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Taplin, Mary-Ellen

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Taplin

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Mary-Ellen

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Taplin, Mary-Ellen
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    Whole exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer
    (2014) Lohr, Jens; Adalsteinsson, Viktor A.; Cibulskis, Kristian; Choudhury, Atish; Rosenberg, Mara; Cruz-Gordillo, Peter; Francis, Joshua; Zhang, Cheng-Zhong; Shalek, Alex K.; Satija, Rahul; Trombetta, John T.; Lu, Diana; Tallapragada, Naren; Tahirova, Narmin; Kim, Sora; Blumenstiel, Brendan; Sougnez, Carrie; Lowe, Alarice; Wong, Bang; Auclair, Daniel; Van Allen, Eliezer; Nakabayashi, Mari; Lis, Rosina T.; Lee, Gwo-Shu M.; Li, Tiantian; Chabot, Matthew S.; Ly, Amy; Taplin, Mary-Ellen; Clancy, Thomas; Loda, Massimo; Regev, Aviv; Meyerson, Matthew; Hahn, William; Kantoff, Philip; Golub, Todd; Getz, Gad; Boehm, Jesse S.; Love, J. Christopher
    Comprehensive analyses of cancer genomes promise to inform prognoses and precise cancer treatments. A major barrier, however, is inaccessibility of metastatic tissue. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming the challenges of isolating rare cells and sequencing low-input material. Here we report an integrated process to isolate, qualify and sequence whole exomes of CTCs with high fidelity, using a census-based sequencing strategy. Power calculations suggest that mapping of >99.995% of the standard exome is possible in CTCs. We validated our process in two prostate cancer patients including one for whom we sequenced CTCs, a lymph node metastasis and nine cores of the primary tumor. Fifty-one of 73 CTC mutations (70%) were observed in matched tissue. Moreover, we identified 10 early-trunk and 56 metastatic-trunk mutations in the non-CTC tumor samples and found 90% and 73% of these, respectively, in CTC exomes. This study establishes a foundation for CTC genomics in the clinic.
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    Association of tumour microRNA profiling with outcomes in patients with advanced urothelial carcinoma receiving first-line platinum-based chemotherapy
    (Nature Publishing Group, 2016) Bellmunt, Joaquim; Zhou, Chensheng Willa; Mullane, Stephanie A; Werner, Lillian; Taplin, Mary-Ellen; Fay, André P; Choueiri, Toni; Orsola, Anna; Takeda, David; Hahn, William; Kim, Jaegil; Sonpavde, Guru; Bowden, Michaela
    Background: Tumour expression of selected microRNAs (miRs) correlates with cisplatin efficacy in multiple cancers. We investigated the role of selected miRs in patients receiving cisplatin-based therapy for advanced urothelial carcinoma (UC). Methods: RNA was extracted from formalin-fixed paraffin-embedded tumour from 83 advanced UC patients who received cisplatin. A miR panel based on relevance for platinum sensitivity and UC was studied by quantitative reverse transcription quantitative PCR (RT–qPCR). Association of progression-free survival (PFS) with miR expression was analysed using cox regression. Selected TFs were chosen by association with the panel of miRs using the Transcription Regulation algorithm (GeneGo MetaCore+MetaDrug version 6.23 build 67496). Bladder cancer (BC) cell lines were used to investigate the previously described role of miR-21 mediating cisplatin sensitivity. Results: The 83 patients had a median PFS of 8 months. In multivariate analysis, higher levels of E2F1 (P=0.01, HR: 1.95 (1.14, 3.33)), miR-21 (P=0.01, HR: 2.01 (1.17, 3.45)) and miR-372 (P=0.05, HR: 1.70 (1.00, 2.89)) were associated with a shorter PFS. In the 8 BC cell lines, miR-21 was not shown to be necessary nor sufficient for modulating cisplatin sensitivity. Conclusions: In metastatic UC patients treated with cisplatin-based therapy, high primary tumour levels of E2F1, miR-21 and miR-372 are associated with poor PFS independent of clinical prognostic factors. The in vitro study could not confirm miR-21 levels role in modulating platinum sensitivity.
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    Aberrant corticosteroid metabolism in tumor cells enables GR takeover in enzalutamide resistant prostate cancer
    (eLife Sciences Publications, Ltd, 2017) Li, Jianneng; Alyamani, Mohammad; Zhang, Ao; Chang, Kai-Hsiung; Berk, Michael; Li, Zhenfei; Zhu, Ziqi; Petro, Marianne; Magi-Galluzzi, Cristina; Taplin, Mary-Ellen; Garcia, Jorge A; Courtney, Kevin; Klein, Eric A; Sharifi, Nima
    Prostate cancer is driven by androgen stimulation of the androgen receptor (AR). The next-generation AR antagonist, enzalutamide, prolongs survival, but resistance and lethal disease eventually prevail. Emerging data suggest that the glucocorticoid receptor (GR) is upregulated in this context, stimulating expression of AR-target genes that permit continued growth despite AR blockade. However, countering this mechanism by administration of GR antagonists is problematic because GR is essential for life. We show that enzalutamide treatment in human models of prostate cancer and patient tissues is accompanied by a ubiquitin E3-ligase, AMFR, mediating loss of 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which otherwise inactivates cortisol, sustaining tumor cortisol concentrations to stimulate GR and enzalutamide resistance. Remarkably, reinstatement of 11β-HSD2 expression, or AMFR loss, reverses enzalutamide resistance in mouse xenograft tumors. Together, these findings reveal a surprising metabolic mechanism of enzalutamide resistance that may be targeted with a strategy that circumvents a requirement for systemic GR ablation. DOI: http://dx.doi.org/10.7554/eLife.20183.001
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    Somatic Copy Number Abnormalities and Mutations in PI3K/AKT/mTOR Pathway Have Prognostic Significance for Overall Survival in Platinum Treated Locally Advanced or Metastatic Urothelial Tumors
    (Public Library of Science, 2015) Bellmunt, Joaquim; Werner, Lillian; Leow, Jeffrey J.; Mullane, Stephanie A.; Fay, André P.; Riester, Markus; Van Hummelen, Paul; Taplin, Mary-Ellen; Choueiri, Toni; Van Allen, Eliezer; Rosenberg, Jonathan
    Background: An integrative analysis was conducted to identify genomic alterations at a pathway level that could predict overall survival (OS) in patients with advanced urothelial carcinoma (UC) treated with platinum-based chemotherapy. Patients and Methods DNA and RNA were extracted from 103 formalin-fixed paraffin embedded (FFPE) invasive high-grade UC samples and were screened for mutations, copy number variation (CNV) and gene expression analysis. Clinical data were available from 85 cases. Mutations were analyzed by mass-spectrometry based on genotyping platform (Oncomap 3) and genomic imbalances were detected by comparative genomic hybridization (CGH) analysis. Regions with threshold of log2 ratio ≥0.4, or ≤0.6 were defined as either having copy number gain or loss and significantly recurrent CNV across the set of samples were determined using a GISTIC analysis. Expression analysis on selected relevant UC genes was conducted using Nanostring. To define the co-occurrence pattern of mutations and CNV, we grouped genomic events into 5 core signal transduction pathways: 1) TP53 pathway, 2) RTK/RAS/RAF pathway, 3) PI3K/AKT/mTOR pathway, 4) WNT/CTNNB1, 5) RB1 pathway. Cox regression was used to assess pathways abnormalities with survival outcomes. Results: 35 samples (41%) harbored mutations on at least one gene: TP53 (16%), PIK3CA (9%), FGFR3 (2%), HRAS/KRAS (5%), and CTNNB1 (1%). 66% of patients had some sort of CNV. PIK3CA/AKT/mTOR pathway alteration (mutations+CNV) had the greatest impact on OS (p=0.055). At a gene level, overexpression of CTNNB1 (p=0.0008) and PIK3CA (p=0.02) were associated with shorter OS. Mutational status on PIK3CA was not associated with survival. Among other individually found genomic alterations, TP53 mutations (p=0.07), mTOR gain (p=0.07) and PTEN overexpression (p=0.08) have a marginally significant negative impact on OS. Conclusions: Our study suggests that targeted therapies focusing on the PIK3CA/AKT/mTOR pathway genomic alterations can generate the greatest impact in the overall patient population of high-grade advanced UC.
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    Redirecting abiraterone metabolism to fine tune prostate cancer anti-androgen therapy
    (2016) Li, Zhenfei; Alyamani, Mohammad; Li, Jianneng; Rogacki, Kevin; Abazeed, Mohamed; Upadhyay, Sunil K.; Balk, Steven; Taplin, Mary-Ellen; Auchus, Richard J.; Sharifi, Nima
    Abiraterone blocks androgen synthesis and prolongs survival in castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis1,2. Abiraterone is metabolized in patients to D4A, which has even greater anti-tumor activity and structural similarities to endogenous steroidal 5α-reductase substrates, such as testosterone3. Here, we show that D4A is converted to at least 3 5α-reduced and 3 5β-reduced metabolites. The initial 5α-reduced metabolite, 3-keto-5α-abi, is more abundant than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor (AR) agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abi and downstream metabolites are depleted, while D4A concentrations rise, effectively blocking production of a tumor-promoting metabolite and permitting D4A accumulation. Furthermore, dutasteride does not deplete three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacologic 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy.