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RITM0040857, Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in the US. The androgen receptor (AR), a hormone-activated transcription factor, plays vital roles in the development and progression of PCa. Thus, androgen-deprivation therapy (ADT) is a standard-of-care first-line therapy for metastatic PCa. Resistance to ADT leads almost uniformly to lethal disease, termed castration-resistant prostate cancer (CRPC). As such, there is a largely unmet clinical need to identify and develop novel strategies, that work either alone or in concert with AR-directed therapeutics, to combat CRPC. The highly conserved histone acetyltransferases CBP/p300 are potent co-activators for AR, and high p300 expression is associated with locally advanced disease and castration-resistant AR function. This study shows that CBP and p300 are highly expressed and correlate closely with AR gene expression and AR activity score in primary PCa and CRPC. Thus, it will be critical to determine the role of CBP/p300 in PCa in order to potentially develop novel therapeutic targets for precision medicine to enhance patient outcome. By employing clinically relevant PCa models, the clinical significance of CBP/p300 expression in PCa patients as well as mechanistic evaluation of CBP/p300 transcriptional reprogramming and DNA damage response pathways have been undertaken. Lastly, the molecular response to CBP/p300 inhibition will be assessed to discern novel metrics for precision medicine for PCa patients to improve therapeutic efficacy. Previous studies have relied on non-specific compounds and genetic silencing to target CBP/p300 and its associated transcriptional machinery. CCS1477 (inobrodib) is a first-in-class bromodomain inhibitor developed by Cell Centric and targeted to inhibit CBP/p300 mediated bromodomain activity, and thus regulate cell survival. The IC50 values of CCS1477 in hormone therapy-sensitive and CRPC cell lines were determined to demonstrate effective inhibition i

The Circadian Cryptochrome, CRY1, Displays Disease-Specific Functions in Prostate Cancer Michael Smith1,2, Lakshmi Ravindranath1,2, and Ayesha A. Shafi1,211Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, 20817, USA 2The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, 20817 USA Conclusions Prostate cancer (PCa) ranks first in the prevalence of male malignant tumors and second in mortality. First-line treatment for the disease consists of androgen deprivation therapy (ADT), as PCa cells are exquisitely dependent on androgen receptor (AR) signaling for growth and survival. Although ADT treatment is effective, most patients undergoing ADT therapy will progress to the incurable form of the disease termed castration resistant PCa (CRPC). Epidemiological studies indicate circadian rhythm disruptions are associated with increased cancer risk including breast, lung, and PCa. CRY1 (cryptochrome 1) is a transcriptional coregulator and core component of the circadian clock that has recently been shown to function as an effector of DNA repair in PCa. Recent studies revealed that CRY1 expression increases with disease progression and is associated with poor outcome. Moreover, CRY1 suppression significantly blocks PCa cell growth, causes G2/M arrest of the cell cycle, and compromises DNA repair through directly mediating homologous recombination (HR)-mediated repair in late-stage disease. However, the role of CRY1 on human prostate tumor progression from hormone therapy sensitive (HTS) to CRPC stage of disease has not yet been explored in detail. In order to address this, several models were utilized including doxycycline-inducible HTS and CRPC models to knockdown CRY1 (shCRY1) and pharmacological conditions to mimic clinically relevant high CRY1 condition with KL001. Next, examining the altered CRY1 transcrip, RITM0040862, Prostate cancer (PCa) ranks first in the prevalence of male malignant tumors and second in mortality. First-line treatment for the disease consists of androgen deprivation therapy (ADT), as PCa cells are exquisitely dependent on androgen receptor (AR) signaling for growth and survival. Although ADT treatment is effective, most patients undergoing ADT therapy will progress to the incurable form of the disease termed castration resistant PCa (CRPC). Epidemiological studies indicate circadian rhythm disruptions are associated with increased cancer risk including breast, lung, and PCa. CRY1 (cryptochrome 1) is a transcriptional coregulator and core component of the circadian clock that has recently been shown to function as an effector of DNA repair in PCa. Recent studies revealed that CRY1 expression increases with disease progression and is associated with poor outcome. Moreover, CRY1 suppression significantly blocks PCa cell growth, causes G2/M arrest of the cell cycle, and compromises DNA repair through directly mediating homologous recombination (HR)-mediated repair in late-stage disease. However, the role of CRY1 on human prostate tumor progression from hormone therapy sensitive (HTS) to CRPC stage of disease has not yet been explored in detail. In order to address this, several models were utilized including doxycycline-inducible HTS and CRPC models to knockdown CRY1 (shCRY1) and pharmacological conditions to mimic clinically relevant high CRY1 condition with KL001. Next, examining the altered CRY1 transcriptome and cistrome via omics analyses, combined with biological assays, were employed to elucidate the molecular function and biological outcome of altered CRY1 across PCa diseasespecific stages. Transcriptomic data revealed the transcriptional networks utilized by CRY1 in HTS and CRPC disease stages. Importantly, metabolic pathways such as ether lipid, purine, sphingolipid, glycerophospholipid are strongly associated with CRY1 in CRPC. Intriguingly, DNA damage

RITM0034380, Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in the US. The androgen receptor (AR), a hormone-activated transcription factor, plays vital roles in the development and progression of PCa. Thus, androgen-deprivation therapy (ADT) is a standard-of-care first-line therapy for metastatic PCa. Resistance to ADT leads almost uniformly to lethal disease, termed castration-resistant prostate cancer (CRPC). As such, there is a largely unmet clinical need to identify and develop novel strategies, that work either alone or in concert with AR-directed therapeutics, to combat CRPC. The highly conserved histone acetyltransferases CBP/p300 are potent co-activators for AR, and high p300 expression is associated with locally advanced disease and castration-resistant AR function. This study shows that CBP and p300 are highly expressed and correlate closely with AR gene expression and AR activity score in primary PCa and CRPC. Thus, it will be critical to determine the role of CBP/p300 in PCa in order to potentially develop novel therapeutic targets for precision medicine to enhance patient outcome. By employing clinically relevant PCa models, the clinical significance of CBP/p300 expression in PCa patients as well as mechanistic evaluation of CBP/p300 transcriptional reprogramming and DNA damage response pathways have been undertaken. Lastly, the molecular response to CBP/p300 inhibition will be assessed to discern novel metrics for precision medicine for PCa patients to improve therapeutic efficacy. Previous studies have relied on non-specific compounds and genetic silencing to target CBP/p300 and its associated transcriptional machinery. CCS1477 (inobrodib) is a first-in-class bromodomain inhibitor developed by Cell Centric and targeted to inhibit CBP/p300 mediated bromodomain activity, and thus regulate cell survival. The IC50 values of CCS1477 in hormone therapy-sensitive and CRPC cell lines were determined to demonstrate effective inhibition i

The Importance of Time: Circadian Rhythm Disruption and Prostate Cancer Sierra T. Pence1 and Ayesha A. Shafi1,2 1Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, 20817, USA, 2The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, 20817 USA Background Conclusion Methods Results Results - Circadian cycles run continuously to integrate human physiology and the environment. - Disruption to these cycles, caused by exposure to light during night hours or sleeping during daylight, has been linked to an increased risk of prostate cancer (PCa).1,2,3 - Shift work is recognized by the World Health Organization’s International Agency for Research on Cancer as a probable human carcinogen.4 - The core components of the circadian clock, core clock genes (CCGs) have been identified and are illustrated in Figure 1. Circadian disruption and its effect on PCa is not completely understood, although epidemiologic studies have identified an increased risk and CCGs have been identified in PCa samples. There are many limitations, with the majority of human research being observational. Additionally, the data from cBioPortal is incomplete and a compilation of databases. Even still, the evidence is interesting and chronotherapy remains relatively unexplored with the potential to impact many patients as a therapeutic enhancement. For that reason alone, future research is warranted to distinguish at-risk populations, potential screening tools, and the effect of chronotherapy on PCa. - CCGs tables are from literature review Pence et al., Urology, 2023. - Information regarding CCG alterations and patients’ clinical outcomes with prostate cancer was analyzed using multiple online databases via cBioPortal for Cancer Genomics.5,6 The contents of this publication are the sole responsibility of the author(s) and do not necessarily re, RITM0034522, Circadian cycles run continuously to integrate human physiology and the environment. - Disruption to these cycles, caused by exposure to light during night hours or sleeping during daylight, has been linked to an increased risk of prostate cancer (PCa).1,2,3 - Shift work is recognized by the World Health Organization’s International Agency for Research on Cancer as a probable human carcinogen.4

RITM0030757, Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in the US. The androgen receptor (AR), a hormone-activated transcription factor, plays vital roles in the development and progression of PCa. Thus, androgen-deprivation therapy (ADT) is a standard-of-care first-line therapy for metastatic PCa. Resistance to ADT leads almost uniformly to lethal disease, termed castration-resistant prostate cancer (CRPC). As such, there is a largely unmet clinical need to identify and develop novel strategies, that work either alone or in concert with AR-directed therapeutics, to combat CRPC. The highly conserved histone acetyltransferases CBP/p300 are potent co-activators for AR, and high p300 expression is associated with locally advanced disease and castration-resistant AR function. This study shows that CBP and p300 are highly expressed and correlate closely with AR gene expression and AR activity score in primary PCa and CRPC. Thus, it will be critical to determine the role of CBP/p300 in PCa in order to potentially develop novel therapeutic targets for precision medicine to enhance patient outcome. By employing clinically relevant PCa models, the clinical significance of CBP/p300 expression in PCa patients as well as mechanistic evaluation of CBP/p300 transcriptional reprogramming and DNA damage response pathways have been undertaken. Lastly, the molecular response to CBP/p300 inhibition will be assessed to discern novel metrics for precision medicine for PCa patients to improve therapeutic efficacy. Previous studies have relied on non-specific compounds and genetic silencing to target CBP/p300 and its associated transcriptional machinery. CCS1477 is a first-in-class bromodomain inhibitor designed by Cell Centric and targeted to inhibit CBP/p300 mediated bromodomain activity, and thus regulate cell survival. The IC50 values of CCS1477 in hormone therapy-sensitive and CRPC cell lines were determined to demonstrate effective inhibition in growth and