Targeting PHGDH in Multiple Myeloma.
Multiple myeloma (MM) is hematological cancer characterized by the abnormal clonal expansion of plasma cells infiltrating the bone marrow, and it accounts for 10% of all hematological malignancies. Despite the recent improvements in the life expectancy of MM patients, the disease is still incurable and new drugs are urgently needed. Although most patients will initially respond to standard treatment of proteasome inhibitors and immunomodulatory drugs, they eventually develop drug resistance and relapse.
In this study, we aim to see if targeting PHGDH, the first enzyme in the de novo serine synthesis pathway, can have a therapeutical advantage alone or in combination with a proteasome inhibitor. We have already found that an inhibitor of PHGDH reduces the growth of myeloma cells in vitro. Before this drug can be used in clinical trials, it needs to be tested in vivo in an animal model. This inhibitor has never been used in MM animal model before, hence it is of interest to test it. Intratibial injection of human myeloma cells into immunodeficient mice is the best way of testing potential drugs against MM. The animals will be injected with myeloma cells, treated with the drugs and monitored for tumor growth. The mice are expected to be under a moderate level of distress.
MM is characterized by the presence of different clones of cancer cells. Therefore, we will test 2 different human myeloma cell lines. The choice of cell lines and time need for tumor growth will be base on the pilot study (FOTS ID 19428). The pilot study assesses the tumor growth of different human MM cell lines following an intratibial injection (IT). The immunodeficient NOD.CB17/Prkdcscid/scid/Rj mice will be used in this experiment; 80 mice total, 40 mice per group, 10 mice per subgroup.
To reduce the number of mice used in these experiments, a literature search and power analysis were done. If the PHGDH inhibitor is found to reduce myeloma cell growth, it could be used to augment treatment with standard therapy or used in patients that have developed resistance to standard treatment.
In this study, we aim to see if targeting PHGDH, the first enzyme in the de novo serine synthesis pathway, can have a therapeutical advantage alone or in combination with a proteasome inhibitor. We have already found that an inhibitor of PHGDH reduces the growth of myeloma cells in vitro. Before this drug can be used in clinical trials, it needs to be tested in vivo in an animal model. This inhibitor has never been used in MM animal model before, hence it is of interest to test it. Intratibial injection of human myeloma cells into immunodeficient mice is the best way of testing potential drugs against MM. The animals will be injected with myeloma cells, treated with the drugs and monitored for tumor growth. The mice are expected to be under a moderate level of distress.
MM is characterized by the presence of different clones of cancer cells. Therefore, we will test 2 different human myeloma cell lines. The choice of cell lines and time need for tumor growth will be base on the pilot study (FOTS ID 19428). The pilot study assesses the tumor growth of different human MM cell lines following an intratibial injection (IT). The immunodeficient NOD.CB17/Prkdcscid/scid/Rj mice will be used in this experiment; 80 mice total, 40 mice per group, 10 mice per subgroup.
To reduce the number of mice used in these experiments, a literature search and power analysis were done. If the PHGDH inhibitor is found to reduce myeloma cell growth, it could be used to augment treatment with standard therapy or used in patients that have developed resistance to standard treatment.