High Fidelity Patient-Derived Xenografts for Accelerating Prostate Cancer Discovery and Drug Development

Lin, Dong; Wyatt, Alexander W.; Xue, Hui; Wang, Yuwei; Dong, Xin; Haegert, Anne; Wu, Rebecca; Brahmbhatt, Sonal; Mo, Fan; Jong, Lina; Bell, Robert H.; Anderson, Shawn; Hurtado-Coll, Antonio; Fazli, Ladan; Sharma, Manju; Beltran, Himisha; Rubin, Mark A.; Cox, Michael; Gout, Peter W.; Morris, James; Goldenberg, Larry; Volik, Stanislav V.; Gleave, Martin; Collins, Colin C.; Wang, Yuzhuo

doi:10.1158/0008-5472.can-13-2921-t

Cited by 316 publications

(451 citation statements)

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“…To identify the mechanisms of NEPC initiation, we conducted transcriptomic and genomic analyses on our ADT-induced NEPC model (LTL-331R) and on its hormone-sensitive predecessor (LTL-331). We found that the two models share identical genetic profiles, suggesting that genetic alterations may not exclusively drive NEPC trans-differentiation [36].Interestingly, our analysis revealed that CBX2 and EZH2 (PcG members) were significantly up-regulated in NEPC pre-clinical models and clinical samples [26]. This study also identified 185 PcG target genes that were significantly down-regulated indicating a relevant role of PcG complexes in NEPC.…”

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confidence: 59%

“…Recently, we successfully developed the first-in-field patient tissue-derived xenograft model of complete NEPC trans-differentiation from prostate adenocarcinoma [36,52]. To identify the mechanisms of NEPC initiation, we conducted transcriptomic and genomic analyses on our ADT-induced NEPC model (LTL-331R) and on its hormone-sensitive predecessor (LTL-331).…”

Section: The Epigenetic/non-coding Interactome and Its Implication Inmentioning

confidence: 99%

“…Emerging evidence indicates that an epigenetic/non-coding interactome (ENI) could play a more fundamental function in NEPC initiation and progression. We have previously proposed that the ENI confers unique plasticity to cancer cells, thereby allowing them to become metastatic and drug-resistant [28,36]. Notably, these two deadly features are hallmarks of NEPC.…”

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confidence: 99%

“…Notably, these two deadly features are hallmarks of NEPC. Here, we will discuss initial evidence suggesting that the ENI is implicated in NEPC initiation.The ENI is comprised of two major components: epigenetic effectors (proteins) and noncoding RNAs (ncRNAs) [36]. Polycomb group (PcG) proteins are epigenetic effectors organized in multimeric complexes known as the Polycomb Repressive Complexes (PRCs) [37].…”

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confidence: 99%

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The Role of Epigenetics and Long Noncoding RNA MIAT in Neuroendocrine Prostate Cancer

et al. 2016

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Neuroendocrine prostate cancer (NEPC) is the most lethal prostatic neoplasm.NEPC is thought to originate from the trans-differentiation of AR-positive adenocarcinoma cells. We have previously shown that an epigenetic/non-coding interactome (ENI) orchestrates cancer cells' plasticity, thereby allowing the emergence of metastatic, drugresistant neoplasms. The primary objective of this manuscript is to discuss evidence indicating that some components of the ENI (Polycomb genes, microRNAs) play a key role in NEPC initiation and progression. Long non-coding RNAs (lncRNAs) represent vast and largely unexplored component of the ENI. Their role in NEPC has not been investigated. We show preliminary evidence indicating that a lncRNA (MIAT) is selectively up-regulated in NEPCs and might interact with Polycomb genes. Our results indicate that lncRNAs can be exploited as new biomarkers and therapeutic targets for NEPC.Keywords: Neuroendocrine prostate cancer; MIAT; Long non-coding RNAs; Polycomb; Epigenetic/non-coding interactome; Trans-differentiation. Neuroendocrine Prostate Cancer: Clinical and Molecular FeaturesIn adult males, the prostate is a small acorn-shaped tissue with ductal-acinar histology surrounding the urethra at the base of the bladder. Its main function is to contribute secretory proteins to the seminal fluid [1]. The adult prostate is a pseudo-stratified epithelium composed of three main cell lineages (Fig.1, left panel): 1) secretory luminal cells are the predominant cell type; these cells express keratins (K8, K18), the androgen receptor (AR) and secretory proteins such as prostate-specific antigen (PSA) and prostatic specific acid phosphatase (PSAP);2) basal cells expressing K5 and K14 keratins and p63 are the second major cell type;3) neuroendocrine cells (NEC) expressing chromogranin A (CHGA), synaptophysin (SYP), and neuropeptides are scattered throughout the basal layer and comprise less than 1% of normal prostatic glandular epithelium [1][2][3].Prostate cancer (PCa) represents the second most frequently diagnosed neoplasm and is the sixth leading cause of cancer-related deaths in males worldwide [4,5]. In keeping with the composition of prostate epithelium, more than 95% of PCas are classified as adenocarcinomas, which show luminal phenotype and AR expression [6] (Fig.1, middle panel).Endogenous androgens, mainly produced by the testis, bind to the AR and fuel prostate adenocarcinoma proliferation [7]. For this reason, androgen-deprivation therapy (a.k.a. castration) is an effective therapeutic strategy for this disease. However, patients invariably relapse despite castrate androgen levels (castration-resistant PCa, CRPC) mainly via genetic and epigenetic alterations that facilitate ligand-independent AR activation, amplify the ARdependent signaling, or trigger different proliferative pathways [7]. CRPCs are characterized by substantially worse prognoses, but chemotherapeutics and newly approved hormonal treatments (e.g., Enzalutamide [8] and Abiraterone [9]) are still effective in p...

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Section: The Epigenetic/non-coding Interactome and Its Implication Inmentioning

confidence: 99%

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confidence: 99%

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The Role of Epigenetics and Long Noncoding RNA MIAT in Neuroendocrine Prostate Cancer

et al. 2016

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“…This study will open up new avenues into the investigation of PIP5K1α as a therapeutic target in preclinical models of prostate cancer, in addition to other cancers dependent on the PI3K pathway for growth and survival. It will be important to evaluate this compound further, individually and in combination, in several preclinical models of advanced prostate cancer including genetically engineered mouse models (such as PTEN −/− ) (17), mouse and human tissue recombination cancer models (18)(19)(20), and CRPC models (21). If verified, this might be a new promising member in the ever-expanding list of PI3K pathwayspecific inhibitors.…”

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PIP5K1α inhibition as a therapeutic strategy for prostate cancer

Drake

Huang

2014

Proc. Natl. Acad. Sci. U.S.A.

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Whole-Exome Sequencing of Metastatic Cancer and Biomarkers of Treatment Response

et al. 2015

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Importance Understanding molecular mechanisms of response and resistance to anticancer therapies requires prospective patient follow-up and clinical and functional validation of both common and low-frequency mutations. We describe a whole-exome sequencing (WES) precision medicine trial focused on patients with advanced cancer. Objective To understand how WES data affect therapeutic decision making in patients with advanced cancer and to identify novel biomarkers of response. Design, Setting, and Patients Patients with metastatic and treatment-resistant cancer were prospectively enrolled at a single academic center for paired metastatic tumor and normal tissue WES during a 19-month period (February 2013 through September 2014). A comprehensive computational pipeline was used to detect point mutations, indels, and copy number alterations. Mutations were categorized as category 1, 2, or 3 on the basis of actionability; clinical reports were generated and discussed in precision tumor board. Patients were observed for 7 to 25 months for correlation of molecular information with clinical response. Main Outcomes and Measures Feasibility, use of WES for decision making, and identification of novel biomarkers. Results A total of 154 tumor-normal pairs from 97 patients with a range of metastatic cancers were sequenced, with a mean coverage of 95× and 16 somatic alterations detected per patient. In total, 16 mutations were category 1 (targeted therapy available), 98 were category 2 (biologically relevant), and 1474 were category 3 (unknown significance). Overall, WES provided informative results in 91 cases (94%), including alterations for which there is an approved drug, there are therapies in clinical or preclinical development, or they are considered drivers and potentially actionable (category 1-2); however, treatment was guided in only 5 patients (5%) on the basis of these recommendations because of access to clinical trials and/or off-label use of drugs. Among unexpected findings, a patient with prostate cancer with exceptional response to treatment was identified who harbored a somatic hemizygous deletion of the DNA repair gene FANCA and putative partial loss of function of the second allele through germline missense variant. Follow-up experiments established that loss of FANCA function was associated with platinum hypersensitivity both in vitro and in patient-derived xenografts, thus providing biologic rationale and functional evidence for his extreme clinical response. Conclusions and Relevance The majority of advanced, treatment-resistant tumors across tumor types harbor biologically informative alterations. The establishment of a clinical trial for WES of metastatic tumors with prospective follow-up of patients can help identify candidate predictive biomarkers of response.

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High Fidelity Patient-Derived Xenografts for Accelerating Prostate Cancer Discovery and Drug Development

Cited by 316 publications

References 53 publications

The Role of Epigenetics and Long Noncoding RNA MIAT in Neuroendocrine Prostate Cancer

The Role of Epigenetics and Long Noncoding RNA MIAT in Neuroendocrine Prostate Cancer

PIP5K1α inhibition as a therapeutic strategy for prostate cancer

Whole-Exome Sequencing of Metastatic Cancer and Biomarkers of Treatment Response

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