogenesis inhibitors in EOC. The treatment of EOC and a general overview of angiogenesis inhibitors are covered separately:
- Brown MR, Blanchette JO, Kohn EC. Angiogenesis in ovarian cancer. Baillieres Best Pract Res Clin Obstet Gynaecol 2000; 14:901.
- Ramakrishnan S, Subramanian IV, Yokoyama Y, Geller M. Angiogenesis in normal and neoplastic ovaries. Angiogenesis 2005; 8:169.
- Burger RA. Overview of anti-angiogenic agents in development for ovarian cancer. Gynecol Oncol 2011; 121:230.
- Chen H, Ye D, Xie X, et al. VEGF, VEGFRs expressions and activated STATs in ovarian epithelial carcinoma. Gynecol Oncol 2004; 94:630.
- Burger RA, Sill MW, Monk BJ, et al. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. J Clin Oncol 2007; 25:5165.
- Garcia AA, Hirte H, Fleming G, et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol 2008; 26:76.
- Azad NS, Annunziata CM, Steinberg SM, et al. Lack of reliability of CA125 response criteria with anti-VEGF molecularly targeted therapy. Cancer 2008; 112:1726.
- Apte SM, Bucana CD, Killion JJ, et al. Expression of platelet-derived growth factor and activated receptor in clinical specimens of epithelial ovarian cancer and ovarian carcinoma cell lines. Gynecol Oncol 2004; 93:78.
- Lu C, Thaker PH, Lin YG, et al. Impact of vessel maturation on antiangiogenic therapy in ovarian cancer. Am J Obstet Gynecol 2008; 198:477.e1.
- Matei D, Emerson RE, Lai YC, et al. Autocrine activation of PDGFRalpha promotes the progression of ovarian cancer. Oncogene 2006; 25:2060.
- Wilczynski SP, Chen YY, Chen W, et al. Expression and mutational analysis of tyrosine kinase receptors c-kit, PDGFRalpha, and PDGFRbeta in ovarian cancers. Hum Pathol 2005; 36:242.
- Erber R, Thurnher A, Katsen AD, et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 2004; 18:338.
- Steele IA, Edmondson RJ, Bulmer JN, et al. Induction of FGF receptor 2-IIIb expression and response to its ligands in epithelial ovarian cancer. Oncogene 2001; 20:5878.
- Whitworth MK, Backen AC, Clamp AR, et al. Regulation of fibroblast growth factor-2 activity by human ovarian cancer tumor endothelium. Clin Cancer Res 2005; 11:4282.
- Batchelor TT, Sorensen AG, di Tomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007; 11:83.
- Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008; 8:592.
- Bergers G, Song S, Meyer-Morse N, et al. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 2003; 111:1287.
- Laschke MW, Elitzsch A, Vollmar B, et al. Combined inhibition of vascular endothelial growth factor (VEGF), fibroblast growth factor and platelet-derived growth factor, but not inhibition of VEGF alone, effectively suppresses angiogenesis and vessel maturation in endometriotic lesions. Hum Reprod 2006; 21:262.
- Lu C, Kamat AA, Lin YG, et al. Dual targeting of endothelial cells and pericytes in antivascular therapy for ovarian carcinoma. Clin Cancer Res 2007; 13:4209.
- Eskander RN, Tewari KS. Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma--mechanistics, review of phase III randomized clinical trials, and regulatory implications. Gynecol Oncol 2014; 132:496.
- Robson EJ, Ghatage P. AMG 386: profile of a novel angiopoietin antagonist in patients with ovarian cancer. Expert Opin Investig Drugs 2011; 20:297.
- Karlan BY, Oza AM, Richardson GE, et al. Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer. J Clin Oncol 2012; 30:362.
- Monk BJ, Poveda A, Vergote I, et al. Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 2014; 15:799.
- Amgen announces top-line secondary endpoint results of phase 3 trebananib TRINOVA-1 trial In patients with recurrent ovarian cancer http://www.amgen.com/media/media_pr_detail.jsp?year=2014&releaseID=1985448 (Accessed on November 05, 2014).
- Hilberg F, Roth GJ, Krssak M, et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 2008; 68:4774.
- Ledermann JA, Hackshaw A, Kaye S, et al. Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. J Clin Oncol 2011; 29:3798.
- du Bois A, Huober J, Stopfer P, et al. A phase I open-label dose-escalation study of oral BIBF 1120 combined with standard paclitaxel and carboplatin in patients with advanced gynecological malignancies. Ann Oncol 2010; 21:370.
- Kumar R, Knick VB, Rudolph SK, et al. Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther 2007; 6:2012.
- Friedlander M, Hancock KC, Rischin D, et al. A Phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer. Gynecol Oncol 2010; 119:32.
- Lindsay CR, MacPherson IR, Cassidy J. Current status of cediranib: the rapid development of a novel anti-angiogenic therapy. Future Oncol 2009; 5:421.
- Matulonis UA, Berlin S, Ivy P, et al. Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol 2009; 27:5601.
- Hirte HW, Vidal L, Fleming GF, et al. A phase II study of cediranib (AZD2171) in recurrent or persistent ovarian, peritoneal or fallopian tube cancer: Final results of a PMH, Chicago and California consortia trial (Abstract #5521). J Clin Oncol 2008; 26s:5521.
- Ledermann JA, Embleton AC, Raja F, et al. Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2016; 387:1066.