Targeted Cancer Drugs, Cytostatic Agents-Wave of the Future

MIAMI BEACH, Fla—The development of chemotherapy agents peaked between 1985 and 1990, Dr. Eric Rowinsky said at the annual meeting of the Network of Oncology Communication and Research (NOCR). “However, we saw the same types of drugs being developed (analogs of the platinums and anthracyclines) because we were using the same old screening system,” he said.

When the National Cancer Institute (NCI) came up with a panel to screen for agents active in specific tumors, the result was 15,000 compounds screened in 1 year. “We’re now seeing a variety of targeted therapeutics that are just beginning to hit the clinical arena,” said Dr. Rowinsky, director of clinical research, the Institute for Drug Development, San Antonio.

He sees the system of screening for new drugs evolving from a tumor-type-based screen into a molecular-target-based screen, and projects that in 5 to 10 years, a pathologist will be able to screen a tumor for an analysis of possible molecular targets, which will result in individualized therapy.

Some new agents under development zero in on subcellular targets such as ribonucleotide reductase and thymidylate synthetase. These include ribonucleotide inhibitors such as MDL 101,731, currently in phase I trials, which has shown activity against human breast cancer, non-small-cell lung cancer (NSCLC), and colon tumor xenografts.

Thymidylate Synthetase Inhibitors

A number of direct thymidylate synthetase inhibitors are currently in trials. Dr. Rowinsky said that the most interesting is LY231514, an antifol that inhibits the folate-dependent enzymes glycinamide ribonucleotide formyltransferase (GARFT) and dihydrofolate reductase (DHFR) as well as thymidylate synthetase. Early trials show that LY231514 is active in NSCLC and in breast and colorectal cancers.

“Another exciting area under investigation,” Dr. Rowinsky said, “is the use of adenoviruses that target the p53 tumor suppressor oncogene.”

ONYX-015 is a genetically engineered attenuated adenoviral vector that is specifically incorporated into the genome and divides within tumor cells that have p53 mutations or deficiencies, killing them. ONYX-015 is showing activity in head and neck cancers when injected directly into the tumor.

Along the same vein is the idea of using adenoviruses to deliver a replacement p53 gene into tumor cells to restore p53 tumor suppressor function.

Cancer as a Chronic Disease

Dr. Rowinsky said that perhaps one of the most exciting ideas to come out of the new therapeutics is that of delaying disease progression and maintaining a patient’s functionality, rather than attempting a “cure,” defined as maximal cytoreduction.

“We need a reality check,” he said. “Cure is not the therapeutic objective in other serious diseases like cardiovascular disease.” The new wave of antineoplastic agents is going to focus more on tumor growth delay and less on “stamping every last cancer cell into the ground,” he said.

As an example, he cited the development of agents aimed at the tyrosine kinase receptor, an epidermal growth factor (EGF) receptor active in proliferation of oncogenes—particularly the ras oncogene. By using an EGF tyrosine receptor antagonist, tumor activity (growth and proliferation) may be inhibited. So far, he said, three oral EGF tyrosine kinase inhibitors are in development.

Another way of targeting proliferating cells is to kill the messenger—the ras messenger. A mutated ras messenger occurs in about 30% of human tumors overall, and is found in 90% of pancreatic tumors and 50% of colorectal carcinomas. Farnesylation, one of the chemical steps involved in maturation of the ras protein, is being targeted with the use of farnesyl transferase inhibitors.

Another cytostatic agent aimed at slowing or stopping proliferation of cancer cells is squalamine lactate, undergoing study as MS1-1256. This agent, derived from the liver of the dogfish shark, inhibits the stimulation of growth factors in malignant blood cells.

This array of new substances currently in development “presents some very unique developmental problems,” Dr. Rowinsky said, “and we may have to think about new paradigms in drug development and in clinical trials when talking about cytostatic agents.”

For example, the “nonproliferative” cytostatic drugs generally have low toxicity profiles and require long-term administration. Thus, toxicology and side effects need to be assessed in a chronic situation.

Under the old paradigm, boluses of drugs were given to the maximum tolerated dose. If a certain level of tumor reduction was achieved at that dose, then the green light was given to move through phase I to phase II to phase III trials. “We don’t really know how to design studies to get to the green light with these new cytostatic agents,” Dr. Rowinsky said.

Perhaps the index used to measure the efficacy of gemcitabine (Gemzar) in its pivotal trials, the Clinical Benefit Index, will come more into play, as will measures such as the Q-twist index that assess improvements in quality of life. “Q-twist gives the functional parameters you want—the time patients spend without symptomatic manifestations of the disease and without the toxicity of the drug,” he said.

Dr. Rowinsky feels that the potential for major therapeutic advancement is at hand, providing there are enough patients available for the large randomized trials necessary to evaluate the new agents. “These new agents are going to be competing for the same 3% to 5% of US cancer patients who enroll in clinical trials as are the cytotoxic analogs also in development,” he said, adding that “marketing will be the name of the game with the new therapies.”

He called for a national policy to incorporate early clinical evaluations into the clinical practice mainstream. “Otherwise,” he said, “in this era of abundance, progress in clinical oncology could grind to a halt.”