CPT1A

THURSDAY, July 13, 2023 -- A preclinical study offers a potential new therapy for treatment-resistant prostate cancer, offering new hope for men with the disease. The study used the chemotherapy drug cisplatin, administered orally, to disrupt the metabolism of prostate cancer cells and bring the medication directly into treatment-resistant cells. University of Miami researchers validated their targets in human prostate cancer biopsies. Then they tested the treatment in human cancer cells and a mouse model of prostate cancer, to show it could be safe and effective in shrinking these cancers. Cisplatin is a potent drug but it has not been effective in treating prostate cancer. For this study, the researchers used a compound called Platin-L to break down a process that malignant prostate cancer cells use to fuel their growth and also to deliver the cisplatin directly into treatment-resistant cancer cells. “We believe Platin-L can circumvent these resistance mechanisms,” said senior study author Shanta Dhar , assistant director of technology and innovation at the university's Sylvester Comprehensive Cancer Center. Prostate cancer differs from most other cancers. While most cancers use a biochemical reaction to turn glucose into energy to support their growth and spread, as prostate cancer advances, it instead alters enzymes that enable it to get energy from fat instead of sugar. That process is called fatty acid oxidation (FAO). Platin-L targets CPT1A, a protein that is a part of this process. “We are also making prostate cancer cells choose a less favorable metabolic pathway, which is insufficient to their needs, making it difficult for them to survive,” Dhar said. The researchers treated patient prostate tumor samples as well as cisplatin-resistant animal models. Platin-L destroyed the cancer cells by robbing them of their energy source, dismantling both mitochondrial and nuclear DNA. The medication is what’s known as a “prodrug” because it only activates when the body metabolizes it, the study authors explained in a university news release. For the study, Platin-L was encapsulated in nanoparticles targeting a protein called prostate-specific membrane antigen (PSMA). This made it possible to administer the drug orally. Side effects in other parts of the body were limited. In the study’s mouse models, tumors shrank and the treated mice had steady body weight, increased survival rates and little evidence of the peripheral nerve damage that often results from cisplatin treatment. The researchers think other nanoparticles could be engineered to target other cancers. “We made a dual-targeted nanoparticle,” Dhar said. “The first targeting is needed to get it through the gut barrier, and the second targeting takes it to the prostate. The beauty is, now we can deliver a cisplatin-based chemotherapeutic orally, which is usually never done. And by targeting the prostate, we can reduce kidney and liver toxicity and the risk of peripheral neuropathy.” The results appear promising for future clinical trials and development, Dhar said. “The impact of this current targeted metabolic modulation of the tumor microenvironment for advanced prostate cancer extends beyond this cancer type,” the authors wrote. “The reported mechanistic investigations will allow us to find the clues to make this platform more general to be used for cancers where these cellular pathways can be altered.” The study was published July 12 in ACS Central Science , an American Chemical Society journal. Posted July 2023

A scientific team has designed a strategy to fight obesity and diabetes in mice through ex vivo gene therapy which consists of implanting cells that have been manipulated and transformed in order to treat a disease. This is the first study to apply the ex vivo gene therapy technique to generate and implant cells that express the CPT1AM protein, an enzyme that plays a decisive role in many metabolic diseases such as obesity. A scientific team from the University of Barcelona and the CIBERobn has designed a strategy to fight obesity and diabetes in mice through ex vivo gene therapy which consists of implanting cells that have been manipulated and transformed in order to treat a disease. This is the first study to apply the ex vivo gene therapy technique to generate and implant cells that express the CPT1AM protein, an enzyme that plays a decisive role in many metabolic diseases such as obesity. The study, published in the journal Metabolic Engineering, is led by Professor Laura Herrero, from the Faculty of Pharmacy and Food Sciences and the Institute of Biomedicine of the University of Barcelona (IBUB), and from the Physiopathology of Obesity and Nutrition Networking Biomedical Research Centre (CIBERobn). Cell therapy describes the process of introducing new cells into a tissue in order to fight a disease. Cell therapies are currently focused on addressing hereditary diseases -- with and without the help of gene therapy -- or degenerative diseases. "In this new therapy, animal models have been implanted subcutaneously stem cells derived from adipose tissue, differentiated into adipocytes, so that they can express an active form of the CPT1AM protein, an enzyme located in the mitochondria that is key in lipid oxidation and is related to metabolic diseases," says Laura Herrero, a member of the UB Department of Biochemistry and Physiology. "As a result, in obese mice, it has been possible to reduce weight, fatty liver (hepatic steatosis), cholesterol and glucose levels. In conclusion, the implantation of adipocytes expressing the mitochondrial enzyme CPT1AM helps to reduce obesity and glucose intolerance in mice." As the cell transformation process takes place outside the body of the organism, this type of therapy is much easier to carry out and allows for greater control of the altered cells. Obesity and cell therapy Obesity and associated metabolic disorders represent a worldwide health and social problem, which is why new therapeutic approaches are urgently needed. Adipose tissue plays a key role in regulating energy balance, and adipose-derived mesenchymal stem cells -- cells with the ability for self-renewal -- have gained interest in cell therapy. "Specifically, carnitine palmitoyltransferase 1A (CPT1A) is the enzyme that controls mitochondrial fatty acid oxidation. Our aim was to generate adipocytes that could express a constitutively active form of CPT1A -- CPT1AM -- capable of burning excess fat and improving the obese metabolic phenotype of mice after implantation." The results of the new study support the future clinical use of this ex vivo gene therapy approach as a new strategy to reduce obesity and cholesterol rates in the population. This preclinical study could open the doors to future therapeutic strategies to address the treatment of obesity, which today represents a global health problem. "To approximate the therapy in humans, we need to optimize several processes such as the quality and viability of stem cells from adipose tissue isolated from people with obesity, the percentage of infection with lentivirus, and the number of cells used for transplantation," concludes researcher Laura Herrero.