NEAR PROGRESS IN PANCREATIC CANCER

June 21, 2012 — At last it appears that some progress is being made in pancreatic cancer, according to a number of investigators who presented research at the "first-ever conference on pancreatic cancer research." The meeting, held in Lake Tahoe, Nevada, was organized by the American Association for Cancer Research.

"We now have a variety of compelling observations coming in on the disease from different angles," said Sanjay Awasthi, MD, professor of medical oncology and therapeutics research at City of Hope in Duarte, California. He was speaking at a presscast that highlighted some of the presentations. "We have some really interesting scientific ideas on how to shrink the tumors and make our patients better."

"I really think we are at a tipping point for the field," said Rachelle Stopczynski, an MD/PhD student at the University of Pittsburg in Pennsylvania, who was involved in setting up the meeting. "We really feel like we have turned the corner on this disease."

The progress being made in research already seems to have trickled down to the clinic, at least for some patients. "There are now some long-term survivors, so something is happening," said Daniel Von Hoff, MD, distinguished professor at the Translational Genomic Research Institute (TGen) and professor of medicine at the Mayo Clinic Phoenix, Arizona. Dr. Von Hoff was cochair of the conference and moderated the presscast.

Notoriously Difficult to Treat

"Cancer of the pancreas is notoriously difficult to treat; it usually presents at a late stage because of its minimal or nonspecific symptoms in the early stage," Dr. Awasthi told journalists. "Thus, surgical treatment is either not possible or fails to cure most patients, resulting in a dismal prognosis — 90% of patients are likely to die within a year."

One of the reasons pancreatic cancer is so difficult to treat is that the tumor cells are largely resistant to the cell death induced by chemotherapy and radiation, he explained.

"Pancreatic cancer patients are a special case of the particularly unlucky," Dr. Awasthi said. "The drug and radiation resistance of this cancer is legendary."

"Fortunately, our data show that the seemingly unconquerable pancreatic cancer has an Achilles heel," he said.

The weak point identified is the RLIP76 protein, which transports metabolites out of the cell. "It works like an exhaust system," Dr. Awasthi explained. "It pumps out toxic chemicals that accumulate in the cancer cell as a result of chemo- or radiotherapy before they can cause cell death."

Blocking this protein has led to some encouraging results, although so far they are all from the preclinical setting.

Dr. Awasthi and colleagues found that cancerous human pancreatic cells have a higher concentration of RLIP76 than normal pancreatic cells. In studies of human pancreatic tumor cells, blocking this protein resulted in the death of cultured cells and dramatically enhanced the action of doxorubicin on cultured cells.

In mouse-model studies, the team showed that blocking RLIP76 resulted in the shrinkage of established human pancreatic tumors and in a decrease in blood sugar, cholesterol, and triglyceride levels. In addition, knockout mice lacking the RLIP76 protein are resistant to cancer caused by carcinogens (e.g., benzopyrene), and are naturally antidiabetic, with low blood sugar, cholesterol, and triglyceride levels. The findings suggest that this research might lead to progress in treating diabetes in addition to pancreatic cancer, the researchers note.

"We hope to translate these studies into clinical trials in the near future," Dr. Awasthi said.

Potential to Change Treatment Approach

Another approach already tested in the clinic — although so far only in a few patients — focuses on inhibiting thehedgehog signaling pathway.

This pathway is important in embryonic development but is not required in normal adults cells; however, it becomes reactivated in cancer. Targeting this pathway provides a way of attacking cancer cells while leaving healthy tissue intact.

This approach has generated considerable excitement among cancer researchers and has already yielded a success. The hedgehog pathway inhibitor vismodegib (Erivedge [formerly GDC-0449], Genentech) was recently approved for use in basal cell carcinoma and has been hailed as the "greatest advance in therapy" for this disease.

Early results with vismodegib in pancreatic cancer look promising.

"We believe that vismodegib has the potential to change the approach to treating pancreatic cancer," said Edward Kim, MD, PhD, medical oncologist at the University of Michigan Comprehensive Cancer Center in Ann Arbor, Michigan.

In pancreatic cancer, the hedgehog pathway is thought to contribute to the extensive scarring, or desmoplastic stroma, that is characteristic of this disease. This dense stroma is thought to act as a physical barrier to chemotherapy, preventing it from reaching the pancreatic cancer cells and contributing to the chemotherapy resistance commonly seen in these patients.

Dr. Kim and colleagues reasoned that using vismodegib before chemotherapy would disrupt this dense stroma and allow better penetration of chemotherapeutic agents, improving its effectiveness.

In addition, hedgehog levels are increased in pancreatic cancer stem cells, which form the "hub" of the tumor and drive tumor growth. These cancer stem cells are also notoriously resistant to chemotherapy and radiation.

"Even if a therapy succeeds in achieving an initial visible response, cancer stem cells may persist and contribute to resistance and progression of disease," Dr. Kim explained. Therefore, the researchers reasoned that suppressing hedgehog activity within the stem cells would enhance the effectiveness of subsequent chemotherapy.

The team put these theories to the test in a study that will accrue 25 patients; at the meeting, they reported the initial results from 20 patients assessable for response.

These patients had advanced pancreatic cancer and had not received any previous treatment. They were initially given oral vismodegib as daily monotherapy for 3 weeks; needle biopsies of the cancer were taken before and after this treatment. After the second biopsy, patients continued on vismodegib but were also given gemcitabine, a standard chemotherapy for pancreatic cancer.

Of the 20 patients assessed, 5 achieved a confirmed partial response (25% response rate) and 5 had stable disease as their best response. When these 2 groups were combined, the progression-free survival rate at 3 months was 50%.

Vismodegib appears to be effective in a subset of patients with advanced pancreatic cancer, Dr. Kim noted. Analysis of the tissue obtained from biopsies before and after vismodegib showed that the pretreatment level of hedgehog expression was the best predictor of response to treatment, and serves as a predictive biomarker for this regimen, Dr. Kim reported.

Analysis of the tissue samples is ongoing, he said.

There is a lot of interest in this approach within the pancreatic cancer community, said Dr. Von Hoff.

In particular, the preclinical results showing that the hedgehog pathway is involved in the stroma and in cancer stem cells provide hope that inhibiting this pathway will have a clinical impact, he said.

However, a clinical trial with another investigational hedgehog pathway inhibitor did not show any improvement in progression-free survival, which "rather depressed us all," Dr. Von Hoff noted. But this is a different compound, and the response rate reported here for vismodegib is very high, he explained. Normally in pancreatic cancer, you would expect a response rate of only 5% to 9% with gemcitabine alone.

"I am really interested to see the next results," he said, adding that these need to come from a randomized trial. "The good news is that these hedgehog inhibitors do not add any substantial toxicity," he added.

Adding Another Targeted Drug

Another early clinical trial indicates "promising activity" with a combination of 2 targeted therapies with chemotherapy. The results were presented by Christopher Crane, MD, chief of the gastrointestinal section in the Department of Radiation Oncology at the University of Texas M.D. Anderson Cancer Center in Houston.

Previous studies have established the benefit of adding bevacizumab (Avastin) to chemoradiotherapy for locally advanced pancreatic cancer. In this phase 1 trial of 17 patients conducted by Dr. Crane and colleagues, high-dose erlotinib (Tarceva) was added to this regimen.

Patients received radiotherapy (50.4 Gy) with concurrent capecitabine, bevacizumab, and erlotinib. Doses were escalated using a continual reassessment method, and patients were then reassessed for potential surgical resection of their tumors.

"Of 5 patients who underwent margin-negative resections, 4 had tumors that were originally deemed unresectable," Dr. Crane reported.

"Three patients had excellent pathological responses at pancreatectomy and are alive at 13, 21, and 22 months, with no local or distant failures," he said.

"We were pleasantly surprised by the long median survival duration (23.6 months from diagnosis) and the high degree of pathologic response among the 5 patients who were able to have surgery," Dr. Crane explained.

"Importantly, there was a very low toxicity rate," he added. Three patients developed grade 3 acute toxicity (2 with diarrhea and 1 with rash); no grade 4 or 5 toxicities were seen.

"This is the third single-arm study using erlotinib concurrently with radiotherapy that has resulted in encouraging median survival duration," Dr. Crane noted. Further study is warranted, he added.

Dr. Awasthi is the founder of Terapio, a company that makes recombinant RLIP protein for the treatment of radiation poisoning but does not work on the RLIP76 blockading technology that is being tested for cancer. Dr. Von Hoff reports that his institution receives research support for ongoing clinical trials from Genentech. Dr. Kim and Dr. Crane have disclosed no relevant financial relationships.