Nascent Prostate Cancer Heterogeneity Drives Evolution and Resistance to Intense Hormonal Therapy

Wilkinson, Scott; Ye, Huihui; Karzai, Fatima; Harmon, Stephanie; Terrigino, Nicholas T.; VanderWeele, David J.; Bright, John R.; Atway, Rayann; Trostel, Shana Y.; Carrabba, Nicole V.; Whitlock, Nichelle C.; Walker, Stephanie M.; Lis, Rosina T.; Sater, Houssein Abdul; Capaldo, Brian J.; Madan, Ravi A.; Gulley, James L.; Chun, Guinevere; Merino, María J.; Pinto, Peter A.; Salles, Daniela C.; Kaur, Harsimar; Lotan, Tamara L.; Venzon, David; Türkbey, Barış; Dahut, William L.; Sowalsky, Adam G.

doi:10.1016/j.eururo.2021.03.009

Cited by 52 publications

(47 citation statements)

References 29 publications

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“…Understanding how IDC-P responds to standard PCa treatment is crucial for the design of new targeted therapies. These questions have mostly been addressed in retrospective studies or in clinical trials with IDC-P as a secondary endpoint [15,17,19,37,[50][51][52][56][57][58][59] (summarized in Supplemental Table S2). Currently, two ongoing studies in China focus on IDC-P treatment.…”

Section: Treatment Responsementioning

confidence: 99%

Intraductal Carcinoma of the Prostate as a Cause of Prostate Cancer Metastasis: A Molecular Portrait

Pantazopoulos

Diop

Grosset

et al. 2022

Cancers

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Intraductal carcinoma of the prostate (IDC-P) is one of the most aggressive types of prostate cancer (PCa). IDC-P is identified in approximately 20% of PCa patients and is associated with recurrence, metastasis, and PCa-specific death. The main feature of this histological variant is the colonization of benign glands by PCa cells. Although IDC-P is a well-recognized independent parameter for metastasis, mechanisms by which IDC-P cells can spread and colonize other tissues are not fully known. In this review, we discuss the molecular portraits of IDC-P determined by immunohistochemistry and genomic approaches and highlight the areas in which more research is needed.

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Section: Treatment Responsementioning

confidence: 99%

Intraductal Carcinoma of the Prostate as a Cause of Prostate Cancer Metastasis: A Molecular Portrait

Pantazopoulos

Diop

Grosset

et al. 2022

Cancers

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“…The copyright holder for this preprint (which this version posted April 21, 2021. ; https://doi.org/10.1101/2021.04.20.440657 doi: bioRxiv preprint 10 prostate cancer 30 , as well as progression-free survival for standard ADT alone in metastatic castration-sensitive prostate cancer 60 . Notably, the genomic profiles of pre-treatment HRLPC samples from an independent neoadjuvant API clinical trial cohort revealed the presence of SPOP mutations exclusively in exceptional responders 61 . Our findings, paired with this external validation, demonstrate the translational relevance of mutations in this gene with API in HRLPC.…”

Section: Discussionmentioning

confidence: 99%

Molecular features of exceptional response to neoadjuvant anti-androgen therapy in high-risk localized prostate cancer

Tewari

Cheung

Crowdis

et al. 2021

Preprint

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High-risk localized prostate cancer (HRLPC) is associated with a substantial risk of recurrence and prostate cancer-specific mortality1. Recent clinical trials have shown that intensifying anti-androgen therapies administered prior to prostatectomy can induce pathologic complete responses (pCR) or minimal residual disease (MRD) (<5 mm), together termed exceptional response, although the molecular determinants of these clinical outcomes are largely unknown. Here, we performed whole exome (WES) and whole transcriptome sequencing (RNA-seq) on pre-treatment multi-regional tumor biopsies from exceptional responders (ER: pCR and MRD patients) and non-responders (NR: pathologic T3 or lymph node positive disease) treated with intensive anti-androgen therapies prior to prostatectomy. SPOP mutation and SPOPL copy number loss were exclusively observed in ER, while TP53 mutation and PTEN copy number loss were exclusively observed in NR. These alterations were clonal in all tumor phylogenies per patient. Additionally, transcriptional programs involving androgen signaling and TGFβ signaling were enriched in ER and NR, respectively. The presence of these alterations in routine biopsies from patients with HRLPC may inform the prospective identification of responders to neoadjuvant anti-androgen therapies to improve clinical outcomes and stratify other patients to alternative biologically informed treatment strategies.

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“…In analyses of post-surgery outcomes of CS-CaP patients enrolled in clinical trials of intense neoadjuvant ADT prior to surgery, PTEN loss was also associated with biochemical recurrence and CaP ERG positivity, and PTEN losses were associated with more extensive residual tumors [104,105]. In another study, targeted biopsies from men with intermediate-to high-risk CS-CaP before receiving 6 months of ADT plus enzalutamide were used for whole-exome sequencing and immunohistochemistry (IHC); loss of chromosome 10q (containing PTEN) and alterations to p53 were predictive of poor response, as were the expression of nuclear ERG on IHC [106].…”

Section: Ar Target Gene Expression Associated Genomic Marks and Cap Treatment Responsesmentioning

confidence: 99%

Somatic Alterations Impact AR Transcriptional Activity and Efficacy of AR-Targeting Therapies in Prostate Cancer

Chauhan

Heemers

2021

Cancers

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Inhibiting the activity of the ligand-activated transcription factor androgen receptor (AR) is the default first-line treatment for metastatic prostate cancer (CaP). Androgen deprivation therapy (ADT) induces remissions, however, their duration varies widely among patients. The reason for this heterogeneity is not known. A better understanding of its molecular basis may improve treatment plans and patient survival. AR’s transcriptional activity is regulated in a context-dependent manner and relies on an interplay between its associated transcriptional regulators, DNA recognition motifs, and ligands. Alterations in one or more of these factors induce shifts in the AR cistrome and transcriptional output. Significant variability in AR activity is seen in both castration-sensitive (CS) and castration-resistant CaP (CRPC). Several AR transcriptional regulators undergo somatic alterations that impact their function in clinical CaPs. Some alterations occur in a significant fraction of cases, resulting in CaP subtypes, while others affect only a few percent of CaPs. Evidence is emerging that these alterations may impact the response to CaP treatments such as ADT, radiation therapy, and chemotherapy. Here, we review the contribution of recurring somatic alterations on AR cistrome and transcriptional output and the efficacy of CaP treatments and explore strategies to use these insights to improve treatment plans and outcomes for CaP patients.

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Nascent Prostate Cancer Heterogeneity Drives Evolution and Resistance to Intense Hormonal Therapy

Cited by 52 publications

References 29 publications

Intraductal Carcinoma of the Prostate as a Cause of Prostate Cancer Metastasis: A Molecular Portrait

Intraductal Carcinoma of the Prostate as a Cause of Prostate Cancer Metastasis: A Molecular Portrait

Molecular features of exceptional response to neoadjuvant anti-androgen therapy in high-risk localized prostate cancer

Somatic Alterations Impact AR Transcriptional Activity and Efficacy of AR-Targeting Therapies in Prostate Cancer

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