SummaryAdaptation of cancer cells to targeted therapy follows ecological paradigms observed in natural populations that encounter resource depletion and changing environments, including activation of pro-survival mechanisms, migration to new locations, and escape of predation. We identified the p38 MAPK pathway as a common molecular driver of these three responses during the adaptation to hormone therapy resistance in prostate cancer. The p38 pathway is activated in therapy-resistant cells and mechanistically drives these three convergent responses through sustained AR activity, enhanced invasion and metastasis, and immune evasion. Targeting p38 signaling may represent a new therapeutic strategy to treat men with metastatic, hormone therapy-resistant prostate cancer.

No abstract

Introduction: The incidence of T1D in young children is increasing, yet the majority of children do not achieve glycemic targets, and little is known about predictors of A1c in young children. This study examines demographic predictors of A1c among young children through 18 months post-diagnosis. Methods: Participants were 37 young children (age 1-6 years, Mage=4.53(1.64), MA1c at diagnosis= 10.47(1.93)) with T1D whose parents were randomized to the usual care condition of a multi-site behavioral intervention trial within 8 weeks of diagnosis. At baseline, parents self-reported on sociodemographic information, CGM use and depression symptoms; DKA status at diagnosis and A1c values at 18 months were obtained from medical records. Child A1c at 18-months post-diagnosis (MA1c= 8.05 (0.93)) was dichotomized into “below target” (≤7.5%; n=15; 40.5%) or “above target” (>7.5%; n=22; 59.5%). Results: Family income (two-tailed Fisher’s exact test, p=.019), parent race/ethnicity (χ2(1, N=37)=8.97 p=.003), and child sex (χ2(1, N=37)=3.96, p=.047) were all significantly associated with 18-month A1c. Post hoc analyses using Bonferroni corrections indicated families with higher income, parents who identified as non-Hispanic white, and male children were more likely to be in the “below target” group compared to families with lower income, parents who identify as a racial/ethnic minority and female children, respectively. The 18-month A1c was not associated with baseline CGM use or parent depressive symptoms, nor DKA at diagnosis (p>.05). Conclusions: There are limited prospective studies of early predictors of A1c in young children. Our results are consistent with findings regarding demographic correlates of A1c found in older children and highlight the importance of social determinants of health. Future research using larger samples should explore the role of additional potential correlates of later glycemic control. Disclosure J. S. Eng: None. K. Rooney: None. C. Henderson: None. B. E. Marks: None. C. Tully: None. M. Monaghan: None. M. E. Hilliard: None. R. Streisand: None. C. H. Wang: None. Funding National Institute of Diabetes and Digestive and Kidney Disease (R01DK102561)

Background: Novel agents that inhibit the androgen receptor (AR), including abiraterone acetate and enzalutamide, have significantly prolonged life in many men with metastatic castration-resistant prostate cancer (mCRPC). However, after 1-2 years of therapy acquired resistance to these drugs is nearly universal. Therefore, identifying mechanisms of resistance and innovative therapies to treat enzalutamide-resistant disease represents a major unmet clinical need. Methods: In this study, we developed four enzalutamide-resistant cell lines and analyzed each cell line by RNA-seq and phospho-proteomics to identify common pathways deregulated during disease progression to enzalutamide resistance. We manipulated p38 levels and activity in order to determine its mechanistic relationship to resistance. We measured p38 activity in metastatic biopsies from men with both hormone-sensitive and metastatic prostate cancer. Results: At the nexus of acquired enzalutamide resistance in four independently derived prostate cancer model systems, we identified a convergent mechanism of resistance through activation of the p38 stress response/dormancy pathway. Enzalutamide-resistant cells are sensitized to p38 inhibition, and enzalutamide- sensitive cells developed resistance to enzalutamide with constitutive activation of p38 signaling. Enzalutamide-resistant cells have sustained AR activity, which is blocked with genetic or small-molecule p38 inhibition, indicating that p38 promotes AR activity in the absence of ligand binding. Finally, we found common activation of p38 in lymph node, visceral, and bone metastases from men with mCRPC. Conclusions: We have identified the stress response/dormancy p38-signaling pathway as a common mechanism driving enzalutamide resistance. Most importantly, p38 is a targetable pathway activated in tumors from men with mCRPC, suggesting that novel therapeutic strategies could be applied to prolong the lives of men with metastatic, drug-resistant prostate cancer. Citation Format: Kathryn E. Ware, Santosh Gupta, Jared Eng, Wen-Chi Foo, Lorin Crawford, Garland Austin, Bhairavy Puviindran, Jennifer Freedman, Steven R. Patierno, Tian Zhang, David Corcoran, Mariaelena Pierobon, Emanuel Petricoin, Jason A. Somarelli, Andrew J. Armstong. Convergent hormone therapy resistance mediated by stress/dormancy-like pathways in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B038.

No abstract