MIAMI BEACH, FlaThe 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. Were 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
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 patients 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 oncogenesparticularly 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
messengerthe 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 dont 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 wantthe 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.