Defining the role of TTK in neuroendocrine prostate cancer

About This Grant

ABSTRACT Neuroendocrine prostate cancer (NEPC) is an aggressive and lethal subtype of prostate cancer (PC). While NEPC can develop as de novo disease, more commonly it develops as a resistance mechanism to Androgen Receptor (AR) targeted therapies in castrate resistance prostate cancer (CRPC) patients. NEPC patients often present with high metastatic burden. The prognosis of NEPC is poor with a 5-year survival rate of less than 20% with limited treatment options. Thus, new tractable molecular targets to combat NEPC are urgently needed. In our preliminary studies we have identified Tyrosine Threonine Kinase (TTK) as a new high value NEPC molecular target. TTK, also referred to as Monopolar Spindle 1 (Mps1), is a dual specificity protein kinase that plays a significant role in mitosis and the spindle assembly checkpoint (SAC). TTK expression is undetectable in normal cells and upregulated in transformed cells, making it an ideal therapeutic target. Moreover, TTK is a highly translational target, which as five small molecule inhibitors in clinical development. TTK expression progressively increases throughout PC disease progression and is highest in NEPC. The TTK expression trend holds in PC cell lines and patient-derived xenograft (PDX) models, wherein TTK expression is highest in cell lines and PDXs of NEPC origin. Genetically and pharmacologically targeting TTK slows NEPC cell growth in vitro and in vivo. These data support that TTK is an actionable target that may impede NEPC tumor growth. The objective of our proposal is to test the potential of TTK as a target for NEPC and define TTK mechanisms of action. For the latter, we conducted high resolution differential phospho-proteomic analysis in TTK targeted NEPC cells. We have prioritized Rab-Like Protein 6 (RABL6) as a candidate TTK NEPC phospho-target. In specific Aim 1, we will evaluate TTK phospho-target RABL6 and test the role of RABL6 in NEPC. In Aim 2, we will utilize a combination of NEPC cell line, patient derived xenografts and syngeneic NEPC models to rigorously test the effects of targeting TTK in vivo. Along with genetic approaches we will utilize clinical grade TTK inhibitors and preclinical TTK proteolysis targeting chimeras (PROTAC). In Aim 3 we will evaluate the therapeutic efficacy of combining leading TTK clinical inhibitor with first line NEPC chemotherapies. Transcriptomic analysis and immune cell profiling of tumors will be conducted to assess therapeutic response and identify biomarkers. Successful completion of these studies will confidently determine if TTK is a high value target which may ultimately help to lessen the morbidity of NEPC.