Dual approach to pancreatic cancer

BUFFALO, N.Y.—Pancreatic cancer is known for a particularly poor prognosis following diagnosis, due to the absence of telltale symptoms when in its early stages and the cancer’s remarkable ability to replicate and metastasize while resisting existing treatment options. There are usually no symptoms in the disease’s early stages, and symptoms that are specific enough to suggest pancreatic cancer typically do not develop until the disease has reached an advanced stage. By the time of diagnosis, pancreatic cancer has often spread to other parts of the body.

Two recently published articles outline promising research emerging from Roswell Park Comprehensive Cancer Center that may help reverse the lethality of pancreatic cancer. Companion articles published in the journals Oncogene and Clinical Cancer Research report on Roswell scientists’ preclinical efforts to apply treatments known to be effective in treating other kinds of solid-tumor cancers.

“Pancreatic adenocarcinoma is a particularly complex cancer with many different genetic subtypes,” says Dr. Agnieszka Witkiewicz, director of the Center for Personalized Medicine and chief of Research in the Department of Pathology at Roswell Park, who is senior author on the Oncogene article. “Pancreatic cancer has a very poor prognosis, and determining new mechanisms for therapeutic intervention are obviously important. It will become the second leading cause of cancer deaths in the United States, and trying to understand mechanisms of drug resistance and new approaches to treatment are really needed.”

The study featured in Oncogene details Witkiewicz’s research into how pancreatic cancer survives efforts to treat it with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors such as palbociclib, ribociclib and abemaciclib, and explores a strategy for overcoming that resistance—combining CDK4/6 inhibitors with drugs inhibiting another growth-promoting kinase, MTOR.

“We demonstrate through our work here that many pancreatic cancers have intrinsic resistance to CDK4/6 inhibition and that we can overcome this resistance by taking advantage of its reliance on the MTOR pathway,” wrote the authors. “Our findings from studies in many different cell lines and preclinical models show that combination treatment with MTOR and CDK4/6 inhibitors can be potent against many distinct types of pancreatic cancer.”

The Clinical Cancer Research study establishes that conjoining chemotherapy treatment with cell cycle checkpoint inhibitors may effectively surmount the multiple ways that pancreatic adenocarcinoma tumors repel treatments.

“For this study, we exploited the replication stress that is known to be evoked by drivers of pancreatic cancer, in particular KRAS mutations,” says Dr. Erik Knudsen, chair of Molecular and Cellular Biology at Roswell Park, who was an author on both studies. “We had to work through multiple unexpected resistance mechanisms of this notoriously recalcitrant cancer type, pancreatic adenocarcinoma, but ultimately were able to show that through coordinated targeting of cell cycle checkpoints with particular chemotherapy combinations you can effectively control pancreatic tumors—which was an exciting and welcome result.”

The Roswell Park team is developing clinical studies to further pursue both approaches, capitalizing on significant recent investments to better understand the specific biology of pancreatic cancers. They expect to continue to explore these and other treatment options in laboratory models to ensure that they are identifying the best approaches for clinical deployment. They have been involved in previous clinical trials around pancreatic cancer and intend to develop new clinical trials based on the recently published research. In order to make an impact on pancreatic cancer outcomes, according to Witkiewicz, their laboratory findings need to be interrogated clinically to determine if impressive results in the lab hold up for the patient.

“We’re quite excited by the prospect of further developing these interventions, particularly in the context of such a hard-to-treat cancer, where new therapeutic options are urgently needed,” adds Knudsen. “Since the drugs utilized target fundamental features of cell division that are commonly deregulated across cancers, one could predict that the strategies uncovered in pancreatic cancer could be applicable to other cancers. We are currently translating some of the findings from this work into other forms of cancer, including triple-negative breast cancer. The delivery of such ideas to the clinic is driven by strong interactions with the early-phase clinical trial program at Roswell Park.”