Dealing with Drugs
With new computing power and knowledge, scientists hope to develop lifesaving drugs more quickly and with better results.
It took 115 years from the first description of blood cancer in 1845 until the discovery of a genetic abnormality instrumental in the disease. Now, 41 years later, a new drug, Gleevec, seems to be the first to offer promise as a treatment.
Powerful drugs just beginning to be tested for similar glimpses of potential will join Gleevec and hundreds of other drugs in the years ahead.
But where do these drugs come from?
"To the public, it may seem like a trial-and-error process of chemical guesswork, but cancer drug discovery has come a long way," says Nouri Neamati, Ph.D., assistant professor of pharmaceutical sciences in the USC School of Pharmacy and the USC/Norris Comprehensive Cancer Center.
"Drug discovery has entered a new era, with not only better techniques for producing and screening new drugs, but with computing power that was unimaginable a decade ago," he says. "These techniques give us the opportunity to submit new compounds to a rigorous virtual screening to predict how a drug will work even before we begin testing in the laboratory."
Neamati notes that prescreening is just one method that can save academic laboratories, pharmaceutical companies and government agencies from pursuing wrong leads. By following a systematic plan, potential new drugs are being explored at rapid speed, with thousands of scientists worldwide contributing to a growing body of knowledge of life enhancing therapies.
Drug tailoring
Even with significant advances in drug therapies, more than 1.2 million new cancer cases will be diagnosed in the United States in 2002, according to the American Cancer Society. Projections show that 555,500 Americans will succumb to the disease this year-more than 1,500 a day.
By definition, cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells. Caused by both internal factors-heredity, genetic mutations-and external factors-tobacco, chemicals, radiation, infections-cancerous cells are known for their ability to divide and spread throughout the body, often invading more than one site at a time.
"When cancer cells divide and multiply, they develop a mechanism that allows them to survive without undergoing cell death," says Jacek Pinski, M.D., Ph.D., assistant professor of medical oncology at USC/Norris. "Only a small percentage of cancer cells are proliferating at a time. In order for chemotherapy to be effective, it has to kill the cells while they are multiplying and dividing in the cell cycle."
Additionally, some cancer cells develop a resistance to particular chemotherapeutic agents over time, decreasing their effectiveness on the disease, he says.
Chemotherapeutic agents must be tailored to an individual's cancer type because different tumors respond to different therapies. Even patients diagnosed with the same disease may require different drug combinations for treatment, Neamati says.
A chemotherapeutic agent may also damage normal cells in a patient's body, specifically cells that also divide rapidly, such as those found in the gastrointestinal (GI) tract, hair follicles and bone marrow. This is why cancer patients often experience side effects such as nausea, hair loss, infection and bleeding.
With this in mind, researchers seek more effective drugs that kill the cancerous cells without destroying the normal cells.
Rubik's cube
"Within the last few years, there has been a greater understanding of why cancer develops," Pinski says. "By determining the mechanisms involved at the cellular level, researchers can design better cancer therapies, which means improved results for patients."
To find the mechanisms involved with cancer development, researchers study proteins and the roles they play in the biological functioning of the body, and ultimately in the development of cancer.
To aid in their investigations, researchers have developed databases or "libraries" that contain thousands of potential drug compounds and proteins-all of which have a potential role in the prevention and treatment of cancer and other diseases. The idea is to find a protein important in disease development or progression, then find a drug to counteract that protein.
For example, in cancer research scientists begin by testing the protein to make sure it plays a role in cancer. They do this testing in groups of cells in a Petri dish in the laboratory, then in animal models.
Once they are certain how the protein works, they search for a particular drug that binds to its active site. They may create a new compound or pick one from the drug library. A drug binds with a protein by chemically interlocking with it, like a lock and key. The researchers can see how the
protein and the drug will interlock partly by viewing a 3-D image of each molecule, and then, like a Rubik's cube, twisting and turning the visual images until a match is made.
Ideally, once in the body, the drug molecule will interlock with the protein molecule and block its action, helping to fight cancer.
"Proteins come in all different shapes and sizes, with a variety of unique surface structures," Neamati says. "A drug compound has to be specific for the targeted protein. You have to continuously modify it until you find the right fit."
With these techniques, researchers have been able to isolate key proteins and develop novel therapies with the potential for treating cancer.
Parkash Gill, M.D., professor of medicine, division of hematology and pathology, Keck School of Medicine of USC and USC/Norris, has spent the last 20 years working on therapies to treat Kaposi's sarcoma (KS), a cancer of the connective tissue that is often associated with HIV/AIDS. From his work with KS, Gill has developed a research
interest in blood vessel growth and its role in the spread of cancer tumors.
In cancer, mutations allow for the production of a protein that increases blood vessel development inside a tumor, giving the tumor the blood supply it needs to grow and spread.
Gill recently developed the drug Veglin, which inhibits the protein that allows for growth and maturation of blood vessels.
"Veglin will be tested on a variety of cancer tumors, specifically advanced stages of cancer," Gill says. "Patients with advanced cancer have more blood vessels in their tumors and could benefit from a treatment like this."
Narrowing the field
Once a new drug has been identified, it must be tested for standard "drug-like" properties.
"A new drug must be screened for key criteria referred to as ADME/T, which stands for absorption, distribution, metabolism, excretion and toxicity," Neamati says. "Most drugs taken orally are absorbed in the GI tract and carried throughout the blood stream to the receptors at the sites in the body where they are needed."
It is key for the drug to be metabolically stable and maintain a reasonably long half-life, he says. This refers to how long the drug stays in the blood stream before it is excreted, which is critical for determining when the next dose is given to the patient.
"ADME/T information during the early stages of drug discovery helps determine the fate of a drug," Neamati says. "Poor ADME/T results account for failure of nearly 60 percent of new drugs during development."
Neamati, a chemist with expertise in drug design and discovery, has recently designed two new drugs with the potential to treat breast and bladder cancers. He and his USC collaborators are one of the few groups that not only accomplish drug design and discovery, but also have the necessary techniques to test compounds for favorable ADME/T. This expedites the process and allows them and others to begin testing the new drug in pre-clinical trials.
Before clinical trials of a drug can begin, the Food and Drug Administration (FDA) requires that a drug be tested in animal models that mimic the human body's response to the compound. The main goal of this phase is to determine toxicity and side effects.
Once a drug is determined to be safe, researchers and physicians work together to develop a protocol or "game plan" for how a clinical trial should work, including specifics about how the drug will be given, who will participate and for how long.
In any clinical trial, there are four distinct phases, each with a different goal. Phase I and II clinical trials that test drug safety offer patients with advanced cancer the opportunity to try experimental treatments after the standard of care has failed-and potentially extend their life.
"It is critical to understand patients involved with phase I and II cancer clinical trials have a very short life expectancy," explains Pinski. "The general standard of care has not worked, for whatever reason. Doctors want to try to save their lives, possibly with this new drug."
Phase I determines the maximum drug dose tolerated by the patient volunteers and looks for any toxic effects that may not have occurred in the animal studies. During phase I, any reduction in tumor size is seen as a side benefit, Pinski says, but it is not the goal.
In phase II, efficacy or effectiveness of the drug is tested-the intention is to see if cancer tumors actually shrink. Often patients who participate in a phase I clinical trial and tolerate the drug well will continue on to phase II, explains Pinski.
Once the new drug has been determined safe and effective in phases I and II, it can be tested in phase III, where it is compared against the standard therapy that has already been proven to work. Generally, patients involved in phase III are beginning treatment for their cancer and have an optimistic prognosis, while also fulfilling criteria specific to the clinical trial.
Phase IV usually occurs while waiting for final FDA approval and coincides with the marketing of the new product to treat cancer in the general population.
Young and old not alike
Pinski notes that the distinct advantage of an academic institution is that many faculty physicians and scientists are initiating clinical trials based on their research with new and existing drug therapies. Influenced by the increased knowledge of how drugs function in eliminating disease, many researchers are turning their attention to therapies for special populations such as children and senior citizens.
"In the past, children were given 'hand-me-down' adult drugs and drug companies did not specifically seek from the FDA labeling for safety, dosing or indications in children for many drugs," says C. Patrick Reynolds, M.D., Ph.D., head of the developmental therapeutics section at Childrens Hospital Los Angeles and professor of pediatrics and pathology, Keck School of Medicine. "Once a drug has been approved for use in adults, it generally can be used in pediatrics 'off-label', but this is clearly less desirable then formalizing drug use in the pediatric population."
New FDA regulations and incentive programs developed in recent years are encouraging researchers and drug companies to carry out studies of drugs in children that will enable formal labeling of the drugs for use in the pediatric population, Reynolds says. It is anticipated that these new FDA programs will also result in more rapid access for children to new pharmaceuticals, particularly in life- threatening diseases such as cancer.
Wonder drugs
In the Los Angeles area, hundreds of clinical trials are taking place on any given day. Thousands more are underway around the world.
When the drug Gleevec came on the market in May 2001, it had gone through a successful run of clinical trials at the City of Hope Comprehensive Cancer Center in Duarte, Calif., Jonsson Comprehensive Cancer Center at UCLA, Robert H. Lurie Cancer Center at Northwestern University and the Oregon Cancer Center at Oregon Health Sciences University.
Gleevec was first indicated for patients with chronic myeloid leukemia and was later found effective in treating aggressive gastrointestinal stromal tumors. Patients who participated in the Gleevec clinical trials were the first to benefit from its therapeutic effects.
FDA regulations allow any drug that has the potential to successfully treat a serious or life-threatening illness to be fast-tracked through the approval process to make the drug available to patients sooner, Neamati says, which is what happened with Gleevec.
According to Neamati, for every 20,000 to 50,000 compounds tested, only one drug is deemed to be effective and safe and to have advantages over similar existing drugs, such as fewer side effects. He says on average it takes 12 years and $250 to $400 million to successfully market a new drug that meets all of the necessary criteria.
"Since the 1940s, scientists have been developing new drug therapies," Neamati says. "This updated process of drug discovery creates a clinical standard for researchers to follow. As a result, we hope to bring potentially life-saving drugs to the public in a shorter amount of time and with better results."
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