Marc Gillard

Low‐grade prostate cancer diverges early from high grade and metastatic disease

Understanding the developmental relationship between indolent and aggressive tumors is central to understanding disease progression and making treatment decisions. For example, most men diagnosed with prostate cancer have clinically indolent disease and die from other causes. Overtreatment of prostate cancer remains a concern. Here we use laser microdissection followed by exome sequencing of low‐ and high‐grade prostate cancer foci from four subjects, and metastatic disease from two of those subjects, to evaluate the molecular relationship of coincident cancer foci. Seventy of 79 (87%) high‐confidence somatic mutations in low‐grade disease were private to low‐grade foci. In contrast, high‐grade foci and metastases harbored many of the same mutations. In cases in which there was a metastatic focus, 15 of 80 (19%) high‐confidence somatic mutations in high‐grade foci were private. Seven of the 80 (9%) were shared with low‐grade foci and 65 (82%) were shared with metastatic foci. Notably, mutations in cancer‐associated genes and the p53 signaling pathway were found exclusively in high‐grade foci and metastases. The pattern of mutations is consistent with early divergence between low‐ and high‐grade foci and late divergence between high‐grade foci and metastases. These data provide insights into the development of high‐grade and metastatic prostate cancer.

Selective Glucocorticoid Receptor Modulators (SGRMs) Delay Castrate-Resistant Prostate Cancer Growth

Increased glucocorticoid receptor (GR) expression and activity following androgen blockade can contribute to castration-resistant prostate cancer (CRPC) progression. Therefore, we hypothesized that GR antagonism will have therapeutic benefit in CRPC. However, the FDA-approved nonselective, steroidal GR antagonist, mifepristone, lacks GR specificity, reducing its therapeutic potential. Here, we report that two novel nonsteroidal and highly selective GR modulators (SGRM), CORT118335 and CORT108297, have the ability to block GR activity in prostate cancer and slow CRPC progression. In contrast to mifepristone, these novel SGRMs did not affect androgen receptor (AR) signaling, but potently inhibited GR transcriptional activity. Importantly, SGRMs decreased GR-mediated tumor cell viability following AR blockade. In vivo, SGRMs significantly inhibited CRPC progression in high GR–expressing, but not in low GR–expressing xenograft models. Transcriptome analysis following AR blockade and GR activation revealed that these SGRMs block GR-mediated proliferative gene expression pathways. Furthermore, GR-regulated proliferation-associated genes AKAP12, FKBP5, SGK1, CEBPD, and ZBTB16 are inhibited by CORT108297 treatment in vivo. Together, these data suggest that GR-selective nonsteroidal SGRMs potently inhibit GR activity and prostate cancer growth despite AR pathway inhibition, demonstrating the therapeutic potential of SGRMs in GR-expressing CRPC. Mol Cancer Ther; 16(8); 1680–92. ©2017 AACR.

Circulating tumor cells capture disease evolution in advanced prostate cancer

BackgroundGenetic analysis of advanced cancer is limited by availability of representative tissue. Biopsies of prostate cancer metastasized to bone are invasive with low quantity of tumor tissue. The prostate cancer genome is dynamic, however, with temporal heterogeneity requiring repeated evaluation as the disease evolves. Circulating tumor cells (CTCs) offer an alternative, “liquid biopsy”, though single CTC sequencing efforts are laborious with high failure rates.MethodsWe performed exome sequencing of matched treatment-naïve tumor tissue, castrate resistant tumor tissue, and pooled CTC samples, and compared mutations identified in each.ResultsThirty-seven percent of CTC mutations were private to CTCs, one mutation was shared with treatment-naïve disease alone, and 62% of mutations were shared with castrate-resistant disease, either alone or with treatment-naïve disease. An acquired nonsense mutation in the Retinoblastoma gene, which is associated with progression to small cell cancer, was identified in castrate resistant and CTC samples, but not treatment-naïve disease. This timecourse correlated with the tumor acquiring neuroendocrine features and a change to neuroendocrine-specific therapy.ConclusionsThese data support the use of pooled CTCs to facilitate the genetic analysis of late stage prostate cancer.

MEIS1 and MEIS2 Expression and Prostate Cancer Progression: A Role For HOXB13 Binding Partners in Metastatic Disease

Purpose: Germline mutations within the MEIS-interaction domain of HOXB13 have implicated a critical function for MEIS–HOX interactions in prostate cancer etiology and progression. The functional and predictive role of changes in MEIS expression within prostate tumor progression, however, remain largely unexplored. Experimental Design: Here we utilize RNA expression datasets, annotated tissue microarrays, and cell-based functional assays to investigate the role of MEIS1 and MEIS2 in prostate cancer and metastatic progression. Results: These analyses demonstrate a stepwise decrease in the expression of both MEIS1 and MEIS2 from benign epithelia, to primary tumor, to metastatic tissues. Positive expression of MEIS proteins in primary tumors, however, is associated with a lower hazard of clinical metastasis (HR = 0.28) after multivariable analysis. Pathway and gene set enrichment analyses identified MEIS-associated networks involved in cMYC signaling, cellular proliferation, motility, and local tumor environment. Depletion of MEIS1 and MEIS2 resulted in increased tumor growth over time in vivo, and decreased MEIS expression in both patient-derived tumors and MEIS-depleted cell lines was associated with increased expression of the protumorigenic genes cMYC and CD142, and decreased expression of AXIN2, FN1, ROCK1, SERPINE2, SNAI2, and TGFβ2. Conclusions: These data implicate a functional role for MEIS proteins in regulating cancer progression, and support a hypothesis whereby tumor expression of MEIS1 and MEIS2 expression confers a more indolent prostate cancer phenotype, with a decreased propensity for metastatic progression. Clin Cancer Res; 24(15); 3668–80. ©2018 AACR.

Integrative Genomic Analysis of Coincident Cancer Foci Implicates CTNNB1 and PTEN Alterations in Ductal Prostate Cancer

BACKGROUND Ductal adenocarcinoma of the prostate is an aggressive subtype, with high rates of biochemical recurrence and overall poor prognosis. It is frequently found coincident with conventional acinar adenocarcinoma. The genomic features driving evolution to its ductal histology and the biology associated with its poor prognosis remain unknown. OBJECTIVE To characterize genomic features distinguishing ductal adenocarcinoma from coincident acinar adenocarcinoma foci from the same patient. DESIGN, SETTING, AND PARTICIPANTS Ten patients with coincident acinar and ductal prostate cancer underwent prostatectomy. Laser microdissection was used to separately isolate acinar and ductal foci. DNA and RNA were extracted, and used for integrative genomic and transcriptomic analyses. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Single nucleotide mutations, small indels, copy number estimates, and expression profiles were identified. Phylogenetic relationships between coincident foci were determined, and characteristics distinguishing ductal from acinar foci were identified. RESULTS AND LIMITATIONS Exome sequencing, copy number estimates, and fusion genes demonstrated coincident ductal and acinar adenocarcinoma diverged from a common progenitor, yet they harbored distinct alterations unique to each focus. AR expression and activity were similar in both histologies. Nine of 10 cases had mutually exclusive CTNNB1 hotspot mutations or phosphatase and tensin homolog (PTEN) alterations in the ductal component, and these were absent in the acinar foci. These alterations were associated with changes in expression in WNT- and PI3K-pathway genes. CONCLUSIONS Coincident ductal and acinar histologies typically are clonally related and thus arise from the same cell of origin. Ductal foci are enriched for cases with either a CTNNB1 hotspot mutation or a PTEN alteration, and are associated with WNT- or PI3K-pathway activation. These alterations are mutually exclusive and may represent distinct subtypes. PATIENT SUMMARY The aggressive subtype ductal adenocarcinoma is closely related to conventional acinar prostate cancer. Ductal foci contain additional alterations, however, leading to frequent activation of two targetable pathways.