Clinical Trial Failures Further Signal Pancreatic Cancer’s Intractable Nature

This year has been disappointing for physicians and patients hoping for new treatment options for pancreatic cancer. Pfizer terminated its Phase III development  of axitinib in pancreatic cancer in January. Sanofi-Aventis and Regeneron Pharmaceuticals also nixed their late-stage study of aflibercept for the same disease on September 11.

Both these trials ended as independent review boards determined that the combination of gemcitabine and either drug would not produce statistically significant survival improvements compared to gemcitabine alone. Single-agent gemcitabine thus remains the standard treatment for advanced pancreatic cancer.

“How to treat a nonresectable pancreatic cancer has been a challenging topic for all medical oncologists,” commented Yale University Cancer Center researchers Jia Li, Ph.D., and Muhammad Wasif Saif, M.D., in the Journal of the Pancreas. “Numerous combinations using gemcitabine as a backbone have been tested in clinical trials; unfortunately, none of the combinations including the ones with biological agents were significantly superior to gemcitabine alone.

“In general, all combinations significantly rely on the backbone of gemcitabine,” Drs. Li and Saif continued. “Thinking beyond the gemcitabine box and exploring novel agents are very crucial now.”

Even as clinical researchers throw more combinations of drugs at the disease as first- or second-line therapies, pancreatic cancer remains the fourth leading cause of cancer deaths in the U.S. Complete remissions are extremely rare. Due to difficulties in diagnosis, the aggressive nature of pancreatic cancer, and the limited systemic treatments available, the five-year survival rate for patients who have pancreatic adenocarcinoma remains at only about 5%.

About 95% of exocrine pancreatic cancers are adenocarcinomas. The remaining 5% include adenosquamous carcinomas, squamous cell carcinomas, and giant cell carcinomas.

Drugs That Have Failed

The failure of newer noncytotoxic drugs to significantly impact pancreatic cancer is of particular concern, as these medications have proven useful in other intractrable cancers. Neither axitinib or aflibercept were conventional cytotoxics. Axitinib is a small molecule tyrosine kinase inhibitor with multiple targets including VEGFR-1, 2, and 3, platelet-derived growth factor receptor , and cKIT. Aflibercept is a fusion protein that binds all forms of VEGF-A, VEGF-B, and placental growth factor with what is said to be a higher affinity than their natural receptors.

Additionally, trials reported at the 2007 annual American Society of Clinical Oncology annual meeting conducted by the Cancer and Leukemia Group B and Southwest Oncology Group showed no survival benefit for the combinations of gemcitabine and bevacizumab (Roche's Avastin, an anti-VEGF mAb) or cetixuimab (BMS/Merck Serono/ImClone's Erbitux, an anti-EGFR receptor mAb).

Erlotinib (Roche/OSI's Tarceva), an epidermal growth factor receptor inhibitor, in combination with gemcitabine, was approved for the first-line treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer in 2007. Added to gemcitabine, it produces a modest two-week survival benefit and causes significant toxicity.

It has prompted clinicians to question the clinical relevance of its use, but they have concluded that until they are able to better select which drugs should be used for a particular patient with advanced pancreatic cancer, gemcitabine plus erlotinib will be considered as an acceptable choice.

Early Diagnosis Key to Treating the Disease

According to studies conducted within the last three years, if the disease is detected early enough, it can be slowed to some extent. The use of chemotherapy following surgery reduces the risk of death from operable pancreatic cancer by around 30%, according to research published in the British Journal of Cancer in January. One of the strongest predictors for survival is the use of adjuvant chemoradiotherapy; the three-year survival rate being higher among those who received it compared to those who did not (45% versus 30%).

Diagnosis remains extremely challenging, though, due to a lack of specific symptoms and no accurate, noninvasive way to detect pancreatic cancer. Over 50% of cases are correctly identified only after the cancer has metastasized, obviating surgical removal and some chance of longer-term survival. Oncologists treating this disease say early diagnosis is critical given that individuals with pancreatic cancer have a short life expectancy, and the window for any given treatment may be quite small.

The NCI's Early Detection Research Network (EDRN) backs multiple efforts to discover methods for early cancer detection. One potential route to early detection was reported in September in Cancer Prevention Research by Subrata Sen, Ph.D., assistant professor of pathology, and his colleagues at the University of Texas M. D. Anderson Cancer Center’s department of molecular pathology.

The EDRN-supported researchers reported detection of four specific miRNA markers in the blood of pancreatic cancer patients that accurately detected pancreatic cancer 64% of the time and identified individuals who did not have the disease 89% of the time. While the small study only compared the extremes of pancreatic cancer or the complete absence of the disease, it provided proof of principle, supporting further development of a blood test for the disease.

“While this test is in no way ready for the clinic, we have proven that we can detect and quantify miRNA in the plasma and have shown that we can distinguish pancreatic cancer patients from normal individuals, achieving sensitivity and specificity,” Dr. Sen told GEN. “We plan to find other miRNA markers associated with pancreatic cancer that would be useful as part of a panel for a blood-based assay.” They will also try to use these markers to distinguish among patients with various stages of the disease.

Reporting in the September issue of the Journal of Clinical Investigation, scientists at Case Western Reserve University School of Medicine identified a pro-prion in a subpopulation of pancreatic cancer patients who had significantly shorter survival times than patients lacking the pro-prion. Prions are infectious agents composed of proteins that do not replicate but can propagate disease by causing misfolding of the same polypeptide in the host organism.

Chaoyang Li, Ph.D., Wei Xin, M.D., and Man-Sun Sy, Ph.D., first discovered the pro-prion, or nonglycosylated and non-GPI-anchored form of the prion, in human pancreatic cancer cells. This incompletely processed molecule, which retained its GPI anchor peptide signal sequence was shown to bind to filamin A, a molecule that normally regulates cytoskeletal processes and signaling. When the pro-prion level was reduced, the tumor cells didn’t grow well in tissue culture and in animals.

The investigators further found that a subgroup of pancreatic cancer patients had significantly shorter survival compared to patients whose tumors did not have the pro-prion. “Currently there is no early diagnostic marker for pancreatic cancer,” noted Dr. Sy. “Detection of the incompletely processed prion may provide such a marker. Preventing the binding of prion to filamin A may open new avenues for therapeutic intervention of this deadly disease.”

These steps toward development of early detection markers may eventually result in more effective treatments as well as provide novel drug targets for pancreatic cancer.