Pancreatic Cancer Research

Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, boasts the most deadly statistics among major cancer types. The reasons for the low survival rates can be ascribed in part to the late presentation of disease, when patients are no longer candidates for surgical resection. Additionally, the anatomical location of the pancreas and a complete lack of effective biomarkers make diagnosis all the more challenging, and patients are often not aware that they have disease until very late in its course.

These clinical features notwithstanding, efficacious therapeutic options do not exist and less than 10% of patients respond meaningfully to standard of care (Gemcitabine). While some progress developing combination therapies has been achieved in the past few years, these are all still toxic chemotherapy-based regimes that are difficult to tolerate and extend median survival marginally. More to the point, targeted therapies – those that avoid harmful side-effects of chemotherapy and provide a majority of patients with meaningful and durable response – are completely absent in the therapeutic arsenal available for pancreatic cancer. Given this information, it has become resoundingly clear that a strategy not altogether the same as that applied successfully in other solid tumors is going to be required to develop effective treatment options for patients with pancreatic cancer. As such, our research focuses on the unique metabolic nature of pancreatic tumors and is aimed at defining and exploiting metabolic vulnerabilities in search of new, selective drug targets (Lyssiotis, Cantley. Clin Cancer Res 2014).

Subsequent work in collaboration with the Draetta and DePinho labs, again using our mouse model, revealed that tumors can relapse 2-4 months after Kras* withdrawal. Through detailed analyses of tumors 1 week after Kras* extinction, we found that a sub-population of tumor cells survives independent of Kras* and that these cells possess stem cell characteristics. In contrast to the Kras* (and anabolic glucose metabolism) -dependent tumor bulk, these resistant cells depend on mitochondrial energy production (see second figure inset). By targeting both populations, with inhibitors of glucose and mitochondrial metabolism, we can eliminate pancreatic tumors in mice and prevent disease relapse (Viale, Pettazzoni, Lyssiotis, et al. Nature 2014). Based on the promise of these findings, together with the Draetta labs and colleagues and MD Anderson, we have been funded by the Pancreatic Cancer Action Network to develop mitochondrial inhibitors to exploit these concepts in human pancreatic cancer clinical trials.

Concurrent with these studies, and in collaboration with the Kimmelman lab, we found that pancreatic cancer requires glutamine metabolism for growth and survival through a pathway that we were the first to describe (*Son, *Lyssiotis, et al. Nature 2013). Namely, we showed that pancreatic cancers use glutamine to generate antioxidants to protect from harmful free radicals (see third figure inset). Perhaps more importantly, we found that this pathway is unique to pancreatic cancer. We also have promising evidence that targeting this glutamine addiction is even more efficacious when combined with currently deployed chemotherapeutics.

In addition to the clinical trial being initiated at MD Anderson, we are now also developing a program to examine glutamine addiction. Namely, in collaboration with the Kimmelman and Lairson labs and through funding from the Lustgarten Foundation, we have run drug screens on >2Mi molecules against two pancreatic cancer metabolism targets and are now validating lead candidates. In the near future, their activity will be assessed in animal models of pancreatic cancer in combination with currently available therapeutic modalities. Highly promising methods will be developed for clinical application, as is being done with our inhibitors of mitochondrial metabolism. Ultimately, it is our hope that these new understandings in pancreatic tumor metabolism will bring about better therapeutic options for this dreaded disease.