NIH Press Release
NATIONAL INSTITUTES OF HEALTH
National Cancer Institute

FOR RESPONSE TO INQUIRIES
Friday, May 8, 1998

NCI Press Office
(301) 496-6641


Questions and Answers
About Anti-Angiogenesis Research

Introduction

A news article on the front page of the New York Times, Sunday, May 3, 1998 discussed research on the effects of angiostatin and endostatin in treating cancer in mice. That article and subsequent coverage by other media generated intense public interest about these compounds. The major questions raised by the media coverage are addressed below:

1. Was there a formal announcement about angiostatin and endostatin?

There was no public announcement regarding any new research finding about angiostatin and endostatin made by the National Cancer Institute (NCI) or any other research institution.

2. Was there new information in the news article?

No. On Nov. 27, 1997, Dr. Judah Folkman and colleagues at Children's Hospital in Boston had reported data in the scientific journal Nature indicating that endostatin and angiostatin worked better in combination than either one alone in inducing the regression of tumors in mice. So far, these are the only published data from the Folkman laboratory on this subject. The journal citation is Nature 390: 404-407.

3. Has Dr. Folkman's work been reproduced in other laboratories?

There have been several published articles replicating Dr. Folkman's findings on angiostatin. (See references at the end of this "Questions and Answers about Anti-Angiogenesis Research.")

The research with angiostatin has been easier to replicate than that with endostatin because production of adequate quantities of angiostatin is less complicated than that of endostatin.

Dr. Folkman has presented other unpublished data on both angiostatin and endostatin at several meetings recently but it will be several more months before these results will appear in a scientific journal.

4. What exactly are angiostatin and endostatin?

Angiostatin and endostatin are anti-angiogenic proteins that inhibit the formation of blood vessels which feed tumors. When the supply of nutrients from the blood is cut off, the tumor shrinks and dies. Used as drugs in mice, angiostatin and endostatin have been shown to stop tumor growth in preclinical studies in mice. Unlike many other anti-angiogenesis drugs currently under investigation, angiostatin and endostatin are naturally occurring proteins found in the body.

5. Is further development of these drugs NCI's highest priority?

The priority of the NCI is to facilitate the movement of promising new ideas and new treatments from the laboratory to testing in people. In this context, evaluation of new drugs, including anti-angiogenic agents (drugs that inhibit the blood supply to growing tumors), are of high interest to the NCI. However, this research is by no means the only promising research currently under way. There is no one "top priority" of the NCI.

6. Are other anti-angiogenesis compounds under study and where are they in development?

There are at least 11 compounds now in clinical trials that may target angiogenesis. Some of these are proteins; some are smaller molecules. While most are in early, Phase I or II trials, some are in later stage, or Phase III trials, potentially leading to the Food and Drug Administration's (FDA) approval and more widespread use. A number of other angiogenesis inhibitors, including angiostatin and endostatin, should enter clinical trials in about a year. The table below lists the angiogenesis inhibitors now in clinical trials, and whether they are in Phase I, II, or III. The NCI is involved in the evaluation of thalidomide and Col-3 and is negotiating with biotechnology companies to work on other compounds, some of which are listed below:

DRUG
PHASE OF TRIAL
SPONSOR
TNP-470
Phase II
TAP Pharmaceuticals, Inc.,
Deerfield, Wis.
Squalamine
Phase I
Magainin Pharmaceuticals, Inc.,
Plymouth Meeting, Pa.
Vitaxin
Phase I
Ixsys, Inc.
San Diego, Calif.

Thalidomide
Phase II against Kaposi's sarcoma,
breast, prostate and primary brain cancers
EntreMed, Inc.
Rockville, Md.

RhuMab
VEGF
Phase II
Genentech, Inc.
South San Francisco, Calif.

SU5416
Phase I
Sugen, Inc.
Redwood City, Calif.

Marimastat
Phase III against pancreas, lung, gastric
and breast cancers and glioma
British Biotech, Inc.
Annapolis, Md.

Bay 12-9566
Phase III against lung and pancreas cancers
Bayer Corp.
West Haven, Conn.

AG3340
Phase III against lung and prostate cancers
Agouron Pharmaceuticals, Inc.,
LaJolla, Calif.
Col-3
Phase I
CollaGenex Pharmaceuticals, Inc.,
Newton, Pa.
CM101
Phase I
Carbomed
Brentwood, Tenn.

7. At what stage of development are angiostatin and endostatin?

There are a number of important steps that must occur in the development of these agents before their evaluation in people. First, a scientific effort has created very small quantities of a human equivalent of the mouse proteins. The human proteins need to be tested in the laboratory and, once that is done, an adequate supply of the human proteins must be produced for the preclinical tests and the initial human clinical trials. Second, scientists must ensure that the proteins that are produced are free of any impurities that might cause side effects in people. Third, as part of the preclinical development process, scientists also must perform the necessary toxicologic and pharmacologic studies of the agents. These studies are critical in establishing a safe starting dosage and duration for the initial clinical trials.

In order to move angiostatin and endostatin from laboratory to clinical research, researchers first need adequate supplies of equivalents of the mouse proteins made specifically for human use. NCI and several pharmaceutical companies are working out what forms of these drugs would be the first to enter clinical trials. Through genetic engineering, researchers are developing bacterial, mammalian cell, or yeast "factories" that produce the proteins. They have developed a drug production process that ensures purity. They are developing tests for each drug for its action on body chemistry and organ systems. These studies of the chemistry of the purified drug products will help predict the drugs' effects on human body processes and organ systems. Required safety testing will follow.

8. What are some of the differences between animals and humans that researchers deal with when trying to develop new drugs?

Currently, research on angiostatin and endostatin has only been done in animals. Humans are very different than animals. Also in the published work with mice, scientists have been treating tumors that were transplanted into the mice, rather than tumors that developed naturally in mice, as they do in people. Tumors transplanted into mice have a different biology than naturally occurring tumors and are often not accurate predictors of what will happen in natural human cancers. Laboratory animals such as mice metabolize drugs very differently than humans, which can affect the success of treatments with proteins. Moreover, the relative size of humans compared to mice would require much more drug to treat a human. For reasons such as these, scientists follow a systematic process to move drugs from the laboratory to clinical trials.

NCI has a major research initiative under way to find better animal models for naturally occurring human cancers. For example, researchers can now alter mouse genes and introduce the same mutations that occur in human cancer. These mutant mice predictably develop specific cancers and pass these susceptibilities to their offspring in the same way that humans may inherit a predisposition to a particular type of tumor. Such models will enable scientists to begin to examine every stage of cancer development, and provide what are hoped to be more suitable settings for testing the vast number of new treatment or prevention agents that are in the pipeline to clinical testing.

9. How long will it take to bring these two drugs to clinical trials?

NCI and biotechnology and pharmaceutical companies are moving as fast as possible to make these drugs available for clinical testing, and NCI is ensuring that adequate resources are available. In addition, NCI and industry scientists have extensive experience in bringing drugs from the laboratory to clinical trials. Assuming all research steps leading to clinical trials are successful, it will take at least a year before clinical trials may begin.

10. What types of limitations could delay the start of clinical trials?

There are many "if's" between an exciting laboratory result and a clinical breakthrough. In this case:

if the human proteins have anticancer activity in humans similar to the mouse proteins'
anticancer activity in mice
if researchers can find a good way to make the drug in sufficient quantities
if the drug they make can be purified easily
if researchers find that the drug can be metabolized safely in humans at the
doses at which it will be tested in patients
if the drug passes other required safety tests.

11. How soon can new anti-angiogenic treatments be used in everyday practice?

If ongoing clinical trials are positive, the agents now in late-phase clinical trials could be approved by the FDA and available for general use as cancer treatments within two to five years. These include Marimastat, a matrix metalloproteinase inhibitor, and thalidomide, a drug with multiple mechanisms that has shown some evidence of biologic activity in gliomas (brain tumors) and Kaposi's sarcoma. Many of the most promising angiogenesis inhibitors, including angiostatin and endostatin, are not yet in clinical trials and, if they prove to be effective, are years away from general use.

A number of currently available agents have some degree of anti-angiogenesis activity, including certain steroids, hormonal agents, and interferons, but they are not very potent angiogenesis inhibitors.

12. Will angiostatin and endostatin be available outside of clinical studies (compassionate use)?

Neither angiostatin nor endostatin has entered any human studies yet and researchers expect they will not begin such testing for at least a year. The compounds would not be available for compassionate use until after they had shown some activity against cancer in studies with cancer patients.

If the angiostatin and endostatin compounds can be successfully developed for testing in humans, the sponsor of the drugs can work with the FDA to permit patients who are not participating in clinical trials to have access to drugs being studied in clinical trials (such access is often called "compassionate use"). The "compassionate use" mechanism allows patients to receive promising but not yet fully studied or approved cancer therapies that are undergoing clinical testing when no other satisfactory options exist. Compassionate use mechanisms are often activated once a drug has been shown to have activity against human cancer.

13. Are there compounds that had promising results in mice but proved less successful in treating human cancers?

Yes, many. A prime example is interleukin-2. In the 1980s, this drug was very successful in treating tumors in mice. But subsequent studies in people showed that interleukin-2 caused significant side effects, such as severe drops in blood pressure and the leaking of fluid from blood vessels. These difficulties in people were not predicted based on the mouse studies. A large number of chemotherapy drugs have much greater effectiveness against mouse tumors than against human cancers.

Questions The Public Is Asking

14. How can I get these drugs?

Endostatin and angiostatin are not available at this time. However, other anti-angiogenic compounds and other treatments for cancer are now being evaluated in clinical trials (treatment studies) with patients. The Cancer Information Service (CIS) at 1-800-4-CANCER can provide information about these trials from PDQ, the NCI's cancer information database.

Physicians may request information about trials in PDQ from the PDQ Search Service by calling 1-800-345-3300 or sending a fax to 1-800-380-1575 ( (313)-831-8929 outside the United States) or by sending an e-mail to pdqsearch@icicc.nci.nih.gov.

15. Can a patient get on a waiting list to get the drugs when they are available?

A waiting list for the drugs is not being maintained. When they are available for use in clinical trials, NCI will make this information widely available to health professionals and the public.

16. When angiostatin and endostatin become available, how can a patient get them?

The drugs will be evaluated through NCI and company-sponsored clinical trials. First, they will be tested separately for safety and effectiveness and then they may be tested together. For more information about clinical trials, patients should talk to their doctor, call the NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237), or visit the NCI's clinical trials website at http://cancertrials.nci.nih.gov on the World Wide Web.

17. In addition to the CIS, are there other ways to get information from the NCI about cancer treatments?

Information about cancer treatment is available from CancerFax, a fax-back document delivery service that makes some information from PDQ available via fax. To use CancerFax, individuals should dial (301) 402-5874 and listen to the recorded instructions. Cancer information from PDQ also is available on the web at http://cancernet.nci.nih.gov and through e-mail by sending an internet e-mail message to cancernet@icicc.nci.nih.gov with the word "help" in the body of the message; a contents list and instructions will be returned via e-mail.

18. How will NCI get accurate information about angiostatin and endostatin to the public and professionals?

NCI will provide information about the angiostatin and endostatin studies to the public and health professionals through several mechanisms:

References for research replicating Folkman's findings (Question No. 3):

Doug Z., Kumar R., Yang X., Fidler I.J. Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma. Cell 1997; 88:801-10.

Gately S., Twardowski P., Stack M.S., et al. Human prostate carcinoma cells express enzymatic activity that converts human plasminogen to the angiogenesis inhibitor, angiostatin. Cancer Research 1996; 56:4887-90.

Gately S., Twardowski P.K., Stack M.S., et al. The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin. Proc Natl Acad Sci USA 1997; 94:10868-72.

Lannutti B.J., Gately S.T., Quevedo M.E., Soff G.A., Paller A.S. Human angiostatin inhibits murine hemangioendothelioma tumor growth in vivo. Cancer Research 1997; 57:5277-80.