IITRI Wins Major NCI Program to Support Development of New Cancer Drugs

In April 2004, IITRI was awarded a $17.3 million contract with the National Cancer Institute (NCI) to advance the development of novel cancer therapeutics. The seven-year program, "Preclinical Toxicology and Pharmacology of Drugs Developed for Cancer, AIDS, and AIDS-Related Illnesses," represents the largest single drug development contract IITRI has received from the National Institutes of Health, of which NCI is an arm.

The program's primary emphasis is the conduct of preclinical toxicology and pharmacology studies that will support the filing of investigational new drug (IND) applications for novel cancer therapeutics. Its secondary focus is on cancer imaging agents, and the program may also include studies of new AIDS drugs.

	"The development of new cancer drugs is being based on our understanding of how cancer cells grow, proliferate and divide. If we can interrupt those processes, we can control the growth and hopefully the spread of the tumor." David L. McCormick, Ph.D., D.A.B.T. Vice President and Director, IITRI

The program will include all preclinical studies required for development of novel cancer therapeutics, ranging from preliminary range-finding toxicology and pharmacology studies through detailed IND-directed toxicology studies in both rodent and non-rodent species. The program will also involve substantial work in proteomics and genomics.

Sponsored by the Toxicology and Pharmacology Branch (T&PB) of the Developmental Therapeutics Program of NCI's Division of Cancer Treatment and Diagnosis, this program represents a major expansion of the work that IITRI has been doing with T&PB since 1998. IITRI has worked closely with scientists from other branches and divisions of NCI since the early 1960s.

Program Incorporates State-of-the-Art Technologies into Preclinical Toxicology Studies

Working with NCI, there is a constant impetus to incorporate state-of-the-art technologies into study protocols. For example, the new program will involve substantial efforts to determine how endpoints such as genomics and proteomics may predict toxicity, says David L. McCormick, Ph.D., D.A.B.T., Vice President and Director of IITRI. This focus keeps IITRI at the cutting edge of advances in drug development.

"What we've seen over the last 20 years is that the types of studies we do for the NCI often predate the demand for those same types of studies and experimental endpoints for commercial sponsors," says Dr. McCormick, who has been conducting cancer research for nearly 30 years. He received his Ph.D. in Environmental Medicine/Biology from New York University in 1979, completing a thesis on cancer chemoprevention, and has been continuously active in this field ever since. "The programs supported by NCI have at their core protocols that will meet FDA requirements for new drug development, but also often include more exploratory endpoints."

New Drugs Target Molecular Mechanisms

Cancer therapy is changing. Traditional cytotoxic agents were designed to kill proliferating cells; the problem is that many normal cells in the body are regularly proliferating, as well -- in the bone marrow, in the gut, and in hair follicles. Thus, conventional treatments often cause serious side effects in the patient. "It was always kind of a race to kill the tumor before really severe, limiting toxicity was seen in other tissues in the patient," Dr. McCormick says.

Now, the focus is shifting to biological mechanisms. "New drugs are now being designed to target specific molecular features characteristic of cancer cells, including genetic mutations, factors causing changes in gene expression, structural changes in the proteins that are products of mutated genes, and alterations in signaling pathways," according to NCI's "Plans and Priorities for Cancer Research" (2004). In contrast to traditional cancer treatments that may attack both cancerous and healthy cells, "molecularly targeted therapies hold the promise of being more highly selective, drastically reducing the incidence of side effects in patients," NCI's report states.

Research in Prevention and Treatment Converge

Molecular targeting in cancer therapeutics is converging with such targeting for cancer prevention research, a field in which IITRI has been a major player for more than three decades.

"The development of new cancer drugs is being based on our understanding of how cancer cells grow, proliferate and divide. If we can interrupt those processes, we can control the growth and hopefully the spread of the tumor," Dr. McCormick explains. "Often times those mechanisms to control the growth of the tumor are the same as those which would prevent the development of the tumor in the first place. So there is an increasing convergence between prevention and therapy."

IITRI has been working extensively in cancer chemoprevention since the mid 1970s. "We've probably done more cancer prevention studies in this building than any place in the world," Dr. McCormick notes.

Clearing Developmental Hurdles

The initial demonstration of anti-tumor efficacy in experimental model systems is generally done in cell culture. The challenge then becomes transferring that efficacy to animal models.

"The most important single question is: Can you attain blood levels of the drug in vivo, in whole animals, that are sufficient to demonstrate the pharmacologic effect?" Dr. McCormick says. Short-term animal studies combined with pharmacology/ pharmacokinetic studies are performed to answer this question.

If a therapeutic concentration of the drug can be achieved, then a more detailed series of toxicology and pharmacology studies is conducted to characterize drug toxicity, to determine its dose-response relationships, and to relate the level of toxicity to the presence of the parent drug or specific metabolites that may be present either in the blood or in tissues.

Balancing Efficacy and Toxicity

The overwhelming obstacle encountered in cancer drug development is unexpected toxicity. "Sometimes you can have a drug that looks tremendous in cell culture and is active at very low concentrations. The problem is that those drugs very often are extremely toxic at very low concentrations, as well," Dr. McCormick says.

"What we're looking to do is to identify these issues at the earliest possible stage, so that if toxicity is going to be an important limiting factor, the sponsor knows that at a very early point in in vivo studies," he says.

While new molecularly targeted agents often cause fewer adverse effects than do traditional therapeutics, many of them have their own unique toxicology profiles. "Our job is to identify those toxicities and define sensitive target organs that will support the clinicians who are going to be initially studying these drugs in people." Findings from this research are used to establish dose levels, to identify the target organs most likely to be affected, and to determine appropriate measures to prevent limiting toxicity.

Experienced, Doctoral-Level Staff Lead IITRI Toxicology Programs

Preclinical toxicology and other studies at IITRI are led by Ph.D. or D.V.M. scientists with many years of experience in drug development. IITRI has the capability to integrate biochemical and molecular studies into toxicology study designs. An analytical team led by several Ph.D. chemists provides complete analytical chemistry and pharmacokinetics support on-site, using state-of-the-art instrumentation, including LC, GC, LC/MS, and LC/MS/MS, combined with virtually every standard type of detection system. Our staff of molecular biologists offers extensive expertise in studies of gene expression, using microarray, polymerase chain reaction, and other technologies.

IITRI also has initiated a major facility expansion that will bring 30,000 square feet of new laboratory space on line, all of which will be suitable to support drug development studies.

For more information on IITRI's cancer research services, please visit the Carcinogenesis and Toxicology pages of our web site.