Anti-tumor Mechanisms of Mitochondria-Targeted Compounds
Mentor 1
Michael Dwinell
Start Date
28-4-2023 12:00 AM
Description
In the United States pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death with a 5-year survival rate of ~10%. PDAC is highly resistant to radiation and chemical therapies, including immune therapies. New therapeutic approaches focus on targeting PDAC energy metabolism of OXPHOS to disrupt tumor progression using mitochondria-targeted inhibitors. We hypothesize that inhibition of energy metabolism with mitochondria-targeted inhibitors of OXPHOS stimulates apoptosis (programmed cell death) in PDAC cells. We will measure apoptosis initiated by MMe and FlMMe using the Incucyte Live-Cell Analysis system. As cells grow the area covered is increased. The Incucyte system will measure the area and expression of cell death inducers of treated PDAC cell lines. We will use immunoblotting to determine the mechanisms behind programmed cell death of OXPHOS inhibited PDAC. Using immunoblotting we can analyze the expression of pro-apoptotic and anti-apoptotic mediators in treated cell lines. We’ve observed that MMe and FlMMe demonstrate PDAC growth inhibition by decreasing mitochondrial respiration, inhibiting complex I, and decreasing ATP levels. MMe has shown promise at inhibiting growth both in vitro and in vivo. Although 1000x more selective than its parent compound Metformin, MMe is not easily trackable. Our new novel analogue FlMMe has proven to be more selective, and safer than MMe while maintaining the same functional capacity and increasing detectability in vitro and in vivo. These analogues possess the capability to preferentially accumulate within cancer cells and disrupt mitochondrial respiration. Therefore, inhibiting growth, and inducing metabolic changes that affect the tumor, immune response, and TME. The progressive development of TPP+ conjugated mitochondria targeted inhibitors may lead to new immunotherapeutic treatment options in PDAC.
Anti-tumor Mechanisms of Mitochondria-Targeted Compounds
In the United States pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death with a 5-year survival rate of ~10%. PDAC is highly resistant to radiation and chemical therapies, including immune therapies. New therapeutic approaches focus on targeting PDAC energy metabolism of OXPHOS to disrupt tumor progression using mitochondria-targeted inhibitors. We hypothesize that inhibition of energy metabolism with mitochondria-targeted inhibitors of OXPHOS stimulates apoptosis (programmed cell death) in PDAC cells. We will measure apoptosis initiated by MMe and FlMMe using the Incucyte Live-Cell Analysis system. As cells grow the area covered is increased. The Incucyte system will measure the area and expression of cell death inducers of treated PDAC cell lines. We will use immunoblotting to determine the mechanisms behind programmed cell death of OXPHOS inhibited PDAC. Using immunoblotting we can analyze the expression of pro-apoptotic and anti-apoptotic mediators in treated cell lines. We’ve observed that MMe and FlMMe demonstrate PDAC growth inhibition by decreasing mitochondrial respiration, inhibiting complex I, and decreasing ATP levels. MMe has shown promise at inhibiting growth both in vitro and in vivo. Although 1000x more selective than its parent compound Metformin, MMe is not easily trackable. Our new novel analogue FlMMe has proven to be more selective, and safer than MMe while maintaining the same functional capacity and increasing detectability in vitro and in vivo. These analogues possess the capability to preferentially accumulate within cancer cells and disrupt mitochondrial respiration. Therefore, inhibiting growth, and inducing metabolic changes that affect the tumor, immune response, and TME. The progressive development of TPP+ conjugated mitochondria targeted inhibitors may lead to new immunotherapeutic treatment options in PDAC.
