USC / Norris Cancer Researchers Show Potential of Fighting Angiogenesis
Phase I trial shows experimental drug is safe and lowers level of key blood protein
Keck School of Medicine of USC researchers have reported that the antiangiogenesis drug they developed—called Veglin—not only is safe for patients with a wide variety of cancers, but also lowers levels of a key protein that tumors need to grow and stabilizes or even reverses some cancers for a period.
Alexandra M. Levine, M.D., Distinguished Professor of Medicine and chief of hematology at the Keck School of Medicine and medical director of the USC/Norris Cancer Hospital, presented results from the ongoing Veglin trial at the 40th Annual Meeting of the American Society of Clinical Oncology this past weekend.
“Veglin continues to show its safety, even though we’ve escalated the dose significantly. Blood levels of key enzymes we are targeting also have gone down in about 50-percent of the cases, and we are pleased so far,” says Levine, the Ronald H. Bloom Family Chair in Lymphoma at the Keck School.
Veglin originated with USC/Norris Comprehensive Cancer Center researcher Parkash Gill, M.D., Keck School professor of medicine. Los Angeles, Calif.-based VasGene Therapeutics Inc., which was co-founded by Gill, now leads its development.
In 2003, a team of USC/Norris scientists opened a phase I trial of Veglin for patients with any malignancy that failed to respond to previous treatment. The study evaluates the safety of the drug at increasing doses and examines response. So far, researchers have increased the dosage tenfold, with no significant toxic side effects seen.
Nearly three quarters of the 35 patients who have participated in the clinical trial so far have had solid tumors of the kidneys, colon or lung, or cancers such as melanoma or sarcoma. More than a quarter of the patients have had hematologic cancers, such as lymphoma, Kaposi’s sarcoma and myeloma.
Veglin clinically and visibly reduced cancerous tissue for several months in cases of Kaposi’s sarcoma and cutaneous T-cell lymphoma, researchers reported. Patients with lymphoma, bronchoalveolar carcinoma, renal cell carcinoma, multiple myeloma and chondrosarcoma also saw disease stabilization or other clinical benefits from the drug.
The drug targets a family of proteins called vascular endothelial growth factors, or VEGF.
Cancer cells develop rapidly and need an ever-increasing blood supply, researchers explain. As a result, tumors must encourage new blood vessels to develop around them—a process called angiogenesis. VEGF is critical to the growth of these new blood vessels.
But that is not all. VEGF also directly helps certain cancers grow.
“VEGF serves as an autocrine growth factor for certain types of cancers,” Levine says. “The analogy would be the following: If a car were able to make its own gasoline, it would drive forever. The gasoline for the cancer cell is VEGF; it is made by the cancer cell, and comes back to work on the cancer cell that made it, causing the cancer cell to divide and proliferate.”
Veglin is meant to counteract that. Called an antisense oligonucleotide, Veglin is a bit of DNA that binds directly to the gene that produces VEGF—essentially plugging it.
Researchers hope that if Veglin can keep tumor cells from producing VEGF, it will block their growth and metastasis, while also killing the cancer cells themselves.
Patients in the trial receive Veglin intravenously over two hours, for five straight days. They then get a week off. This cycle continues for four months.
Veglin lowered blood levels of a form of VEGF, called VEGF-A, in 47 percent of participants. It also lowered levels of VEGF-C in 21 percent of participants.
In addition to Kaposi’s sarcoma and cutaneous T-cell lymphoma patients, whose cancer growth was reversed for several months, other patients saw clinical benefits, too. Veglin stabilized cancer levels in patients with renal cell cancer for two or more months, chondrosarcoma for five months and bronchoalveolar carcinoma for more than seven months.
“We have seen tumor shrinkage and stabilization in diverse disease types. These are good indications for a single agent,” Levine says. “In the future, optimally we would combine it with other drugs.”
Researchers are now planning phase II clinical trials for patients with renal cell carcinoma, mesothelioma, leukemia and lymphoma. Studies will initially begin at USC/Norris, with additional centers added later.
Alexandra M. Levine, David I. Quinn, Gerry Gorospe, Heinz-Josef Lenz, Anil Tulpule and Parkash S. Gill, “Phase I Trial of Antisense Oligonucleotide against Vascular Endothelial Growth Factor (VEGF-AS, Veglin) in Relapsed and Refractory Malignancies,” 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, La., June 3-8, 2004.
Jon Weiner | USC