NASHVILLEA variety of novel therapeutic mechanisms that utilize
our knowledge of cancer biology holds great promise for the future
treatment of advanced colorectal cancer (CRCA), Jordan D. Berlin, MD,
told a clinical investigators workshop. Predicting that these
new advances will end the reign of 5-fluorouracil (5-FU) as the only
colorectal cancer treatment option, Dr. Berlin declared,
The era of 5-FU vs 5-FU regimens is over.
Dr. Berlin is Assistant Professor of Medicine and oncology at
Vanderbilt University Medical Center, Nashville, TN. The workshop was
jointly sponsored by the University of Texas M. D. Anderson Cancer
Center and Pharmacia Oncology.
Dr. Berlins presentation centered on new agents for colorectal
cancer that are in or near phase III trials. These include monoclonal
antibodies such as trastuzumab (Herceptin), tumor vaccines, gene
therapies, and epidermal growth factor (EGF) receptor and
angiogenesis inhibitors. As options grow, targeting individual
tumors based on their biology may help improve results, Dr.
Manipulating EGF Receptor
Researchers are attempting either to inhibit the EGF receptor (also
called HER-1 or erbB1) or to use it to cause toxicity to tumor cells.
EGF receptor ligands include transforming growth factor-alpha
(TGF-alpha), heparin-binding EGF, amphiregulin, and betacellulin.
EGF receptor activation is caused by ligand binding, which
results in homodimerization or heterodimerization with another member
of the HER family, receptor autophosphorylation, and activation of
tyrosine kinase. This leads to downstream activities that impact cell
survival and apoptosis, angiogenesis, motility, and
invasiveness, Dr. Berlin said.
EGF receptor overexpression in colorectal cancer is suspected of
contributing to poor prognosis, although conflicting reports suggest
there may be no effect on survival, according to Dr. Berlin.
Overexpression does appear to increase metastatic potential, and
resistant tumors tend to have higher levels of EGF receptor expression.
Anti-EGF receptor antibodies, ligand conjugates, immunoconjugates,
antisense oligonucleotides, and tyrosine kinase inhibitors are being
tested as ways of inhibiting the EGF receptor.
Angiogenesis Needed for Growth
Angiogenesis appears necessary for tumors to grow larger than 1-2
mm3. Neovascularization appears to allow tumors to grow more
rapidly, to confer increased potential for metastasis formation, and
to confer a poor prognosis in many tumor types, including CRCA,
Dr. Berlin said.
Despite the flurry of news reports about angiostatin and endostatin,
Dr. Berlin pointed out that both are still in phase I trials with no
reported data. Matrix metalloproteinase inhibitors have also
been through much testing without significant results, he
Newer approaches include inhibitors of endothelial cell proliferation
such as anti-vascular endothelial growth factor receptor 2 (VEGFR2)
antibody and inhibitors of the Flk-1 receptor for VEGF. Headache
keeps showing up as a side effect with anti-VEGF treatment,
Dr. Berlin said. Data from a phase II trial of an anti-VEGF antibody
were presented at the American Society of Clinical Oncology (ASCO)
meeting this year and suggested benefit from anti-VEGF antibody, but
showed no advantage to a higher-dose anti-VEGF regimen.
The VEGF receptor inhibitor SU5416 is in a phase III trial. Dr.
Berlin reported concern about the required twice-weekly dosing
schedule. Dose-limiting toxicities have been headache and nausea/vomiting.
Results of a phase I/II study of SU5416 in combination with either
the Mayo Clinic or the Roswell Park colorectal cancer regimens were
also presented at the ASCO meeting. Response rates look
promising with the Roswell regimen of 5-FU/leucovorin (LV) and
SU5416, Dr. Berlin said. In preliminary studies, these have
included 4% complete response, 37% partial response, 11% minor
response, and 37% stable disease. Adverse effects were mild, with
headaches and nausea/vomiting as the dose-limiting toxicities. SU5416
is currently being investigated in phase I studies in combination
with irinotecan and irinotecan/5-FU.