Alec Kimmelman, MD, PhD
Professor and Chair
Department of Radiation Oncology
NYU Langone Medical Center
Perlmutter Cancer Center
Pancreatic cancer, the fourth-leading cause of cancer death in the United States, has a 5-year survival rate of less than 7%. Pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer, is usually diagnosed after the cancer has reached an advanced stage. The only cure is to catch the disease early. As a result, only a minority survive, with most patients dying within a year of diagnosis. There is an urgent need for novel therapeutic approaches.
My laboratory is taking an approach that focuses on the unique metabolic adaptations of this tumor. One area of study involves the incredible metabolic flexibility that enables pancreatic tumor cells to fuel their growth. Pancreatic tumor cells are metabolic scavengers. When oxygen and glucose, normally supplied by the bloodstream, are in short supply, pancreatic tumor cells can produce needed metabolic substrates through a self-digestion process called autophagy.
During autophagy, damaged cell parts are enveloped into vesicles, which fuse with lysosomes. These pockets in turn break down proteins and fats into metabolites, which are recycled to build new DNA strands and membranes that support uncontrolled cell growth of these cancers. We have shown that inhibition of autophagy inhibits the growth of pancreatic cancer cells in culture and in mouse models.
We have recently identified a new kind of metabolic crosstalk between pancreatic tumor cells and pancreatic stellate cells, which also is related to metabolic flexibility. We found that pancreatic tumor cells signal stellate cells to secrete the amino acid alanine. Stellate cells degrade proteins through autophagy, releasing alanine, which in turn is taken up by the tumor cells and used as fuel instead of glucose. Inhibition of autophagy in the stellate cells disrupts this metabolic crosstalk and impairs the growth tumors. Clinical trials are underway using hydroxychloroquine, an oral drug commonly prescribed to treat rheumatological conditions, which can block autophagy and has antitumor effects in animal models.
Dafna Bar-Sagi, PhD, my colleague at NYU Langone’s Perlmutter Cancer Center and our vice dean for science and chief scientific officer, has found that pancreatic cancer cells create vesicles on their own surfaces to capture proteins floating nearby, pulling them into the cells in a process called macropinocytosis. We are now collaborating to determine if macropinocytosis and autophagy cooperate to fuel cancer cells.
Additional research in my lab is seeking to understand how pancreatic tumor cells rewire their metabolism. This could provide novel entry points for therapeutic attack. We demonstrated that pancreatic tumors require the continued expression of the KRAS oncogene for growth and identified a critical role for KRAS in rewiring glucose metabolism. Furthermore, we have found that pancreatic tumor cells rely on a novel KRAS-dependent metabolic pathway that is critical for redox balance. Blocking any of several enzyme reactions in this pathway disturbed the redox balance and suppressed the growth of human pancreatic cancer cells transplanted to mice.
This novel pathway does not seem to be important for normal cells, which suggests that drugs inhibiting this pathway could block cancer cells’ growth without harming nontumor cells and could also make pancreatic tumors more susceptible to standard treatments such as radiation and chemotherapy. Ongoing work in the lab is seeking to identify additional metabolic targets, with the goal of discovering new drugs to test in clinical trials in patients. In the meantime, we are assessing potential metabolic vulnerabilities in genetically engineered mouse models.
There is reason to be optimistic for the development of improved therapies over the next 5 to 10 years. We are making great progress in understanding the basic science of pancreatic cancer, and there is a huge push to translate these findings into therapies for patients. Targeting metabolism is still in its infancy, but I expect to see more clinical trials in pancreatic and other cancers.