Targeting NAD Catabolism in Pancreatic Cancer Cells

It has been known since the seminal discoveries of Otto Warburg in the early 1900s that cancer cells have unique metabolic features. However, it was not until recently that cancer cell metabolism became the focus of intense investigation.

In particular, tumor cells undergo metabolic adaptations and have highly active glycolytic, pentose and fatty acid synthesis pathways. All of these metabolic changes contribute to increased tumor cell survival, proliferation and metastasis.

Nicotinamide adenine dinucleotide (NAD) is central for these metabolic changes, and cellular levels of NAD must be balanced to modulate these processes.

A systematic analysis of the metabolism of nicotinamide adenine dinucleotide has not been performed in pancreatic cancer cells. NAD metabolism is regulated at the level of synthesis and degradation. A decrease in cellular nicotinamide adenine dinucleotide levels leads to metabolic collapse and cell death.

Recently, unique features of nicotinamide adenine dinucleotide metabolism have been described in cancer cells. This finding opens the possibility that targeting NAD synthesis or degradation, or both, may lead to cancer-specific metabolic collapse and serve as new therapy for a variety of human tumors, including pancreatic cancer.

SPORE investigators in the Targeting NAD Catabolism in Pancreatic Cancer Cells research project propose that activation of NAD degradation or inhibition of its synthesis will lead to a decrease in pancreatic cancer cell NAD levels and metabolic collapse, with subsequent tumor cell growth arrest and cell death.

The central hypothesis is that increasing degradation of nicotinamide adenine dinucleotide (by activation of the enzyme SIRT1 with small molecules) or inhibiting its synthesis (using inhibitors of the enzyme Nampt) will cause metabolic collapse, resulting in anti-tumor activity by itself and may also increase the anti-tumor activity of other chemotherapeutic agents.

Researchers are performing studies to elucidate the role of NAD metabolism in pancreatic cancer, to characterize the major enzymes in pancreatic tumor tissue and to test the combination of SRT3025 (a SIRT1 activator) with gemcitabine in a clinical trial of patients with metastatic pancreatic cancer. This project has significant relevance for the development of novel therapies for pancreatic cancer.

Hypothesis

Increasing NAD degradation via SIRT1 activation by STACs will cause pancreatic cancer cell-specific metabolic collapse and tumor cell death.

Project aims

Aims of this Pancreatic Cancer SPORE project are to perform:

  • Mechanistic studies on the effect of STACs in pancreatic cancer cells
  • Preclinical studies with STACs and gemcitabine and paclitaxel, and to define potential mechanisms of resistance
  • A phase I trial using the SIRT1 activator SRT3025 combined with gemcitabine and nab-paclitaxel in PDAC patients

Project investigators

Leaders of this Pancreatic Cancer SPORE project are:

The project collaborators are: