Novel Approaches Hold Promise for Future Treatment of Advanced Colorectal Cancers

NASHVILLE—A 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. Berlin’s 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. Berlin stated.

 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 said.

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.