Stahlhut, C. E., Watrud, K. E., Ambrico, A. J., Cho, H., Wang, L. L., Qi, J., Cantley, L. C., Bradner, J., Trotman, L. C. (August 2015) Myc vs. Akt therapy in RapidCap, a GEM model for metastatic prostate cancer. Cancer Research, 75 (Supple). Abstract 2636. ISSN 0008-5472
Abstract
Metastasis is a major driver of mortality and morbidity in prostate cancer, the most common cancer type in men and the second leading cause of cancer-related deaths in the western world. To recapitulate the process in genetically engineered mice, we have developed the RapidCaP system, which uses prostate-directed viral infection to trigger focal loss of Pten and Trp53. The system provides a powerful platform for identification and validation of candidate driver genes and for efficient testing of novel therapeutics. Using this approach, we have recently identified Myc as a critical, spontaneously activated driver in Pten-negative metastatic prostate cancer. In agreement, our previous trials indicated that the Myc-suppressing Brd4 inhibitor JQ1 is ineffective towards primary disease, but causes metastatic regression. Mechanistically, this specificity correlates with the switch from Akt-driven primary to Myc-driven metastatic disease. Intriguingly, however, advanced metastases in RapidCaP do not express the androgen receptor, in spite of being of epithelial origin as shown by the Nkx3.1 prostate marker. As a consequence, metastatic disease often shows little to no response to castration therapy and invariably results in lethal disease. Therefore, we will discuss how, when and why targeting of Myc using JQ1 and the PI 3-Kinase pathway using NVP-BKM120 are best used to treat naïve or castration-resistant metastatic disease.
| Item Type: | Paper |
|---|---|
| Additional Information: | Meeting Abstract |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Akt bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > Myc Publication Type > Meeting Abstract diseases & disorders > cancer > metastasis diseases & disorders > cancer > cancer types > prostate cancer |
| CSHL Authors: | |
| Communities: | CSHL labs > Trotman lab |
| Depositing User: | Matt Covey |
| Date: | August 2015 |
| Date Deposited: | 01 Apr 2016 20:43 |
| Last Modified: | 06 Feb 2018 15:44 |
| URI: | https://repository.cshl.edu/id/eprint/32468 |
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