Koay, E. | Search bioRxiv

bioRxiv2018

Dose Escalation for Locally Advanced Pancreatic Cancer: How High Can We Go?

Introduction Introduction Methods Results Discussion References Locally advanced pancreatic cancer (LAPC) is particularly difficult to treat given that it exhibits a poor response to chemotherapy and is by definition unresectable. A large proportion of patients experience significant morbidity and mortality due to local progression. As systemic therapy improves with the advent of gemcitabine/ abraxane1 and FOLFIRINOX2, the burden of local disease will only increase. Standard radiation therapy doses have failed to improve survival, which is not unexpected given anatomical and technical limitations. Although the LAP-07 trial3 failed to show an overall survival benefit to radiation at standard doses, it did show benefits in terms of local control and t ...

clinical trials↗

bioRxiv2018

Mitochondrial Fusion Suppresses Pancreatic Cancer Growth via Reduced Oxidative Metabolism

Pancreatic cancer is a highly lethal disease whose aggressive biology that is driven by mitochondrial oxidative metabolism. Mitochondria normally form a network of fused organelles, but we find that patient-derived and genetically engineered murine pancreatic cancer cells exhibit highly fragmented mitochondria with robust oxygen consumption rates (OCR). When mitochondrial fusion was activated by the genetic or pharmacological inhibition Drp1, the morphology and metabolism of human and murine pancreatic cancer cells more closely resembled that of normal pancreatic epithelial cells. This reduced metabolism was correlated with slower tumor growth, fewer metastases, and enhanced survival in a syngeneic orthotopic model. Similarly, directly activating mitochondrial fusion by overexpression of Mfn2 also reduced tumor growth and metastases. Mitochondrial fusion in pancreatic cancer cells was associated with reduced mitochondrial mass and Complex I expression and function. Thus, these data suggest that enhancing mitochondrial fusion through Drp1 inhibition or enhanced Mfn2 expression or function has strong tumor suppressive activity against pancreatic cancer and may thus represent a highly novel and efficacious therapeutic target.

cancer biology↗