Bladder cancer is the ninth most common malignancy worldwide. Approximately 30% of cases are muscle invasive bladder cancers (MIBC), and five-year overall survival rate is only 6% once it progresses to metastatic stage. Platinum-based chemotherapy has been the standard-of-care in advanced bladder cancer for decades, but non-responsiveness and the development of resistance limit its success in improving outcomes for patients. Hence, there is an unmet medical need to develop novel therapeutic agents for bladder cancer patients. Casein kinase (CK) 1 delta is a serine/threonine protein kinases that regulates many cellular processes implicated in cancer, including Wnt/β-catenin signaling, apoptosis, DNA damage response and circadian rhythms. Analysis of TCGA dataset revealed that CSNK1D copy number amplification in 50% of bladder tumors, which is correlated with CK1 delta overexpression. Based on the above rationale, we hypothesize that CK1 delta is a highly attractive target for the treatment of bladder cancer. To address this hypothesis, we proposed three specific aims.Specific Aim 1. To investigate the role CK1 delta in the progression of bladder cancer. Our preliminary data suggested that knocking down of CK1 delta decreased the viability, β-catenin expression and migration in bladder cancer cells. We will use genetic and pharmacological approaches to elucidate the mechanism by which CK1 delta regulates proliferation and metastatic process in bladder cancer. The results will flow into studies outlined in Aims 2 and 3 for the discovery of novel and selective CK1 delta inhibitors.Specific Aim 2. Hit-to-lead discovery of selective CK1 delta inhibitors. By screening of a series of N1-arylamidepurine derivatives, we have identified compound L091 is a potential CK1 delta inhibitor with significant anti-bladder cancer activity. We will collaborate with expertise in medicinal chemistry, molecular docking, drug-protein interaction to elucidate the binding mechanism for optimizing the chemical structure of compound L091 to improve the potency, selectivity with favorable pharmacokinetic properties. Top compounds will be tested for their anti-tumor efficacy as single agent and in combination with conventional agents in vitro and in vivo using mouse xenograft models. Specific Aim 3. To perform the mechanisms of action (MOA) study of CK1 delta inhibitors in bladder cancer cells. Our preliminary data suggested that compound L091 significantly inhibited proliferation and migration, and induced apoptosis in bladder cancer cells. Mechanistically, altered expression of β-catenin and EMT markers were observed, and pro-death autophagy was also induced by compound L091. We design experiments to validate whether these effects were resulted from on-target inhibition of CK1 delta, and elucidate detail mechanism by which compound L091 and optimized analogues achieve their anti-bladder cancer activity. The results will shed light on the action mechanisms of CK1 delta inhibitor, provide pharmacodynamic markers in the future. With no choice of approved targeted therapies for treatment of bladder cancer, the completion of our proposal will provide a novel and valuable therapeutic strategy capable of producing a significant impact on the patients affected by this disease.
|Effective start/end date||8/1/18 → 7/1/19|
- bladder cancer
- casein kinase
- cell migration
- epithelial-mesenchymal transition