Thursday, April 10, 2025
4/10/2025
HMGA2 mediates resistance to therapy in prostate cancer - PROJECT SUMMARY Epithelial-mesenchymal transition (EMT) is well characterized in epithelial cancers where tumor cells at the invasive front lose epithelial markers such as E-cadherin, gain mesenchymal markers such as vimentin, to promote invasion, migration and subsequent metastasis; it can be promoted by transcription factors such as High Mobility Group A2 (HMGA2). Treatment for metastatic PCa is problematic, especially if it becomes metastatic and castration-resistant (mCRPC). Current first-line hormone therapy for metastatic PCa includes abiraterone that inhibits androgen biosynthesis, and enzalutamide that binds to androgen receptor (AR) and prevents its translocation to the nucleus, while in less developed nations where these novel hormonal therapies are not available, docetaxel is the main therapy. However, resistance to these drugs usually develops and EMT has been shown to contribute to this resistance. Neuroendocrine advanced PCa has been treated with Aurora A kinase inhibitor, alisertib/MLN8237, while combination treatment of MLN8237 with abiraterone in mCRPC in 9 patients was terminated due to toxicity and lack of clinical benefit. Interestingly, MLN8237 inhibits EMT in pancreatic and ovarian cancer cells. Overexpression of HMGA2 in pancreatic, lung carcinomas and carcinoma of oral cavity, and prostate cancer is published where it promotes EMT, while we reported that full-length but not truncated (missing 3’UTR) HMGA2 promotes EMT. Our preliminary data from cBioportal in 444 metastatic PCa patients shows that 3% of the patients show HMGA2 amplification. 43% of these metastasis patients with HMGA2 amplification received abiraterone treatment, while 21% received enzalutamide and 36% received MLN8237. Interestingly, we further show that MLN8237 is able to inhibit cell growth in LNCaP cells overexpressing both full-length/wild-type and truncated HMGA2 as well as LNCaP Neo control cells. However, only wild-type HMGA2 confers resistance to docetaxel and enzalutamide concomitant with increased AR expression and localization within the nucleus, compared to cells expressing truncated HMGA2. The hypothesis is that wild-type HMGA2 confers resistance to docetaxel and hormone therapy in metastatic PCa via AR-dependent and -independent mechanisms that may be overcome by treatment with MLN8237, or pre-treatment with MLN8237 to first inhibit EMT followed by treatment with hormone therapy. We will confirm resistance to docetaxel, enzalutamide and abiraterone in several AR- dependent and AR-independent cell lines expressing HMGA2 by manipulating HMGA2 expression and analyzing HMGA2 expression and localization in cells resistant to these drugs and elucidate the mechanisms. We will also examine whether MLN8237 inhibits EMT in PCa and the effect of single and combination treatments in vivo. Our studies will be impactful in showing that wild-type HMGA2 can be used as a biomarker to avoid treatment with hormonal therapy and instead utilize MLN8237 or pre-treat with MLN8237 to inhibit EMT followed by treatment with docetaxel or enzalutamide.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).