Recommendation: The NCI should facilitate research into mechanisms of tumor angiogenesis and development of drugs that target the essential tumor vasculature, initially by establishing a resource distribution capability that provides two classes of materials: 1) validated endothelial cell cultures, along with reagents and standardized methods and instruction to maintain those cells and perform reproducible angiogenesis bioassays; and 2) supplies of angiogenic regulatory molecules, both proteins and small molecules, that activate or inhibit endothelial cell growth, migration, & morphogenesis into new vessels. These reagents are intended for research purposes, not as drugs for the treatment of patients.
A. Rationale:
The explosion of knowledge about angiogenesis in the last decade, and in particular the compelling body of evidence that persistent angiogenesis and intimate vascularization is a critical parameter of most if not all cancers, has raised the exciting prospect that tumor angiogenesis represents an important new target for anti-cancer drugs. That prospect has fueled expanding research into the regulatory mechanisms underlying angiogenesis, and discovery efforts aimed at identifying compounds that inhibit angiogenesis. However, the field is fraught with situations that are impeding the progress of angiogenesis research and development. Several particularly important impediments are: i) the propensity of endothelial cells to lose hallmark 'endothelial characteristics' upon growth and continuous passage in culture, ii) the lack of standards for deriving, validating, and maintaining endothelial cells in culture, and of a source for 'standardized' endothelial cells; and iii) the frequent unavailability to the cancer research community of adequate supplies of compounds that are implicated as angiogenic regulators (both activators and inhibitors), which effectively retards their expedient incorporation into angiogenesis research and the development/evaluation of drugs which might disrupt tumor angiogenesis and tumor vasculature. Part of the excitement about the tumor vasculature, as a target is that it is composed of endothelial cells and peri-endothelial support cells, 'normal' cell types recruited by the cancer cells. In contrast to cancer cells, which are typically subject to some form of genomic instability and prone to acquired drug resistance, the implications are that endothelial and other support cells may not readily develop drug resistance, and as such represent a complementary drug target to the cancer cells themselves. Therefore, it is in the interest of the NCI to expedite research that defines the mechanisms controlling tumor angiogenesis and assesses strategies to disrupt that control and abrogate angiogenesis and tumor vascularization. The purpose of this recommendation is to facilitate access to two classes of resources that would serve that goal.
top
B. Specific Recommendations:
B1. The NCI should implement an endothelial cell resource distribution capability, such that scientists can get access to validated human (and other mammalian) endothelial cells, along with standardized methods and instruction for culturing endothelial cells, and for performing angiogenesis bioassays. By providing, directly or indirectly, validated human endothelial cells, along with qualified reagents and protocols to culture endothelial cells, the field of angiogenesis research will be more able to accurately study these cells, and to compare results obtained in different laboratories. There is a need for angiogenesis reagents to be widely and economically available to the angiogenesis research community, current access to these reagents is not sufficient. Therefore, NCI should implement an endothelial cell distribution capability. Efforts should be made to work closely with commercial vendors, in a spirit of cooperation, not competition. A steering committee (see B4), composed of experts in the culturing and validation of endothelial cells, should be formed to provide a standard set of criteria that must be met in order for the endothelial cells to be distributed by NCI. This measure will insure that endothelial cells, distributed by NCI, have been validated and have met the prescribed criteria.
Initially, the NCI-supported resource should distribute validated endothelial cells from human, mouse and bovine, and should include human umbilical vein, dermal microcapillaries, bovine arterial endothelial cells, and mouse endothelial cells.
On a second tier should be organ-specific endothelial cells, and later peri-endothelial support cells.
Recommendations by the steering committee should be considered throughout.
B2. The NCI should establish a capability to produce, or have produced, and freely distribute to the angiogenesis research community, qualified angiogenic regulatory compounds, which in general are unavailable in adequate amounts at reasonable costs. Presently, the inaccessibility of angiogenic regulatory compounds, both proteins and small molecules, is impeding the investigation of their mechanism of action and their evaluation as therapeutics. These include both angiogenesis activators, as well as an enlarging group of angiogenesis inhibitors. Again, NCI should work closely with potential commercial vendors in an effort to complement their efforts. The goal is to provide the angiogenesis research community with adequate quantities of angiogenic regulatory compounds at reasonable cost.
As an initial goal, the following compounds should be provided:
B3. The NCI should establish the angiogenesis inhibitor AGM1470 (TNP470) as the current "working activity standard", providing a baseline with which to compare angiogenesis inhibitors, and should distribute this compound to the angiogenesis research community. AGM1470 is a small molecule, it is stable, and it is reliable as an endothelial cell inhibitor in a variety of cell culture systems, as well as in common in vivo angiogenesis bioassays. Thus, AGM1470 should serve as the current "working activity standard", serving as a control for determining the inhibitory effect of angiogenic regulatory molecules. It is recognized that as the field advances, a more appropriate standard/s may be determined, hence, the steering committee should keep abreast of this issue.
B4. The NCI should form a steering committee composed of experts in the field of angiogenesis. The steering committee should serve as a panel of experts to assist in decisions concerning management and further development of the resource. The committee should determine standard methods for culturing and validating endothelial cells, and should be charged with prioritizing additional resources to be distributed by NCI to the angiogenesis research community. As new reagents are discovered, the efficacy of these agents as potential working activity standards should be evaluated. The NCI-supported facility should be envisioned as a clearinghouse of angiogenesis resources, providing standard assays for culturing and validating endothelial cells, standard angiogenesis bioassays, an electronic database, instruction, and training, and perhaps eventually, a screening facility for the evaluation of angiogenic reagents. It should be the goal of the steering committee to help shape this vision.
B5. The NCI should provide a standard set of in vivo models. Recognizing the need for in vivo models of angiogenesis and the ability to monitor increase in angiogenesis in vivo, the NCI should provide a standard set of in vivo assays and instructions. The use of standard in vivo assays should allow the comparison of results from various laboratories.
top
