Palmbos, Phillip L.

Abstract TRIM29 (Tripartite Motif-Containing Protein 29), also known as ATDC (Ataxia-Telangiectasia Group D-Complementing Protein), is an E3 ubiquitin ligase frequently upregulated in muscle-invasive bladder cancer (MIBC). We have previously shown that TRIM29 overexpression in a genetically engineered mouse model (GEMM) is sufficient to drive development of MIBC. We have also shown that TRIM29 is enriched in basal bladder cancer subtypes and is part of a TP63-regulated program that promotes migration and invasive progression. Prior studies suggest that Keratin 5/14 (K5+/K14+) expressing basal-stem progenitor cells in the urothelium are the cells of origin for MIBC in mice. However, whether Trim29 expression in these basal urothelial cells is required for MIBC development has not been established. In this study, we find that Trim29 expression in K5+ basal cells is linked to the inflammatory response and is critical for bladder tumor formation and invasive progression. We show that urothelial TRIM29 expression is enhanced during inflammation in humans and under inflammatory and genotoxic stress in mice. Knockout (KO) of Trim29 in the K5+ basal urothelium of a GEMM exposed to a bladder-specific chemical carcinogen blocked MIBC development. Further, urothelial Trim29 KO enriches immune cell recruitment to the bladder and upregulates STING and inflammatory signaling in mouse and human bladder cancers. These data reveal a critical role for TRIM29 in immunomodulation of the bladder tumor microenvironment (TME), which may act in concert with pro-migratory basal gene programs to expedite MIBC development.

PURPOSE Preclinical studies suggest the combination of the poly(adenosine diphosphate[ADP]-ribose) polymerase (PARP) inhibitor olaparib and the ataxia telangiectasia–mutated and Rad3-related (ATR) inhibitor ceralasertib has synergistic antitumor activity in homologous recombination proficient (HRP) and homologous recombination repair gene mutation (HRRm) patients. This study aims to determine the efficacy of olaparib plus ceralasertib in metastatic castration-resistant prostate cancer (mCRPC) with and without HRRm. PATIENTS AND METHODS Thirty-five HRP and 12 HRRm PARP inhibitor–naïve patients with mCRPC progressing on ≥1 line of therapy or previous androgen receptor pathway inhibitor were enrolled. Patients received olaparib (300 mg twice daily) and ceralasertib (160 mg once daily, days 1-7) in 28-day cycles. HRRm was defined as biallelic inactivation of BRCA2 or BRCA1 , monoallelic inactivation of ATM , or germline inactivation of any of these genes. The primary end point was disease response rate (dRR; confirmed prostate-specific antigen decline ≥50% and/or complete/partial radiographic response by RECIST v1.1) in HRP patients. Secondary end points included dRR in HRRm patients, progression-free survival (PFS), and safety/toxicity. Two-stage designs were used. RESULTS Four of 35 (11%; 95% CI, 3.2 to 26.7) HRP and four of 12 HRRm patients responded. Median PFS was 8.2 months (95% CI, 5.3 to not reached) for HRP patients. Thirty-six percent of patients had ≥grade 3 toxicity, most commonly from anemia. Limitations include small, single-arm, nonrandomized trial design. CONCLUSION Combining ceralasertib with olaparib had limited activity in patients with HRP mCRPC. HRRm response rate was not greater than previous single-agent PARP inhibitor clinical trials.

The substantial biological heterogeneity of metastatic prostate cancer has hindered the development of personalized therapeutic approaches. Therefore, it is difficult to predict the course of metastatic hormone-sensitive prostate cancer (mHSPC), with some men remaining on first-line androgen deprivation therapy (ADT) for several years while others progress more rapidly. Improving our ability to risk-stratify patients would allow for the optimization of systemic therapies and support the development of stratified prospective clinical trials focused on patients likely to have the greatest potential benefit. Here, we applied a liquid biopsy approach to identify clinically relevant, blood-based prognostic biomarkers in patients with mHSPC. Gene expression indicating the presence of CTCs was greater in CHAARTED high-volume (HV) patients (52% CTChigh) than in low-volume (LV) patients (23% CTChigh; * p = 0.03). HV disease (p = 0.005, q = 0.033) and CTC presence at baseline prior to treatment initiation (p = 0.008, q = 0.033) were found to be independently associated with the risk of nonresponse at 7 months. The pooled gene expression from CTCs of pre-ADT samples found AR, DSG2, KLK3, MDK, and PCA3 as genes predictive of nonresponse. These observations support the utility of liquid biomarker approaches to identify patients with poor initial response. This approach could facilitate more precise treatment intensification in the highest risk patients.