Website The University of Wolverhampton
| Supervisory Team: | Professor Weiguang Wang, Professor Basu Supratik, Dr Vinodh Kannappan |
|---|---|
| Background: | Multiple myeloma (MM) is the second most common blood cancer. Current best therapeutic options involve combining a proteasome inhibitor with one of the immunomodulatory imide drugs (IMiDs, lenalidamide or pomalidomide). All MM patients are ultimately relapsed. MM contains cancer stem cells (CSCs) commonly located in poorly vascularised regions. CSCs are typically associated with resistance to chemotherapy. Therefore, development of new drugs with immunomodulatory and CSC-targeting effect is of clinical urgency. Disulfiram (DS), an anti-alcoholism drug, demonstrates excellent activity against a wide range of cancers without toxicity to normal cells. DS chelates copper and zinc to form copper-diethyldithiocarbamate (Cu-DDC) and zinc-diethyldithiocarbamate (Zn-DDC) which are the active anticancer compounds. The anticancer activity of DS, Cu-DDC and Zn-DDC has been known for more than three decades. Its application in cancer clinic is limited by the very short half-life of these compounds in the bloodstream (< 4 min) and insolubility. Our team developed nanoparticles encapsulated DS, Cu-DDC and Zn-DDC which are injectable with long half-life (7 hours) showing strong anticancer efficacy in numerous cancer animal models. In our pilot studies, PEGylated liposome encapsulated Zn-DDC had stronger immunomodulatory and anti-MM effect than currently available IMiDs. It also reverses CSC-induced resistance and synergistically enhances the anti-MM activity of IMiDs. |
| Methodologies: | 1. Using high-pressure homogenizer to generate PEG-Lipo/Zn-DDC and Cu-DDC. 2. Using MTT cytotoxicity to test the anti-MM activity. 3. Investigating the effect of PEG-Lipo/Zn-DDC and Cu-DDC on IKZF1/3-IRF4-cMYC-IL2 immunomodulatory pathway. 4. Examining the effect on CSCs. |
| Outcomes: | 1. Development of PEG-Lipo/Zn-DDC and Cu-DDC; 2. Examination of the anti-MM effect of PEG-Lipo/Zn-DDC and Cu-DDC; 3. Elucidation of anti-MM mechanisms. |
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