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, all patients will 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. 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 drug 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. To test our hypothesis, we will first do a pilot study to assess 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 these experiments; 20 mice in the pilot study and 80 mice in the main study (10 mice per subgroup), 100 mice in total.
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. 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 drug 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. To test our hypothesis, we will first do a pilot study to assess 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 these experiments; 20 mice in the pilot study and 80 mice in the main study (10 mice per subgroup), 100 mice in total.
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.