The last major advance in the treatment of metastatic bladder cancer (BC) took place in 1997 with the advent of gemcitabine. Despite this advance, visceral metastases are usually fatal. The overall goal of the proposed studies is to develop small molecule inhibitors that block a critical node in the metastatic process. We found that Rai GTPases serve as the molecular switches of a therapeutically tractable signaling pathway that allows UC cells to grow in the lung, the most common visceral metastatic site. The clinical significance of this pathway and validity of Rai as a therapeutic target is supported by finding that high Rai expression in tumors places patients at higher risk for metastasis and the requirement of Rai expression for lung metastasis to occur in animal models of UC. Our Guiding Hypothesis for this application is that small molecules targeting Rai provide effective therapy for metastatic UC. With support from the MD Anderson Bladder SPORE Developmental Research Program (DRP), we evaluated >500K compounds for their ability to bind RalA or RalB in computational and combinatorial screens and selected 99 "hits". These were evaluated in a series of secondary assays allowing us to select Rai Binding Compound (RUC)8 and 10 to be pursued in this application. RUC8 and 10 were selected because they: 1) inhibit RalA to RalBPI binding in human UC cells and RalA induced spreading in murine embryo fibroblasts;2) inhibit in vitro monolayer growth (IC50 0.5-1.9 pM) of human UC cells;3) bind RalB directly by nuclear magnetic resonance (NMR) spectroscopy;and 4) have good pharmacokinetic (PK) properties in mice (Cmax 1.3-23 pM, T1/2 3.7-4.6 hrs). To develop this novel class of agents we propose the following Specific Aims:
Aim 1 : Characterize higher potency 2nd generation compounds based on RUC8 and 10 using medicinal chemistry, computational fragment-based design, and similarity search of chemical databases. In the unlikely situation that higher potency compounds are not found in Aim 1, we will pursue Aim 2 and 3 using RUC8 and 10, given their adequate IC50 and in vivo PK.
Aim 2 : Evaluate 2nd generation compounds for their in vivo therapeutic efficacy in novel human UC models of visceral metastasis.
Aim 3 : Develop predictive biomarkers of response to antlRal therapeutics in human tissues that will position us for Phase 1 trials by end of this project. Documented interest by Astra Zeneca in our work improves overall chances for success in translating our novel Rai inhibitors into the clinical setting as anticancer therapeutics.
Inhibition of GTPases and its translation into viable cancer therapeutics has been unsuccessfully sought since discovery of Ras in 1982. Our preliminary work demonstrates first in class inhibitors of the Rai GTPase which may constitute the first significant therapeutic advance in metastatic bladder cancer since 1997. Since Rai GTPases are also important drivers of human pancreatic and prostate cancer growth and metastasis, this work has the potential to provide an effective therapeutic for several major cancer types.
|Choi, Woonyoung; Porten, Sima; Kim, Seungchan et al. (2014) Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 25:152-65|
|Hoang, Anthony N; Agarwal, Piyush K; Walton-Diaz, Annerleim et al. (2014) Clinical significance of ureteric 'skip lesions' at the time of radical cystectomy: the M.D. Anderson experience and literature review. BJU Int 113:E28-33|
|Benedict, W F; Fisher, M; Zhang, X-Q et al. (2014) Use of monitoring levels of soluble forms of cytokeratin 18 in the urine of patients with superficial bladder cancer following intravesical Ad-IFN?/Syn3 treatment in a phase l study. Cancer Gene Ther 21:91-4|
|Figueroa, Jonine D; Ye, Yuanqing; Siddiq, Afshan et al. (2014) Genome-wide association study identifies multiple loci associated with bladder cancer risk. Hum Mol Genet 23:1387-98|
|Culp, Stephen H; Dickstein, Rian J; Grossman, H Barton et al. (2014) Refining patient selection for neoadjuvant chemotherapy before radical cystectomy. J Urol 191:40-7|
|Chakravarti, Deepavali; Su, Xiaohua; Cho, Min Soon et al. (2014) Induced multipotency in adult keratinocytes through down-regulation of ?Np63 or DGCR8. Proc Natl Acad Sci U S A 111:E572-81|
|Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507:315-22|
|Dinney, Colin P N; Hansel, Donna; McConkey, David et al. (2014) Novel neoadjuvant therapy paradigms for bladder cancer: results from the National Cancer Center Institute Forum. Urol Oncol 32:1108-15|
|Yan, Chao; Liu, Degang; Li, Liwei et al. (2014) Discovery and characterization of small molecules that target the GTPase Ral. Nature 515:443-7|
|Lee, Eugene K; Ye, Yuanquing; Kamat, Ashish M et al. (2013) Genetic variations in regulator of G-protein signaling (RGS) confer risk of bladder cancer. Cancer 119:1643-51|
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