Background The link between diabetes and prostate cancer progression is poorly understood and complicated by obesity. We investigated associations between diabetes and prostate cancer-specific mortality (PCSM), castrate-resistant prostate cancer (CRPC), and metastases in obese and nonobese men undergoing radical prostatectomy (RP). Methods We included 4,688 men from SEARCH, a cohort of men undergoing RP from 1988 to 2017. Diabetes prior to RP, anthropometric and clinical data were abstracted from six Veterans Affairs Medical Centers electronic medical records. Primary and secondary outcomes were PCSM and metastases and CRPC, respectively. Multivariable-adjusted hazard ratios (adj-HRs) and 95% confidence intervals (CIs) were estimated for diabetes and PCSM, CRPC and metastases. Adj-HRs were also estimated in analyses stratified by obesity (BMI: nonobese <30 kg/m2; obese ≥30 kg/m2. All statistical tests were two-sided. Results Diabetes was not associated with PCSM (adj-HR=1.38; 95% CI = 0.86-2.24), CRPC (adj-HR=1.05; 95% CI = 0.67-1.64), or metastases (adj-HR=1.01; 95% CI = 0.70-1.46), among all men. Interaction terms for diabetes and obesity were statistically significant in multivariable models for PCSM, CRPC and metastases (P≤0.04). In stratified analyses, in obese men, diabetes was associated with PCSM (adj-HR=3.06; 95%CI = 1.40-6.69), CRPC (adj-HR=2.14; 95%CI = 1.11-4.15), and metastases (adj-HR=1.57; 95%CI = 0.88-2.78), though not statistically significant for metastases. In nonobese men, inverse associations were suggested for diabetes and prostate cancer outcomes without reaching statistical significance. Conclusions Diabetes was associated with increased risks of prostate cancer progression and mortality among obese, but not among nonobese men, highlighting the importance of aggressively curtailing the increasing prevalence of obesity in prostate cancer survivors.

However, KHO35 of the same dose did not have antitumor effect on other CRPC cell lines, suggesting specific selectivity of KHO35 for NEPC cells. KHO35 inhibited the expression of NEPC-related markers in a dose-dependent manner. The time course changes in NEPC tumor growth were examined using NCI-H660 with KHO35. In vivo, KHO35 had an antitumor effect on NCI-H660 xenograft mice models. These results indicate that KHO35 has a significant antitumor effect on NCI-H660 in vivo as well as in vitro. LCeMS revealed an inhibitory effect of KHO35 on RNA transport and spliceosome pathways.CONCLUSIONS: We identified a candidate drug KHO35 that can convert NEPC signature in CRPC-adeno by reprograming the lineage plasticity. KHO35 could be a promising drug for treating NEPC.