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Signoretti, Sabina

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Signoretti

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Sabina

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Signoretti, Sabina
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Now showing 1 - 10 of 23
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    Programmed death ligand-1 expression in adrenocortical carcinoma: an exploratory biomarker study
    (BioMed Central, 2015) Fay, André P; Signoretti, Sabina; Callea, Marcella; Telό, Gabriela H; McKay, Rana R; Song, Jiaxi; Carvo, Ingrid; Lampron, Megan E; Kaymakcalan, Marina D; Poli-de-Figueiredo, Carlos E; Bellmunt, Joaquim; Hodi, F Stephen; Freeman, Gordon; Elfiky, Aymen; Choueiri, Toni
    Background: Adrenocortical carcinoma (ACC) is a rare tumor in which prognostic factors are still not well established. Programmed Death Ligand-1 (PD-L1) expression in ACC and its association with clinico-pathological features and survival outcomes are unknown. Methods: Formalin-fixed paraffin-embedded (FFPE) specimens were obtained from 28 patients with ACC. PD-L1 expression was evaluated by immunohistochemistry (IHC) in both tumor cell membrane and tumor infiltrating mononuclear cells (TIMC). PD-L1 positivity on tumor cells was defined as ≥5% tumor cell membrane staining. TIMC were evaluated by IHC using a CD45 monoclonal antibody. For PD-L1 expression in TIMC, a combined score based on the extent of infiltrates and percentage of positive cells was developed. Any score greater that zero was considered PD-L1 positive. Baseline clinico-pathological characteristics and follow up data were retrospectively collected. Comparisons between PD-L1 expression and clinico-pathological features were evaluated using unpaired t-test and Fisher’s exact test. Kaplan-Meier method and log-rank test were used to assess association between PD-L1 expression and 5-year overall survival (OS). Results: Among 28 patients with surgically treated ACC, 3 (10.7%) were considered PD-L1 positive on tumor cell membrane. On the other hand, PD-L1 expression in TIMC was performed in 27 specimens and PD-L1 positive staining was observed in 19 (70.4%) patients. PD-L1 positivity in either tumor cell membrane or TIMC was not significantly associated with higher stage at diagnosis, higher tumor grade, excessive hormone secretion, or OS. Conclusions: PD-L1 expression can exist in ACC in both tumor cell membrane and TIMC with no relationship to clinico-pathologic parameters or survival. Electronic supplementary material The online version of this article (doi:10.1186/s40425-015-0047-3) contains supplementary material, which is available to authorized users.
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    Landscape of tumor-infiltrating T cell repertoire of human cancers
    (2016) Li, Bo; Li, Taiwen; Pignon, Jean-Christophe; Wang, Binbin; Wang, Jinzeng; Shukla, Sachet; Dou, Ruoxu; Chen, Qianming; Hodi, F. Stephen; Choueiri, Toni K.; Wu, Catherine; Hacohen, Nir; Signoretti, Sabina; Liu, Jun; Liu, X. Shirley
    We developed a computational method to infer the complementarity determining region 3 (CDR3) sequences of tumor infiltrating T-cells in 9,142 RNA-seq samples across 29 cancer types. We identified over 600 thousand CDR3 sequences, including 15% with full-length. CDR3 sequence length distribution and amino acid conservation, as well as variable gene usage of infiltrating T-cells in many tumors, except brain and kidney cancers, resembled those in the peripheral blood of healthy donors. We observed a strong association between T-cell diversity and tumor mutation load, and predicted SPAG5 and TSSK6 as putative immunogenic cancer/testis antigens in multiple cancers. Finally, we identified 3 potential immunogenic somatic mutations based on their co-occurrence with CDR3 sequences. One of them, PRAMEF4 F300V, was predicted to bind strongly to both MHC-I and MHC-II, with matched HLA types in its carriers. Our analyses have the potential to simultaneously identify immunogenic neoantigens and the tumor-reactive T-cell clonotypes.
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    A Non-integrating Lentiviral Approach Overcomes Cas9-Induced Immune Rejection to Establish an Immunocompetent Metastatic Renal Cancer Model
    (American Society of Gene & Cell Therapy, 2018) Hu, Junhui; Schokrpur, Shiruyeh; Archang, Maani; Hermann, Kip; Sharrow, Allison C.; Khanna, Prateek; Novak, Jesse; Signoretti, Sabina; Bhatt, Rupal; Knudsen, Beatrice S.; Xu, Hua; Wu, Lily
    The CRISPR-based technology has revolutionized genome editing in recent years. This technique allows for gene knockout and evaluation of function in cell lines in a manner that is far easier and more accessible than anything previously available. Unfortunately, the ability to extend these studies to in vivo syngeneic murine cell line implantation is limited by an immune response against cells transduced to stably express Cas9. In this study, we demonstrate that a non-integrating lentiviral vector approach can overcome this immune rejection and allow for the growth of transduced cells in an immunocompetent host. This technique enables the establishment of a von Hippel-Lindau (VHL) gene knockout RENCA cell line in BALB/c mice, generating an improved model of immunocompetent, metastatic renal cell carcinoma (RCC).
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    Lrf suppresses prostate cancer through repression of a Sox9-dependent pathway for cellular senescence bypass and tumor invasion
    (2013) Wang, Guocan; Lunardi, Andrea; Zhang, Jiangwen; Chen, Zhenbang; Ala, Ugo; Webster, Kaitlyn A.; Tay, Yvonne; Gonzalez-Billalabeitia, Enrique; Egia, Ainara; Shaffer, David R.; Carver, Brett; Liu, Xue-Song; Taulli, Riccardo; Kuo, Winston Patrick; Nardella, Caterina; Signoretti, Sabina; Cordon-Cardo, Carlos; Gerald, William L.; Pandolfi, Pier Paolo
    Lrf has been previously described as a powerful proto-oncogene. Here we surprisingly demonstrate that Lrf plays a critical oncosuppressive role in the prostate. Prostate specific inactivation of Lrf leads to a dramatic acceleration of Pten-loss-driven prostate tumorigenesis through a bypass of Pten-loss-induced senescence (PICS). We show that LRF physically interacts with and functionally antagonizes SOX9 transcriptional activity on key target genes such as MIA, which is involved in tumor cell invasion, and H19, a long non-coding RNA precursor for an Rb-targeting miRNA. Inactivation of Lrf in vivo leads to Rb down-regulation, PICS bypass and invasive prostate cancer. Importantly, we found that LRF is genetically lost, as well as down-regulated at both the mRNA and protein levels in a subset of human advanced prostate cancers. Thus, we identify LRF as a context-dependent cancer gene that can act as an oncogene in some contexts but also displays oncosuppressive-like activity in Pten−/− tumors.
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    A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer
    (2013) Lunardi, Andrea; Ala, Ugo; Epping, Mirjam T.; Salmena, Leonardo; Clohessy, John; Webster, Kaitlyn A.; Wang, Guocan; Mazzucchelli, Roberta; Bianconi, Maristella; Stack, Edward C.; Lis, Rosina; Patnaik, Akash; Cantley, Lewis C.; Bubley, Glenn; Cordon-Cardo, Carlos; Gerald, William L.; Montironi, Rodolfo; Signoretti, Sabina; Loda, Massimo; Nardella, Caterina; Pandolfi, Pier Paolo
    Here we report an integrated analysis that leverages data from treatment of genetic mouse models of prostate cancer along with clinical data from patients to elucidate new mechanisms of castration resistance. We show that castration counteracts tumor progression in a Pten-loss driven mouse model of prostate cancer through the induction of apoptosis and proliferation block. Conversely, this response is bypassed upon deletion of either Trp53 or Lrf together with Pten, leading to the development of castration resistant prostate cancer (CRPC). Mechanistically, the integrated acquisition of data from mouse models and patients identifies the expression patterns of XAF1-XIAP/SRD5A1 as a predictive and actionable signature for CRPC. Importantly, we show that combined inhibition of XIAP, SRD5A1, and AR pathways overcomes castration resistance. Thus, our co-clinical approach facilitates stratification of patients and the development of tailored and innovative therapeutic treatments.
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    A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis
    (Backwell Publishing Ltd, 2014) Zadra, Giorgia; Photopoulos, Cornelia; Tyekucheva, Svitlana; Heidari, Pedram; Weng, Qing Ping; Fedele, Giuseppe; Liu, Hong; Scaglia, Natalia; Priolo, Carmen; Sicinska, Ewa; Mahmood, Umar; Signoretti, Sabina; Birnberg, Neal; Loda, Massimo
    5′AMP-activated kinase (AMPK) constitutes a hub for cellular metabolic and growth control, thus representing an ideal therapeutic target for prostate cancers (PCas) characterized by increased lipogenesis and activation of mTORC1 pathway. However, whether AMPK activation itself is sufficient to block cancer cell growth remains to be determined. A small molecule screening was performed and identified MT 63–78, a specific and potent direct AMPK activator. Here, we show that direct activation of AMPK inhibits PCa cell growth in androgen sensitive and castration resistant PCa (CRPC) models, induces mitotic arrest, and apoptosis. In vivo, AMPK activation is sufficient to reduce PCa growth, whereas the allelic loss of its catalytic subunits fosters PCa development. Importantly, despite mTORC1 blockade, the suppression of de novo lipogenesis is the underpinning mechanism responsible for AMPK-mediated PCa growth inhibition, suggesting AMPK as a therapeutic target especially for lipogenesis-driven PCas. Finally, we demonstrate that MT 63–78 enhances the growth inhibitory effect of AR signaling inhibitors MDV3100 and abiraterone. This study thus provides a rationale for their combined use in CRPC treatment.
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    Genomic investigation of etiologic heterogeneity: methodologic challenges
    (BioMed Central, 2014) Begg, Colin B; Seshan, Venkatraman E; Zabor, Emily C; Furberg, Helena; Arora, Arshi; Shen, Ronglai; Maranchie, Jodi K; Nielsen, Matthew E; Rathmell, W Kimryn; Signoretti, Sabina; Tamboli, Pheroze; Karam, Jose A; Choueiri, Toni; Hakimi, A Ari; Hsieh, James J
    Background: The etiologic heterogeneity of cancer has traditionally been investigated by comparing risk factor frequencies within candidate sub-types, defined for example by histology or by distinct tumor markers of interest. Increasingly tumors are being profiled for molecular features much more extensively. This greatly expands the opportunities for defining distinct sub-types. In this article we describe an exploratory analysis of the etiologic heterogeneity of clear cell kidney cancer. Data are available on the primary known risk factors for kidney cancer, while the tumors are characterized on a genome-wide basis using expression, methylation, copy number and mutational profiles. Methods: We use a novel clustering strategy to identify sub-types. This is accomplished independently for the expression, methylation and copy number profiles. The goals are to identify tumor sub-types that are etiologically distinct, to identify the risk factors that define specific sub-types, and to endeavor to characterize the key genes that appear to represent the principal features of the distinct sub-types. Results: The analysis reveals strong evidence that gender represents an important factor that distinguishes disease sub-types. The sub-types defined using expression data and methylation data demonstrate considerable congruence and are also clearly correlated with mutations in important cancer genes. These sub-types are also strongly correlated with survival. The complexity of the data presents many analytical challenges including, prominently, the risk of false discovery. Conclusions: Genomic profiling of tumors offers the opportunity to identify etiologically distinct sub-types, paving the way for a more refined understanding of cancer etiology. Electronic supplementary material The online version of this article (doi:10.1186/1471-2288-14-138) contains supplementary material, which is available to authorized users.
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    Identification of ALK Gene Alterations in Urothelial Carcinoma
    (Public Library of Science, 2014) Bellmunt, Joaquim; Selvarajah, Shamini; Rodig, Scott; Salido, Marta; de Muga, Silvia; Costa, Irmgard; Bellosillo, Beatriz; Werner, Lillian; Mullane, Stephanie; Fay, André P.; O'Brien, Robert; Barretina, Jordi; Minoche, André E.; Signoretti, Sabina; Montagut, Clara; Himmelbauer, Heinz; Berman, David M.; Kantoff, Philip; Choueiri, Toni; Rosenberg, Jonathan E.
    Background: Anaplastic lymphoma kinase (ALK) genomic alterations have emerged as a potent predictor of benefit from treatment with ALK inhibitors in several cancers. Currently, there is no information about ALK gene alterations in urothelial carcinoma (UC) and its correlation with clinical or pathologic features and outcome. Methods: Samples from patients with advanced UC and correlative clinical data were collected. Genomic imbalances were investigated by array comparative genomic hybridization (aCGH). ALK gene status was evaluated by fluorescence in situ hybridization (FISH). ALK expression was assessed by immunohistochemistry (IHC) and high-throughput mutation analysis with Oncomap 3 platform. Next generation sequencing was performed using Illumina Genome Analyzer IIx, and Illumina HiSeq 2000 in the FISH positive case. Results: 70 of 96 patients had tissue available for all the tests performed. Arm level copy number gains at chromosome 2 were identified in 17 (24%) patients. Minor copy number alterations (CNAs) in the proximity of ALK locus were found in 3 patients by aCGH. By FISH analysis, one of these samples had a deletion of the 5′ALK. Whole genome next generation sequencing was inconclusive to confirm the deletion at the level of the ALK gene at the coverage level used. We did not observe an association between ALK CNA and overall survival, ECOG PS, or development of visceral disease. Conclusions: ALK genomic alterations are rare and probably without prognostic implications in UC. The potential for testing ALK inhibitors in UC merits further investigation but might be restricted to the identification of an enriched population.
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    Comprehensive analyses of tumor immunity: implications for cancer immunotherapy
    (BioMed Central, 2016) Li, Bo; Severson, Eric; Pignon, Jean-Christophe; Zhao, Haoquan; Li, Taiwen; Novak, Jesse; Jiang, Peng; Shen, Hui; Aster, Jon; Rodig, Scott; Signoretti, Sabina; Liu, Jun; Liu, X. Shirley
    Background: Understanding the interactions between tumor and the host immune system is critical to finding prognostic biomarkers, reducing drug resistance, and developing new therapies. Novel computational methods are needed to estimate tumor-infiltrating immune cells and understand tumor–immune interactions in cancers. Results: We analyze tumor-infiltrating immune cells in over 10,000 RNA-seq samples across 23 cancer types from The Cancer Genome Atlas (TCGA). Our computationally inferred immune infiltrates associate much more strongly with patient clinical features, viral infection status, and cancer genetic alterations than other computational approaches. Analysis of cancer/testis antigen expression and CD8 T-cell abundance suggests that MAGEA3 is a potential immune target in melanoma, but not in non-small cell lung cancer, and implicates SPAG5 as an alternative cancer vaccine target in multiple cancers. We find that melanomas expressing high levels of CTLA4 separate into two distinct groups with respect to CD8 T-cell infiltration, which might influence clinical responses to anti-CTLA4 agents. We observe similar dichotomy of TIM3 expression with respect to CD8 T cells in kidney cancer and validate it experimentally. The abundance of immune infiltration, together with our downstream analyses and findings, are accessible through TIMER, a public resource at http://cistrome.org/TIMER. Conclusions: We develop a computational approach to study tumor-infiltrating immune cells and their interactions with cancer cells. Our resource of immune-infiltrate levels, clinical associations, as well as predicted therapeutic markers may inform effective cancer vaccine and checkpoint blockade therapies. Electronic supplementary material The online version of this article (doi:10.1186/s13059-016-1028-7) contains supplementary material, which is available to authorized users.
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    Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model
    (Impact Journals LLC, 2016) Suarez, Eloah Rabello; Chang, De-Kuan; Sun, Jiusong; Sui, Jianhua; Freeman, Gordon; Signoretti, Sabina; Zhu, Quan; Marasco, Wayne
    Advances in the treatment of metastatic clear cell renal cell carcinoma (ccRCC) have led to improved progression-free survival of many patients; however the therapies are toxic, rarely achieve durable long-term complete responses and are not curative. Herein we used a single bicistronic lentiviral vector to develop a new combination immunotherapy that consists of human anti-carbonic anhydrase IX (CAIX)-targeted chimeric antigen receptor (CAR) T cells engineered to secrete human anti-programmed death ligand 1 (PD-L1) antibodies at the tumor site. The local antibody delivery led to marked immune checkpoint blockade. Tumor growth diminished 5 times and tumor weight reduced 50–80% when compared with the anti-CAIX CAR T cells alone in a humanized mice model of ccRCC. The expression of PD-L1 and Ki67 in the tumors decreased and an increase in granzyme B levels was found in CAR T cells. The anti-PD-L1 IgG1 isotype, which is capable of mediating ADCC, was also able to recruit human NK cells to the tumor site in vivo. These armed second-generation CAR T cells empowered to secrete human anti-PD-L1 antibodies in the ccRCC milieu to combat T cell exhaustion is an innovation in this field that should provide renewed potential for CAR T cell immunotherapy of solid tumors where limited efficacy is currently seen.