RESUMO
As we move into the era of precision medicine, the growing relevance of genetic alterations to prostate cancer (PCa) development and treatment demonstrates the importance of characterizing preclinical models at the genomic level. Our study investigated the genomic characterization of eight PCa cell lines to understand which models are clinically relevant. We designed a custom AmpliSeq DNA gene panel that encompassed key molecular pathways targeting AR signaling, apoptosis, DNA damage repair, and PI3K/AKT/PTEN, in addition to tumor suppressor genes. We examined the relationship between cell line genomic alterations and therapeutic response. In addition, using DepMap's Celligner tool, we identified which preclinical models are most representative of specific prostate cancer patient populations on cBioPortal. These data will help investigators understand the genetic differences in preclinical models of PCa and determine which ones are relevant for use in their translational research.
Assuntos
Genômica , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Linhagem Celular Tumoral , Genômica/métodos , Transdução de Sinais , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/genética , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Reparo do DNARESUMO
Extracellular vesicles (EVs) provide a minimally invasive liquid biopsy source of tumor-specific markers for patients who have already undergone prostatectomies. Our laboratory has previously demonstrated enrichment of the cancer-type solute carrier organic anion transporter family 1B3 (ct-SLCO1B3) and the ATP Binding Cassette Subfamily Member C (ABCC3) in castration-resistant cell lines (CRPC). However, their expression in EVs has yet to be explored. Our study demonstrated that ct-SLCO1B3 and ABCC3 are highly detectable in CRPC cell line-derived EVs. We also showed that ct-SLCO1B3 and ABCC3 were detectable in a CRPC xenograft mouse model, both intratumorally and in plasma-derived EVs. Our results provide evidence for EV-contained ct-SLCO1B3 and ABCC3 as novel, EV-based tumor markers for prostate cancer progression.
RESUMO
As the era of cancer genomics expands, disproportionate rates of prostate cancer incidence and mortality by race have demonstrated increasing relevance in clinical settings. While Black men are most particularly affected, as data has historically shown, the opposite is observed for Asian men, thus creating a basis for exploring genomic pathways potentially involved in mediating these opposing trends. Studies on racial differences are limited by sample size, but recent expanding collaborations between research institutions may improve these imbalances to enhance investigations on health disparities from the genomics front. In this study, we performed a race genomics analysis using GENIE v11, released in January 2022, to investigate mutation and copy number frequencies of select genes in both primary and metastatic patient tumor samples. Further, we investigate the TCGA race cohort to conduct an ancestry analysis and to identify differentially expressed genes highly upregulated in one race and subsequently downregulated in another. Our findings highlight pathway-oriented genetic mutation frequencies characterized by race, and further, we identify candidate gene transcripts that have differential expression between Black and Asian men.
Assuntos
Desigualdades de Saúde , Neoplasias da Próstata , Humanos , Masculino , Negro ou Afro-Americano/genética , Perfilação da Expressão Gênica , Genômica , AsiáticoRESUMO
PARP inhibitors were recently introduced as a novel targeted therapy for biomarker positive metastatic castration resistant prostate cancer (mCRPC) patients, a population that inevitably acquires resistance to existing standard care regimens. Olaparib and rucaparib are now FDA-approved for mCRPC, while talazoparib and niraparib are advancing through the clinical stage of development. We highlight the recent results of the GALAHAD trial testing the efficacy of niraparib in mCRPC patients with DNA damage repair gene defects and compare its performance to key PARP inhibitor trials (PROFOUND, olaparib; TRITON2, rucaparib; TALAPRO-1, talazoparib). Finally, we briefly discuss recent updates on emerging PARP inhibitor and androgen receptor targeting combination trials as a novel treatment strategy for upfront treatment of mCRPC and in earlier disease settings.
