Amgen’s Jon Oliner, M.D., Ph.D., scientific executive director, Oncology Research, was recently named among R&D Directions “Most Notable People in R&D” for his work in angiopoietin proteins. Read the text from their profile of Jon below.*
Lessons Learned in Tumor Suppression
One promising avenue for attacking cancer comes from therapies that starve tumors by cutting off their blood supply. The theory is, because all solid tumors require an expanding vasculature to support their growth, these drugs, which target angiogenesis – the formation of new blood vessels – might curb the growth of a wide range of cancers. In practice, however, the impact of current agents has been more limited than originally hoped, according to Jon Oliner, M.D., Ph.D., scientific director, oncology research, Amgen Inc. (amgen.com). Dr. Oliner founded and led company efforts to advance an alternative approach to antiangiogenesis, where approved drugs antagonize the vascular endothelial growth factor pathway.
“While the approved antiangiogenic agents provide clinical benefit in a number of cancer indications, they can be quite toxic, and patients commonly acquire resistance to them,” Dr. Oliner says. “We set out to develop a new class of antiangiogenics that might provide greater benefit to patients with less toxicity.”
To that end, Dr. Oliner, upon joining Amgen in 1999, started a new program targeting the angiopoietin proteins. The two best-characterized angiopoietins – Ang1 and Ang2 – were originally considered to play opposing roles.
“Classically, it was thought that Ang1 helped to stabilize normal blood vessels, while Ang2 provided the destabilization needed to initiate angiogenesis,” Dr. Oliner says. “So our initial assumption was that Ang2 inhibition would be efficacious, but Ang1 inhibition might be globally and catastrophically toxic to normal vessels. It turned out we were half right.”
Amgen preclinical studies demonstrated that Ang2 inhibition suppressed angiogenesis and tumor growth, and both Ang 1 inhibition and Ang 2 inhibition were well tolerated. Also, in an animal model, dual Ang1/2 inhibition provided better antitumor efficacy than Ang2 inhibition alone. As a result, Amgen shifted gears and developed a dual inhibitor rather than a selective Ang2 antagonist.
Resulting efforts led to Amgen’s drug candidate AMG 386, the first investigational cancer drug in this new class to enter Phase III clinical trials. The molecule is a peptibody – an active peptide linked to a carrier protein. In this case, the active peptide is an angiopoietin inhibitor. In Phase II results disclosed last June, AMG 386, combined with the chemotherapy agent paclitaxel, extended progression-free survival in patients with recurrent ovarian cancer.
Late-stage trials are under way to assess AMG 386 as a first-line and a second-line treatment for ovarian cancer. Earlier-stage studies are exploring the agent’s potential against other tumors, including cancers of the breast, stomach, liver, kidney, uterus, and colon.
Dr. Oliner was a postdoctoral fellow at the University of California, Berkeley. He earned an M.D. and Ph.D. in human genetics and molecular biology at the The Johns Hopkins University School of Medicine.
* Posted with permission from R&D Directions, March 2011.