Exploiting immunogenic cell death to enhance efficacy of taxane chemotherapy in prostate cancer

Supervisors: Stephen Tait (University of Glasgow/CRUK Beatson Institute), Hing Leung (University of Glasgow/CRUK Beatson Institute)

Docetaxel chemotherapy induce cell death through a combination of apoptosis and necrosis. During mitochondrial apoptosis, caspase proteases are activated leading to rapid cell death, nevertheless caspases are not required to kill the cell, cells can die through a process called caspase independent cell death (CICD). We have recently shown that killing cancer cells through CICD makes them immunogenic, such that they activate anti-tumour immunity - this can lead to complete regression. Building from this work, and supportive preliminary data on ADT-induced CICD, this research focuses on the possibility of applying this concept following chemotherapy treatment. Specifically, we will test if chemotherapy in prostate cancer would induce CICD, and whether such an approach may inhibit prostate cancer tumourigenesis and metastasis – this will draw on the complementary expertise of cell death and prostate cancer between the collaborating groups. We will make extensive use of a novel murine model of prostate cancer, developed in-house, that employs orthotopic transplantation of primary prostate cancer cells into syngeneic, recipient mice.

Keywords: Prostate cancer; caspase independent cell death; docetaxel chemotherapy

Recent Publications:

Giampazolias E, Zunino B, Dhayade S, Bock F, Cloix C, Cao K, Roca A, Lopez J, Ichim G, Proïcs E, Rubio-Patiño C, Fort L, Yatim N, Woodham E, Orozco S, Taraborrelli L, Peltzer N, Lecis D, Machesky L, Walczak H, Albert ML, Milling S, Oberst A, Ricci JE, Ryan KM, Blyth K, Tait SWG. Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency. Nat Cell Biol. 2017 Sep;19(9):1116-1129.

Daniels BP, Snyder AG, Olsen TM, Orozco S, Oguin TH 3rd, Tait SW, Martinez J, Gale M Jr, Loo YM, Oberst A.RIPK3 Restricts Viral Pathogenesis via Cell Death-Independent Neuroinflammation. Cell. 2017 Apr 6;169(2):301-313

Niemi NM, Lanning NJ, Klomp JA, Tait SW, Xu Y, Dykema KJ, Murphy LO, Gaither LA, Xu HE, Furge KA, Green DR, MacKeigan JP. MK-STYX, a catalytically inactive phosphatase regulating mitochondrially dependent apoptosis. Mol Cell Biol. 2011 Apr;31(7):1357-68.

Woodham EF, Paul NR, Tyrrell B, Spence HJ, Swaminathan K, Scribner MR, Giampazolias E, Hedley A, Clark W, Kage F, Marston DJ, Hahn KM, Tait SW, Larue L, Brakebusch CH, Insall RH, Machesky LM. Coordination by Cdc42 of Actin, Contractility, and Adhesion for Melanoblast Movement in Mouse Skin. Curr Biol. 2017 Mar 6;27(5):624-637

Lopez J, Bessou M, Riley JS, Giampazolias E, Todt F, Rochegüe T, Oberst A, Green DR, Edlich F, Ichim G, Tait SW. Mito-priming as a method to engineer Bcl-2 addiction. Nat Commun. 2016 Feb 2;7:10538.

Loveridge CJ, Mui EJ, Patel R, Tan EH, Ahmad I, Welsh M, Galbraith J, Hedley A, Nixon C, Blyth K, Sansom O, Leung HY (2017) Increased T-cell Infiltration Elicited by Erk5 Deletion in a Pten-Deficient Mouse Model of Prostate Carcinogenesis. Cancer Res 77: 3158-3168

Loveridge CJ, van 't Hof RJ, Charlesworth G, King A, Tan EH, Rose L, Daroszewska A, Prior A, Ahmad I, Welsh M, Mui EJ, Ford C, Salji M, Sansom O, Blyth K, Leung HY (2017) Analysis of Nkx3.1:Cre-driven Erk5 deletion reveals a profound spinal deformity which is linked to increased osteoclast activity. Sci Rep 7: 13241

Munkley J, McClurg UL, Livermore KE, Ehrmann I, Knight B, McCullagh P, McGrath J, Crundwell M, Harries LW, Leung HY, Mills IG, Robson CN, Rajan P, Elliott DJ (2017) The cancer-associated cell migration protein TSPAN1 is under control of androgens and its upregulation increases prostate cancer cell migration. Sci Rep 7: 5249

Patek S, Willder J, Heng J, Taylor B, Horgan P, Leung H, Underwood M, Edwards J (2017) Androgen receptor phosphorylation status at serine 578 predicts poor outcome in prostate cancer patients. Oncotarget 8: 4875-4887

Salji M, Hendry J, Patel A, Ahmad I, Nixon C, Leung HY (2017) Peri-prostatic Fat Volume Measurement as a Predictive Tool for Castration Resistance in Advanced Prostate Cancer. Eur Urol Focus



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