The pentose phosphate pathway - targeting metabolism to prevent advanced prostate cancer

Once prostate cancer spreads to bone (bone metastases) there is no cure. To develop new ways to combat this fatal stage, we need to understand exactly how it grows and spreads. Prostate cancer cells need energy to grow. We think specific changes in the energy needs of prostate cancer help prostate cancer grow within bone, and that bone cells talk to prostate cancer cells to cause these changes. We have discovered a specific energy pathway, the pentose phosphate pathway (PPP) that is increased in bone metastatic prostate cancer. When we block this pathway, tumour growth is reduced. We will investigate exactly how the PPP causes prostate cancer bone metastases and whether blocking the PPP, either alone or in combination with current clinical approaches, is effective in reducing tumour burden and bone disease. We will grow human prostate cancer cells in contact with bone cells, mimicking the situation in the human body, and we will increase/decrease the PPP and see how this changes prostate cancer cell growth, death and movement (representing metastatic spread). We will use in vivo (mouse) models to investigate blocking the PPP in prostate cancer bone metastases. This project will uncover the function and potential of the PPP as a novel treatment for bone metastatic prostate cancer.

Once prostate cancer (PCa) metastasizes to bone it becomes incurable. Interactions within the PCa-bone microenvironment promote tumour growth and bone disease, however the metabolic relationship is unknown. We believe that changes in PCa metabolism, specific to the bone microenvironment, mediate disease progression. Our studies support this, with in silico and metabolomic analyses identifying dysregulated metabolism, including the pentose phosphate pathway (PPP) in PCa cells from patients with bone metastases or PCa-bone cocultures. High expression of the PPP rate-limiting enzyme G6PD is associated with a reduction in progression-free survival and inhibition of G6PD reduces PCa growth in bone. We hypothesize that up-regulation of the PPP within the PCa-bone microenvironment drives tumour growth and survival. To address this, we will use a powerful combination of cellular/molecular biology and murine models of PCa bone metastasis. We will investigate PPP function and regulation within the PCa-bone microenvironment. We will determine the effect of PPP blockade on tumour burden and bone disease in vivo, both as monotherapy and in combination with current clinical approaches for advanced PCa. Together, our studies will determine how the PPP contributes to disease progression and identify the therapeutic potential of PPP targeting for the treatment of PCa bone metastases.