(HealthDay News) – Targeting the hedgehog signaling pathway with a smoothened antagonist, GDC-0449, in combination with gemcitabine achieves partial response in some metastatic pancreatic cancer patients; and targeted depletion of the multi-functional cell membrane protein RLIP76 can cause pancreatic cancer tumors in mice to regress, according to two studies presented at the American Association for Cancer Research’s Pancreatic Cancer: Progress and Challenges conference, held from June 18–21 in Lake Tahoe, NV.
Edward J Kim, MD, PhD, from the University of Michigan in Ann Arbor, and colleagues conducted a Phase 1 trial involving sequential delivery of GDC-0449 as monotherapy, followed by GDC-0449 given in combination with gemcitabine, in patients with metastatic pancreatic cancer. Twenty participants underwent paired biopsies before and after treatment with GDC-0449. The researchers found that, although a subset of patients had evidence of disease progression on GDC-0449 monotherapy, there was a response in several patients following continuation of GDC-0449 plus gemcitabine. Partial response was achieved in five patients, and four additional patients had stable disease.
Noting that inhibition of RLIP76 has been shown to antagonize phosphoinositide-3-kinase (PI3K) and protein kinase B (AKT) in other cancers, and that PI3K/AKT may play a role in apoptosis resistance in pancreatic cancer, Kathryn Leake, from the Beckman Research Institute in Duarte, CA, and colleagues investigated whether targeted depletion of RLIP76 could effectively overcome chemo-radio-resistance in pancreatic cancer. The researchers found that, in the mouse xenograft model of pancreatic cancer, RLIP76 depletion caused marked and sustained regression of established human BxPC-3 pancreatic tumors. RLIP76 was able to mediate drug and radiation resistance.
“Fortunately, our data show that the seemingly unconquerable pancreatic cancer has an Achilles heel: its toxin exhaust system,” a coauthor of the Leake study said in a statement. “Moreover, plugging this exhaust caused pancreatic cancer cell death, leaving normal cells relatively unfazed. We hope to translate these studies into clinical trials in the near future.”
One author of the Leake study disclosed financial ties to Terapio, which makes the recombinant RLIP76 protein for the treatment of radiation poisoning.