Background
Pancreatic cancer is the most lethal cancer across the world, with incidence equaling mortality. Resistance to
chemotherapies represents a critical challenge for pancreatic cancer patients, thus novel therapeutic
approaches are desperately needed. Recently, pancreatic cancer emerged as a metabolic outlier characterized
by several metabolic dependencies, particularly glutamine addiction, representing an unmet opportunity for
the development of novel therapeutic approaches.
Hypothesis
Glutamine, the most abundant amino acid in plasma, is a critical nutrient used by cancer cells to sustain
proliferation as well as biosynthetic reactions under metabolic stress conditions. A comprehensive
understanding of glutamine sensing and metabolism is essential for the development of novel metabolic
therapeutic strategies for the treatment of pancreatic cancer.
Aims
The project's aim is to dissect the molecular mechanisms that regulate glutamine sensing in pancreatic cancer.
We will focus on the regulation of the mechanistic target of rapamycin (mTOR) signaling pathway, being the
key regulator of bioenergetic and biosynthetic metabolism in cancer cells. We intend to unravel specific
metabolic vulnerabilities that can be explored to tailor more effective therapies in preclinical studies.
Experimental Design
Our preliminary data identified PI3K-C2γ as a novel negative regulator of mTOR complex 1 (mTORC1) in
response to glutamine deprivation. The reduced expression of PI3K-C2γ has been observed in about 30% of
pancreatic cancer patients and correlates with aggressive features and poor prognosis. We demonstrated that
the increased aggressiveness of PI3K-C2γ-deficient tumors is associated with specific glutamine metabolism
alterations, making these tumors more sensitive to anti-metabolic drugs.
To accurately recapitulate physiologically relevant aspects of pancreatic cancer progression, we will take
advantage of a combination of mouse models, 3D spheroids models together with patients and murine
derived organoids. Hence, this project is divided in two major aims: (i) clarify how hyperactive mTOR axis
(induced by PI3K-C2γ loss) promotes the development of specific metabolic liabilities, (ii) identify synthetic
lethal interactions for the treatment of PI3K-C2γ deficient tumors to tailor more effective therapeutic
strategies.
Expected Results
With this project, we expect to identify new regulators of signaling pathway necessary to support pancreatic
cancer survival during glutamine deprivation, a condition typical of this type of cancer. We expect to establish a
new mechanism by which PI3K-C2γ controls metabolic alterations in pancreatic cancer and to validate the
protein PI3K-C2γ as a novel potential target of synthetic lethality in pancreatic cancer.
Impact On Cancer
Our knowledge of the possible Achille's heel of pancreatic cancer, the most lethal cancer across the word, is
pretty limited to date, as the majority of patients die within few months upon diagnosis. Results obtained from
this study will validate selective inhibition of critical metabolic pathways in PI3K-C2γ-deficient tumors to
maximize therapeutic success.