Research needed to identify relevant targets, molecular pathways of pancreatic ductal adenocarcinoma

NCI committee suggested that better phase-3 trials may be key to combating fourth leading cause of U.S. cancer deaths.

A consensus report issued by the National Cancer Institute has called for enhanced clinical and translational research and improved partnerships among those who manage pancreatic ductal adenocarcinoma.

The NCI’s Gastrointestinal Cancer Steering Committee organized a two-day meeting with representatives from the patient advocacy community, pharmaceutical industry and government agencies to discuss the integration of basic and clinical knowledge in the design of clinical trials for pancreatic ductal adenocarcinoma. The group’s major focus was defining the direction for clinical research into the disease for the next three to five years.

There were four major objectives for the meeting: Address critical questions and unmet needs in treatment and translational research for pancreatic ductal adenocarcinoma; assist innovation and collaboration among clinical and basic investigators; develop strategic priorities for clinical trials in the future; and address ways to distribute these priorities to the relevant oncology communities.

The committee review, published online in the Journal of Clinical Oncology, listed recommendations for five major areas for improving research including developing new targets for drug development; rethinking the utility of preclinical models; redesigning clinical trials, especially phase-3 trials; establishing biorepositories; and developing biomarkers.

In an accompanying editorial, Josep Tabernero, MD, and Teresa Macarulla, MD,, both of the Vall d’Hebron University Hospital in Barcelona, Spain, said the recommendations should be strongly considered when developing future trials. They noted that physicians have learned little from phase-3 trials of the past 20 years that has helped patients.

“Most of the cooperative groups involved in the treatment of patients with advanced pancreatic cancer have learned these historical lessons of limited success and are implementing these new concepts in the clinical development of new therapeutic strategies,” they wrote. “Hopefully, this change in the developmental path will translate into better options for patients with advanced pancreatic cancer.”

The committee said research needs to focus on developing new molecular targets for therapy including genetic alterations in pancreatic tumors and epigenetic changes. They listed the KRAS oncogene, epidermal growth factor receptor, PI3 kinase, and the hedgehog pathways as some of the more promising targets.

Those who treat pancreatic ductal adenocarcinoma also need new agents to attack those new targets; cytotoxic drugs, alone or in combination with targeted agents, are crucial for remedying pancreatic cancer, according to the committee.

Toward that end, they said developing phase-2 trials with a high chance of success in later phase-3 testing is a priority. OS should remain the primary endpoint for such trials, and patients must be carefully selected and monitored.

“The ability to select patients based on predictive biomarkers may reduce the number of patients required in subsequent phase-3 trials,” the committee wrote.

Although the committee acknowledged that a vaccine is unlikely to be successful alone, vaccines may play a role when combined with standard therapies due to the inherent immunogenicity of some chemotherapeutic and targeted agents.

The committee concluded by indicating it will take a collaboration between “the academic community and the pharmaceutical industry” to find a cure.

“The NCI and other public and private agencies and organizations must increase funding for basic, clinical and translational research in pancreatic cancer relative to priorities as defined by the community and include methods to evaluate and refine the process in a dynamic manner,” they wrote. “Active involvement by patient advocates and community physicians as well as the ongoing efforts within the NCI to simplify the protocol development process will hopefully facilitate the necessary advances in this deadly disease.”

Philip PA. J Clin Oncol. 2009;doi:10.1200/JCO.2009.21.9022.

Tabernero J. J Clin Oncol. 2009;doi:10.1200/JCO.2009.23.3098.