BETHESDA, Md-In 1955, concerned that pharmaceutical companies were mounting inadequate efforts to develop anticancer drugs, Congress mandated that the National Cancer Institute (NCI) create a program to screen agents for potential therapeutic activity. Today, NCI’s Developmental Therapeutics Program (DTP) promotes all aspects of drug discovery and development prior to human testing.
BETHESDA, MdIn 1955, concerned that pharmaceutical companies were mounting inadequate efforts to develop anticancer drugs, Congress mandated that the National Cancer Institute (NCI) create a program to screen agents for potential therapeutic activity. Today, NCIs Developmental Therapeutics Program (DTP) promotes all aspects of drug discovery and development prior to human testing.
The Program, however, is in the midst of changes that will radically alter the way NCI pursues its drug development charge. These changes stem in large part from the recent report of an outside committee known as the Developmental Therapeutics Review Group, chaired by Susan Band Horwitz, PhD, of Albert Einstein College of Medicine.
In this interview, Edward A. Sausville, MD, PhD, associate director of NCIs Division of Cancer Treatment and Diagnosis for the DTP, discusses the status and goals of the reorganization with Patrick Young, Washington Bureau Chief of Oncology News International.
ONI:NCIs role in the initial stages of drug development has been quite successful. Why the need for a major restructuring of the program?
DR. SAUSVILLE: First, there has been a change in the level and interest of industrial participation in cancer drug development. An area that was formerly not well served by big pharmaceutical companies is now rather well served. Many, if not all, of the big drug houses, have cancer research programs.
Second, the nature of cancer drug development has clearly changed. Up to maybe 10 years ago, the bellwether for interest in an antineoplastic agent was its initial demonstration of antiproliferative activity in animals or in cancer cells growing in a dish. That has really changed. Over the past 10 or 15 years, we have acquired notably better ways of thinking about how drugs might affect their targets in cancer cells.
Now that we know how cancer cells work to a much better degree than we did in the past, simply finding antipro-liferative or cytotoxic agents might not be the best way to go about finding the most valuable drugs. The way to discover really interesting molecules as drugs is to focus on their interaction with the molecular targets that give cancer cells their destructive potential. Once you get a lead against a target, the challenge is to refine the molecule and turn it into a drug.
Both the presence of industrial activity and the clear advances in science have brought to the fore the need to reflect on whether what we were doing in the past is the best thing to be doing at this time.
ONI:What is the status of implementing the changes proposed by the committee?
DR. SAUSVILLE: We are going to be putting forth RFAs and grant programs that will really beef up investigator involvement in this area. Once a target and potential molecules that interact with that target have been defined, the pharmaceutical industry is really good at advan-cing different new structures. What they dont do so well is to actually define new pathways or molecules or targets. We believe that remains very much the expertise of academics and the essence of what academic investigators do.
We want to get out there with grant programs to support the very best academic investigator involvement in drug discovery. We want to make available to them contract research resources in chemistry, structure determination, and early assessment of in vivo activity.
The second major thing is that we are going to decrease the magnitude of our own screening program and focus less on classic antiproliferative agents. Were not going to stop such screening, but we are going to focus more on defining types of molecules that dont have mechanisms of action similar to the standard agents. Then we will work with the originators of those molecules to rapidly ascertain their mechanisms of action.
ONI:What mechanisms of action interest you?
DR. SAUSVILLE: We would be very interested in discerning molecules that affect the activity of transcription factors, which actually activate genes. Another class of agents would be signal transduction related agents. And recently there has been a great deal of interest in defining the cellular mechanism that actually governs cell death (apoptosis).
ONI: The report also suggests limiting the amount of intramural research to 15% of the DTP research budget. Does that mean a cutback in-house or does it mean increasing the funds to the outside?
DR. SAUSVILLE: We interpret that statement as increasing activity on the outside, but in a sense it probably means both. Partially in response to that report, there have been cuts of the in-house budget in the area of screening. But other parts of the report call for expansion in areas related to biologics. The report clearly calls for a redirection of how funds are allocated.
Focus Primarily on Grants
ONI:Will the extramural expansion be in the form of contracts, grants, or both?
DR. SAUSVILLE: We envision it as primarily grant-directed activities to academics. But the practicalities of drug discovery are such that after you have found a unique molecule, the question of what to do with it usually does not fit within a grant-like box. This might include making analogs of the compound, acquiring pharmacology, and acquiring information about the drugs ability to cause toxicity in animals. So while the focus will be on grants, we envision a need to issue contracts to support the results of the grant activities.
ONI:The report called on the NCI to emphasize the discovery of novel therapeutics and novel drug discovery technologies. This suggests NCI hasnt done so in the past.
DR. SAUSVILLE: One can read the report in various ways. Clearly, one interpretation is exactly what you say. The view I would take is that this is an area that is rapidly advancing quite apart from the NCI. Its not that we, or anyone else in particular, were not interested in new technology. Its just that in the intervening decade or so since the last time this was looked at, there has been an explosion of new technologies.
We are very interested in bringing those technologies to the opportunities of cancer drug discovery. Where is this going to go, academia or industry? Theres a lot of interest in the small business and biotech sectors in these approaches.
Structure of Cellular Targets
ONI:Another recommendation was that the Institute launch an interdisciplinary effort to determine the structure of cellular targets particularly relevant to cancer. How do you plan to implement that?
DR. SAUSVILLE: This is a pretty big ticket item in terms of dollars, and we would want a co-funding effort to promote this. So we are coordinating our activities with the National Institute of General Medical Sciences, which for a number of years has funded activities at x-ray crystallography centers across the country. The exact magnitude of our dollar commitment is currently under discussion. Depending on how we do this, the figures are in the range of $10 to $20 million over 3 to 5 years. It could be more; I dont think it would be less.
ONI: The report called for devoting a large part of the DTP budget to establishing and supporting centers of excellence. What is the thinking about this?
DR. SAUSVILLE: We will propose funding for extramural centers that will be focused on a particular processfor example, signal transduction, angiogenesis, metastasis. We envision there will be a principal investigator, and around that investigator, as a cooperative agreement, would be programs that address the biology of this process, pharmacology of agents that might be directed against this process, and in vivo models so you could assess, in animals, agents that either the center originates or that we provide to the center.
These extramural sites would have the ability to work through the issues that come up in the downstream development of a molecule. This would include its pharmacology, its imaging, even initial clinical trials. We envision having excellent clinicians allied with these centers. We hope to fund a half dozen to a dozen centers of excellence, at a minimum, because of all the different areas that are available for research.
ONI: How do you view the future of drug development at NCI?
DR. SAUSVILLE: We think the next 10 to 20 years are going to be very exciting. Whereas, before, cancer was a bit of a black box in terms of what worked and what didnt, we now believe that we have the tools to make an impact on several levels. We are going to make that impact in collaboration with extramural scientists, who are going to be the leaders in bringing us new targets, and in collaboration with the pharmaceutical companies, which are going to really bring those opportunities to the public.
We think the NCI will have a critical catalytic and leveraging role in speeding the pace at which new discoveries reach the clinic.