Half of patients with advanced pancreatic cancer had objective responses or stable disease when they received a hedgehog pathway inhibitor in addition to standard chemotherapy, results of a small clinical trial showed.
Ten of 20 evaluable patients were alive without progression after 3 months when treated with the combination of vismodegib (Erivedge) and gemcitabine.
Some patients actually progressed during treatment with vismodegib alone but then had a major response when gemcitabine was added to treatment, Edward J. Kim, MD, PhD, reported at the American Association for Cancer Research Pancreatic Cancer Conference in Lake Tahoe, Nev.
“Our analysis of tumor tissue allowed us to examine a number of variables, and we determined that assessment of pretreatment levels of sonic hedgehog was the best predictor of treatment response,” Kim, of the University of Michigan in Ann Arbor, said during a press briefing at the conference.
“Measurement of levels of sonic hedgehog expression in patient tumors appears to serve as a predictive biomarker of benefit with this regimen. Sequential delivery of [vismodegib] followed by gemcitabine is well tolerated in patients and effective in a subset of patients with metastatic pancreatic cancer.”
The clinical trial evolved from previously reported observations that pancreatic cancer stem cells exhibited increased expression of sonic hedgehog, a developmental signaling molecule (Cancer Res 2007; 67: 1030-1037). In the normal adult human pancreas, the hedgehog pathway remains silent but is activated in patients with pancreatic cancer.
Inability to kill cancer stem cells may facilitate tumor regrowth in patients who initially respond to therapy.
“Even if a therapy succeeds in obtaining a response, cancer stem cells may persist and contribute to resistance and progression of disease,” he added. “Having found that pancreatic cancer stem cells have higher hedgehog levels than bulk cancer cells, we were interested in determining whether targeting the hedgehog signaling pathway and, therefore, the cancer stem cells, might lead to improved outcomes in pancreatic cancer.
Hedgehog signaling also contributes to development of desmoplastic stroma that characterizes pancreatic cancer. The dense stroma may confer chemoresistance to cancer cells by providing a physical barrier that conventional chemotherapy cannot penetrate, he added.
Vismodegib targets smoothened protein, a key mediator of hedgehog signaling. The drug recently received FDA approval for treatment of basal cell carcinoma.
Investigators have enrolled 21 patients with advanced pancreatic cancer, and accrual will continue to 25 patients. Kim reported findings for 20 patients who had paired biopsies and could be assessed for treatment response after three cycles of therapy.
All patients received vismodegib daily for 4 weeks, followed by concurrent therapy with gemcitabine. Sonic hedgehog expression and levels of the proliferation marker Ki-67 were evaluated by immunohistochemistry at baseline and follow-up.
Kim reported that five of 20 patients (28%) had partial responses by RECIST criteria after three cycles of therapy. Five other patients had stable disease, resulting in a 3-month progression-free survival of 50%.
There were ten of 20 patients (50%) who had reduced cancer stem-cell populations, and the decline averaged 60%. Additionally, the proliferation index decreased by 54%.
Kim and colleagues found that patients who achieved objective responses or stable disease had higher levels of sonic hedgehog expression prior to treatment, as compared with patients who had progressive disease (P=0.016).
The investigators continue to evaluate the effect of vismodegib on the hedgehog pathway target genes. They also are performing correlative studies of hedgehog signaling and stromal density.The findings might help restore some optimism about a possible therapeutic role for hedgehog inhibition in pancreatic cancer, said Daniel Von Hoff, MD, of the Mayo Clinic in Rochester, Minn.
“A study of another hedgehog inhibitor did not show an improvement in progression-free survival,” said Von Hoff, who moderated the press briefing. “That depressed all of us. It’s very important for us to find out why that didn’t occur.”
“The response rate in this study is very high,” Von Hoff added. “Usually see about a 5% or 9% chance of having a response to gemcitabine by itself. Here it was 25%, which is beyond what one would have expected. The good news about this drug is that it doesn’t add any toxicities whatsoever.”
Kim had no relevant disclosures.
Primary source: AACR Pancreatic Cancer Conference
Kim EJ et al “Cancer stem cells (CSC) and inhibition of hedgehog (Hh) pathway signalling in advanced pancreatic cancer: GDC-0449 in combination with gemcitabine (Gem)” AACR PCC 2012.