Réseau, stratégie et gouvernance

IntroductionWe previously reported that cholesterol homeostasis in prostate cancer (PC) is regulated by 27-hydroxycholesterol (27HC) and that CYP27A1, the enzyme that converts cholesterol to 27HC, is frequently lost in PCs. We observed that restoring the CYP27A1/27HC axis inhibited PC growth. In this study, we investigated the mechanism of 27HC-mediated anti-PC effects.MethodsWe employed in vitro models and human transcriptomics data to investigate 27HC mechanism of action in PC. LNCaP (AR+) and DU145 (AR-) cells were treated with 27HC or vehicle. Transcriptome profiling was performed using the Affymetrix GeneChip™ microarray system. Differential expression was determined, and gene set enrichment analysis was done using the GSEA software with hallmark gene sets from MSigDB. Key changes were validated at mRNA and protein levels. Human PC transcriptomes from six datasets were analyzed to determine the correlation between CYP27A1 and DNA repair gene expression signatures. DNA damage was assessed via comet assays.ResultsTranscriptome analysis revealed 27HC treatment downregulated Hallmark pathways related to DNA damage repair, decreased expression of FEN1 and RAD51, and induced “BRCAness” by downregulating genes involved in homologous recombination regulation in LNCaP cells. Consistently, we found a correlation between higher CYP27A1 expression (i.e., higher intracellular 27HC) and decreased expression of DNA repair gene signatures in castration-sensitive PC (CSPC) in human PC datasets. However, such correlation was less clear in metastatic castration-resistant PC (mCRPC). 27HC increased expression of DNA damage repair markers in PC cells, notably in AR+ cells, but no consistent effects in AR- cells and decreased expression in non-neoplastic prostate epithelial cells. While testing the clinical implications of this, we noted that 27HC treatment increased DNA damage in LNCaP cells via comet assays. Effects were reversible by adding back cholesterol, but not androgens. Finally, in combination with olaparib, a PARP inhibitor, we showed additive DNA damage effects.DiscussionThese results suggest 27HC induces “BRCAness”, a functional state thought to increase sensitivity to PARP inhibitors, and leads to increased DNA damage, especially in CSPC. Given the emerging appreciation that defective DNA damage repair can drive PC growth, future studies are needed to test whether 27HC creates a synthetic lethality to PARP inhibitors and DNA damaging agents in CSPC.

Section: Discussionmentioning

confidence: 70%

27-hydroxycholesterol and DNA damage repair: implication in prostate cancer

Galvan,

Friedrich,

Das

et al. 2023

“…Both TALAPRO-2 (Talazoparib and Enzalutamide) and PROpel (Olaparib and AAP) were conducted in a population of unknown HRR status and showed a benefit for rPFS in the entire population. Moreover, these benefits were observed in both the HRR-mutated and the non-HRR mutated patients (7,8). These results clearly suggested that the combination of PARPi and ARSI could have a synergistic effect, creating a situation similar to that seen in BRCAmutated patients (often referred to as "BRCA-ness").…”

Section: Introductionmentioning

confidence: 80%

“…The phase III trials investigating PARPi in combination with ARSI for mCRPC have not yet been able to confirm or refute this synergistic effect. In MAGNITUDE (6), patients were preselected based on HRRmutation status, while TALAPRO-2 (7) and PROpel ( 8) included an all-comer population and HRR-mutation status was determined after inclusion. These studies cannot be directly compared as they represent different study designs, gene testing strategies and previous exposure to an ARSI.…”

Section: Clinical Evidencementioning

confidence: 99%

“…However, in MAGNITUDE, there was a preselection based on HRR-mutation status, while in TALAPRO-2 and PROpel, an unselected (all-comer) population with a substratification based on HRR-mutation status was included. All three studies showed a marked increase in radiographic progression-free survival (rPFS), time to first subsequent therapy or death (TFST), and a trend towards better overall survival (OS) with the use of PARPi in combination with an ARSI, compared to an ARSI alone in the HRR-mutated population, with the greatest benefit in the BRCA-mutated patients (6)(7)(8). MAGNITUDE (Niraparib and Abiraterone Acetate and Prednisone [AAP]) discontinued the non-HRR mutated arm prematurely due to ineffectiveness in the pre-planned futility analysis (6).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Double trouble for prostate cancer: synergistic action of AR blockade and PARPi in non-HRR mutated patients

Giesen,

Baekelandt,

Devlies

et al. 2023

Prostate cancer (PCa) is the most common cancer in men worldwide. Despite better and more intensive treatment options in earlier disease stages, a large subset of patients still progress to metastatic castration-resistant PCa (mCRPC). Recently, poly-(ADP-ribose)-polymerase (PARP)-inhibitors have been introduced in this setting. The TALAPRO-2 and PROpel trials both showed a marked benefit of PARPi in combination with an androgen receptor signaling inhibitor (ARSI), compared with an ARSI alone in both the homologous recombination repair (HRR)-mutated, as well as in the HRR-non-mutated subgroup. In this review, we present a comprehensive overview of how maximal AR-blockade via an ARSI in combination with a PARPi has a synergistic effect at the molecular level, leading to synthetic lethality in both HRR-mutated and HRR-non-mutated PCa patients. PARP2 is known to be a cofactor of the AR complex, needed for decompacting the chromatin and start of transcription of AR target genes (including HRR genes). The inhibition of PARP thus reinforces the effect of an ARSI. The deep androgen deprivation caused by combining androgen deprivation therapy (ADT) with an ARSI, induces an HRR-like deficient state, often referred to as “BRCA-ness”. Further, PARPi will prevent the repair of single-strand DNA breaks, leading to the accumulation of DNA double-strand breaks (DSBs). Due to the induced HRR-deficient state, DSBs cannot be repaired, leading to apoptosis.

“…Randomization was stratified by HRR gene alteration status and previous treatment with life-prolonging therapy in the castration-sensitive setting. The primary endpoint was radiographic PFS, evaluated in the intention-to-treat population, and at the planned primary analysis, median radiographic PFS was not reached (95% CI, 27.5 months-not reached) for talazoparib plus enzalutamide and 21.9 months (16.6-25.1) for placebo plus enzalutamide HR 0.63 (95% CI, 0.51-0.78; p < 0.0001) (21).…”

Section: Introductionmentioning

confidence: 99%

Outcomes and patterns of use of Radium-223 in metastatic castration-resistant prostate cancer

Anido-Herranz,

Fernandez-Calvo,

Ruiz-Bañobre

et al. 2024

IntroductionRadium-223 dichloride (Ra-223) is recommended as a treatment option for metastatic castration-resistant prostate cancer (mCRPC) patients with symptomatic bone metastases and no visceral disease, after docetaxel failure, or in patients who are not candidates to receive it. In this study, we aimed to ambispectively analyze overall survival (OS) and prognostic features in mCRPC in patients receiving Ra-223 as per clinical routine practice and identify the most suitable treatment sequence.Patients and methodsThis study is observational, multicentric, and ambispective. Eligibility criteria included mCRPC patients treated with Ra-223, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, without visceral metastases, and no more than three cm involved lymph nodes.ResultsA total of 145 patients were included; the median age was 73.97 years, and a Gleason score of more than or equal to 7 in 61 (48%) patients; 73 (81%) had previously received docetaxel. The most important benefit was reached by those patients who received Ra-223 in the second-line setting, with a median OS of 17 months (95% CI, 12–21), and by patients who received six cycles of treatment, with a median OS of 19 months (95% CI, 14–21). An alkaline phosphatase (ALP) decrease was also identified as a prognosis marker. When performing the multivariate analysis, the time to develop castration-resistant disease longer than 24 months was the most important prognostic factor to predict the evolution of the patients receiving Ra-223. Ra-223 was well tolerated, with thrombocytopenia, anemia, and diarrhea being the main adverse events.ConclusionThere is a benefit for those patients who received Ra-223 in the second-line setting, regardless of prior use of docetaxel. In addition, a survival benefit for patients presenting with a decline in ALP was observed.