Angiogenesis and the Strategic Target for Ovarian Cancer Therapy
Special Feature
Angiogenesis and the Strategic Target for Ovarian Cancer Therapy
By Robert L. Coleman, MD, Associate Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman is on the speaker's bureau for GlaxoSmithKline, Bristol-Myers Squibb, and Ortho Biotech.
Angiogenesis is a necessary and crucial aspect of physiologic homeostasis. Under normal circumstances the processes and factors regulating new blood vessel formation are tightly controlled. Activated in response to injury, ovulation, inflammation, among other stressors, the intricate balance between pro- and anti-angiogenic factors favors development of new vasculature. In the malignant state, however, angiogenesis is functionally "switched on" under the influence of specific mitogens produced by tumor cells. This becomes a key step for tumor sustenance, growth and progression. The concept has been considered for more than a century, however, the mechanisms promulgating this paradigm in cancer were only first described about 35 years ago.1 Today, in response to ameliorate the consequences of aberrant and uncontrolled angiogenesis, a virtual explosion of new agents have been developed which are beginning to show promise particularly in the management of solid tumors.
Studies have well documented that tumor cell populations growing beyond 1-2 mm3 in size require new blood vessel formation to enlarge and metastasize.2 The factors initiating this process can occur as a result of genetic changes and/or tumor microenvironment perturbations such as hypoxia, stress and starvation. While mediating factors are primarily produced by cancer cells, recent discoveries have documented that stromal components also contribute to cancer growth and progression. Several mechanisms for establishment of a vascular platform have been documented including ingrowth of new vessels from established vasculature (also referred to as "sprouting"), vessel cooption (growth of tumor around established vasculature), vascular mimicry (the ability of tumors cells to form vascular-like channels) and a peripheral mechanism stemming from the recruitment of bone marrow-derived endothelial cell precursors. Each of these mechanisms fulfill the tumor's request for vital nutrients to continue growth; they also provide a pathway for metastases, as the vasculature being developed is unlike that of established vessels and is characterized by loosely fitted and arranged endothelial cells. Collectively, these new vessels are leaky and exist in tangled networks. The crowded nature of these vessels leads to the increased interstitial pressure, which can limit conventional drug delivery and distribution.
The primary trafficking agent guiding this process is vascular endothelial growth factor (VEGF), which is also known as vascular permeability factor. Practically, tumor and its associated vasculature form a "functional unit" by which VEGF and other secreted mediators of angiogenesis such as epidermal growth factor (EGF) promote growth and survival of both elements. In this manner, VEGF and EGF function in a paracrine and autocrine fashion to propagate the cancerous milieu. Recent studies have documented both cancer cells and the new vasculature, express a number of targetable antigens and receptors, which, along with the growth factors themselves, have become the recent focus of intense clinical investigation.
Ovarian cancer growth and metastases, like many other solid tumors, appear to be dependent in part on this process. Studies evaluating both tissue expression and circulating levels of VEGF in ovarian cancer patients, for example, have demonstrated this growth factor to be prognostic to overall survival.3 This observation along with the ability to selectively target VEGF (and EGF) and their receptors has recently ushered in an era of novel therapeutics and innovative therapeutic strategies. The first specific anti-angiogenesis agent to receive FDA-approval for cancer therapy was bevacizumab—a humanized monoclonal antibody which recognizes VEGF-A isoforms. Successful registration of this agent came from the documentation of a statistically significant improvement in overall survival in colon cancer patients who received bevacizumab in combination with chemotherapy compared to those receiving chemotherapy alone.4 This observation has also been seen in patients with lung, renal, and breast cancer with similar randomized trials now started and planned for untreated and previously treated epithelial ovarian cancer patients. However, interest in this agent for ovarian cancer management was heightened following the recent presentations of 2 open-label trials of bevacizumab in recurrent ovarian cancer patients. The first study, conducted by the Gynecologic Oncology Group, evaluated single-agent bevacizumab in women who had received up to 2 prior regimens for their disease prior to entry.5 Among the 62 enrollees, 11 (18%) achieved a clinical response with nearly 40% being disease-free at 6 months. No severe hematologic toxicity was observed and severe non-hematologic toxicity was limited. In the second, bevacizumab was administered with very low dose (metronomic) cyclophosphamide to 29 patients with recurrent ovarian cancer.6 Responses were observed in 8 (28%) with nearly 60% being disease free at 6 months. Hematologic and non-hematologic toxicity were similarly limited. The data from these biological therapies are impressive given the absence of cytotoxic therapy. In addition, the biological effect of these agents makes combination chemotherapy clinical trials a robust new avenue for ovarian cancer treatment.
While clinical improvement in disease burden is a recognizable reflection of efficacy, does the absence of tumor resolution imply inefficacy? This is an important outcome question to answer as many of the novel biologic therapeutics, targeting specific cellular pathways or growth factors incur cytostatic effects. Their efficacy, however, may be measured in perfusion alterations not readily discernible by conventional imaging. The concern with relying on conventional technology for establishing clinical activity is making a decision to discard a potentially important agent, which may affecting a specific target but not one critical for cancer growth. Such has been the recent focus of creative imaging and biomarker discovery specifically focused on mechanisms altered by biological therapy. For instance, as previously mentioned, the systemic secretion of VEGF will lead to recruitment of peripherally derived (bone marrow) endothelial cell precursors cells. These can be phenotypically identified in the peripheral circulation through specific cellular markers. Therapy targeted to VEGF whether it be to the molecule itself or to its receptor, can affect the peripheral conscription of these cells. In this manner, the level of the endothelial cell precursors can be a "biomarker" of local effect. The proof of principle has been reported in the preclinical and clinical setting including ovarian cancer models.7,8 Future studies are looking at these and other tests (such as circulating cell free nucleic acids) to determine dose and target modulation in cancer treatment.
Finally, evaluating the promise of new angiogenic agents, like cytotoxic (chemotherapy) agents requires systematic clinical study. However, like the issue of imaging, "response" determination needs to be more creative and adaptive to what the agent is targeting. Traditional clinical study designs are clearly not robust enough to provide a clear signal of potential efficacy. For instance, new statistical designs incorporating simultaneous evaluation of agents with similar but different profiles that are matched to the tumor profiles in specific patients are being initiated to allow for the recruitment of more patients who will receive agents that are most likely to work for them. In addition, new adaptive designs allow for real time adjustments in randomization based on the performance of previous patients increasing the likelihood of reaching a statistical end point in the most expeditious fashion.
These are exciting times in the world of cancer therapeutics as the potential for new agents and strategies in ovarian cancer management has never been more promising. Advances in imaging, biomarker development, and statistical design are needed to keep pace with drug discovery to efficiently determine which agent or agents should be elevated to the next "standard of care."
References
- Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182-1186.
- Bergers G, et al. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest. 2003;111:1287-1295.
- Cooper BC, et al. Preoperative serum vascular endothelial growth factor levels: significance in ovarian cancer. Clin Cancer Res. 2002;8:3193-3197.
- Hurwitz H, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335-2342.
- Burger RA, et al. Phase II trial of bevacizumab in persistent or recurrent epithelial cancer or primary peritoneal cancer: a Gynecologic Oncology Group study. Proc Am Soc Clin Oncol. 2005;23:Abst#5009.
- Garcia A, et al. Interim report of a phase II clinical trial of bevacizumab (Bev) and low dose metronomic oral cyclophosphamide (mCTX) in recurrent ovarian (OC) and primary peritoneal carcinoma: A California Cancer Consortium Trial. Proc Am Soc Clin Oncol. 2005;23:Abst#5000.
- Willett CG, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 2004;10:145-147; Erratum in: Nat Med. 2004;10:649
- Asahara T, et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res. 1999;85:221-228.
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