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Giandomenico, Valeria
Publications (10 of 28) Show all publications
Elgendy, M., Abdel-Aziz, A. K., Renne, S. L., Bornaghi, V., Procopio, G., Colecchia, M., . . . Minucci, S. (2017). Dual modulation of MCL-1 and mTOR determines the response to sunitinib. Journal of Clinical Investigation, 127(1), 153-168
Open this publication in new window or tab >>Dual modulation of MCL-1 and mTOR determines the response to sunitinib
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2017 (English)In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 127, no 1, p. 153-168Article in journal (Refereed) Published
Abstract [en]

Most patients who initially respond to treatment with the multi-tyrosine kinase inhibitor sunitinib eventually relapse. Therefore, developing a deeper understanding of the contribution of sunitinib's numerous targets to the clinical response or to resistance is crucial. Here, we have shown that cancer cells respond to clinically relevant doses of sunitinib by enhancing the stability of the antiapoptotic protein MCL-1 and inducing mTORC1 signaling, thus evoking little cytotoxicity. Inhibition of MCL-1 or mTORC1 signaling sensitized cells to clinically relevant doses of sunitinib in vitro and was synergistic with sunitinib in impairing tumor growth in vivo, indicating that these responses are triggered as prosurvival mechanisms that enable cells to tolerate the cytotoxic effects of sunitinib. Furthermore, higher doses of sunitinib were cytotoxic, triggered a decline in MCL-1 levels, and inhibited mTORC1 signaling. Mechanistically, we determined that sunitinib modulates MCL-1 stability by affecting its proteasomal degradation. Dual modulation of MCL-1 stability at different dose ranges of sunitinib was due to differential effects on ERK and GSK3 beta activity, and the latter also accounted for dual modulation of mTORC1 activity. Finally, comparison of patient samples prior to and following sunitinib treatment suggested that increases in MCL-1 levels and mTORC1 activity correlate with resistance to sunitinib in patients.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-316415 (URN)10.1172/JCI84386 (DOI)000392271300019 ()27893461 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme
Available from: 2017-03-02 Created: 2017-03-02 Last updated: 2017-11-29Bibliographically approved
Yu, D., Leja, J., Loskog, A. S., Hellman, P., Giandomenico, V., Öberg, K. & Essand, M. (2017). Preclinical Evaluation of AdVince, an Oncolytic Adenovirus Adapted for Treatment of Liver Metastases from Neuroendocrine Cancer. Neuroendocrinology, 105(1), 54-66
Open this publication in new window or tab >>Preclinical Evaluation of AdVince, an Oncolytic Adenovirus Adapted for Treatment of Liver Metastases from Neuroendocrine Cancer
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2017 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, no 1, p. 54-66Article in journal (Refereed) Published
Abstract [en]

Cancer immunotherapy is becoming a cornerstone in the clinical care of cancer patients due to the breakthrough trials with immune checkpoint blockade antibodies and chimeric antigen receptor T cells. The next breakthrough in cancer immunotherapy is likely to be oncolytic viruses engineered to selectively kill tumor cells and deceive the immune system to believe that the tumor is a foreign entity that needs to be eradicated. We have developed AdVince, an oncolytic adenovirus for treatment of liver metastases from neuroendocrine tumor (NET). AdVince includes the gene promoter from human chromogranin A for selective replication in neuroendocrine cells, miR122 target sequences for reduced liver toxicity, and a cell-penetrating peptide in the capsid for increased infectivity of tumor cells and optimized spread within tumors. This paper describes the preclinical evaluation of AdVince on freshly isolated human gastrointestinal NET cells resected from liver metastases and freshly isolated human hepatocytes as well as in fresh human blood. AdVince selectively replicates in and kills NET cells. Approximately, 73-fold higher concentration of AdVince is needed to induce similar level of cytotoxicity in NET cells as in hepatocytes. AdVince did not activate complement or induce considerable amount of proinflammatory cytokines or chemokines in human blood. The data presented herein indicate that AdVince can be safely evaluated in a phase I/IIa clinical trial for patients with liver-dominant NET.

Place, publisher, year, edition, pages
S. Karger, 2017
Keywords
Neuroendocrine cancer; Oncolytic adenovirus; AdVince; Liver metastases; Immunotherapy
National Category
Neurology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-308877 (URN)10.1159/000448430 (DOI)000403362100006 ()27442441 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2016-12-01 Created: 2016-12-01 Last updated: 2019-02-27Bibliographically approved
Shi, H., Li, S.-C., Khan, M., Caplin, M., Meyer, T., Öberg, K. & Giandomenico, V. (2015). Functional role of miR-196a in neuroendocrine tumor cells. Paper presented at 12th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, Barcelona, SPAIN, MAR 11-13, 2015. Neuroendocrinology, 102(1-2), 87-87
Open this publication in new window or tab >>Functional role of miR-196a in neuroendocrine tumor cells
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2015 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 102, no 1-2, p. 87-87Article in journal, Meeting abstract (Refereed) Published
Place, publisher, year, edition, pages
S. Karger, 2015
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-233206 (URN)10.1159/000431385 (DOI)000361683500030 ()
External cooperation:
Conference
12th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, Barcelona, SPAIN, MAR 11-13, 2015
Available from: 2014-09-30 Created: 2014-09-30 Last updated: 2018-01-11Bibliographically approved
Giandomenico, V., Thirlwell, C. & Essand, M. (2015). Other Novel Therapies: Biomarkers, microRNAs and microRNA Inhibitors, DNA Methylation, Epigenetics, Immunotherapy and Virotherapy. In: Papotti, M; DeHerder, WW (Ed.), Neuroendocrine Tumors: A Multidisciplinary Approach (pp. 248-262). S. Karger
Open this publication in new window or tab >>Other Novel Therapies: Biomarkers, microRNAs and microRNA Inhibitors, DNA Methylation, Epigenetics, Immunotherapy and Virotherapy
2015 (English)In: Neuroendocrine Tumors: A Multidisciplinary Approach / [ed] Papotti, M; DeHerder, WW, S. Karger, 2015, p. 248-262Chapter in book (Refereed)
Abstract [en]

Neuroendocrine tumors (NETs) consist of heterogeneous neoplasms. The neuroendocrine cells of the human body are confined to certain organs, such as the thyroid, pancreas and adrenals, or they are dispersed throughout the body in the respiratory tract and in the intestinal mucosa. The cells belong to the diffuse endocrine cell system, share a neuroendocrine phenotype, and accumulate precursor molecules which are then processed into hormones, peptides or amines. The tightly controlled release on stimulation is either to the blood stream or adjacent cells or neurons. Neuroendocrine cells regulate various processes in the human body, such as gastrointestinal secretion, blood pressure and response to stress. NETs present a wide spectrum of malignant diseases from rather benign to very malignant and lethal variants. NETs may occur in any organ, but are mainly detected in the gastroenteropancreatic system and in the lungs. The understanding of NET biology and treatments has changed dramatically during the last decade. Today, the main problems that clinicians and translational scientists face in overcoming these malignancies relate to various aspects within the molecular pathogenesis of NETs. This chapter focuses on the importance of novel biomarkers: microRNA and microRNA inhibitors; DNA methylation and epigenetics, and immunotherapy and virotherapy to develop novel treatments for NETs.

Place, publisher, year, edition, pages
S. Karger, 2015
Series
Frontiers of Hormone Research, ISSN 0301-3073 ; 44
National Category
Endocrinology and Diabetes Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-284908 (URN)10.1159/000403885 (DOI)000370334100018 ()26303717 (PubMedID)978-3-318-02773-0; 978-3-318-02772-3 (ISBN)
Available from: 2016-04-19 Created: 2016-04-19 Last updated: 2016-04-19Bibliographically approved
Li, S.-C., Shi, H., Khan, M., Caplin, M., Meyer, T., Öberg, K. & Giandomenico, V. (2015). Roles of miR-196a on gene regulation of neuroendocrine tumor cells. Molecular and Cellular Endocrinology, 412(C), 131-139
Open this publication in new window or tab >>Roles of miR-196a on gene regulation of neuroendocrine tumor cells
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2015 (English)In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 412, no C, p. 131-139Article in journal (Refereed) Published
Abstract [en]

This study aims at investigating miR-196a roles using in vitro models. miR-196a was detected in small intestinal neuroendocrine tumors (SI-NETS) and lung NETs. miR-196a target prediction analysis suggested HOXA9, HOXB7, LRP4 and RSPO2 genes for further investigation. The level of these four genes is detectable in SI-NET tissue specimens at different disease stages and serum samples of untreated and somatostatin analogs treated patients with liver metastases. A miR-196a inhibitor was used to silence its effects in NET cells. We show that the four target genes were significantly upregulated at transcriptional level in silenced NET cells. HOXA9, HOXB7, LRP4 and RSPO2 encoded proteins are also upregulated at translational level in miR-196a silenced NET cells. miR-196a downstream genes BMP4, ETS1, CTNNB1, FZD5, LEP5 and LRP6 were significantly upregulated at transcriptional level in miR-196a silenced CNDT2.5 and NCI-H727 cells. In addition, miR-196a clearly does not play a role in NET cell growth control.

Keywords
miR-196a target genes, Neuroendocrine tumor cells, MicroRNA inhibitors, Transfection effects
National Category
Endocrinology and Diabetes Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-262406 (URN)10.1016/j.mce.2015.06.003 (DOI)000359958900015 ()26052033 (PubMedID)
Available from: 2015-09-21 Created: 2015-09-15 Last updated: 2017-12-04Bibliographically approved
Li, S.-C., Khan, M., Caplin, M., Meyer, T., Öberg, K. & Giandomenico, V. (2015). Somatostatin Analogs Treated Small Intestinal Neuroendocrine Tumor Patients Circulating MicroRNAs. PLoS ONE, 10(5), Article ID e0125553.
Open this publication in new window or tab >>Somatostatin Analogs Treated Small Intestinal Neuroendocrine Tumor Patients Circulating MicroRNAs
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, article id e0125553Article in journal (Refereed) Published
Abstract [en]

We previously detected and investigated nine altered microRNAs in small intestinal neuroendocrine tumor (SI-NET) tissues at different stages of disease. The aims of this study are to: 1) analyze whether SI-NET tissue microRNAs can be also detected in patient serum samples, 2) investigate a potential somatostatin analogs (SSAs) role on microRNA levels regulation in SSA-treated patient samples and 3) elucidate whether the serum microRNA levels in samples collected in different hospitals are predictable and steady. Our results show that tissue microRNAs are detectable in patient serum samples, and miR-96, -182, -183, -196a and -200a levels are lower in SI-NET untreated patients than in SSA-treated patients at all different stages. Conversely, miR-31, -129-5p, -133a and -215 levels do not show any difference in untreated SI-NET patients and SSA-treated patients at all different stages. Our findings also show that miR-200a exhibits an atypical behavior with high levels in both untreated and SSA-treated patients at liver metastasis stage, and unequivocally never at the earlier stages. Serum samples collected in two hospitals keep alike microRNA level pattern, elucidating that the results are not dependent on samples handling. In conclusion, SI-NET tissue microRNAs are always detectable in untreated and SSA-treated patient serum samples, SSAs play an unknown role in eliciting SSA-treated patients' microRNA levels higher than in untreated patients, and this study enlightens that miR-200a might be involved in the liver metastasis during SI-NET progression.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-255077 (URN)10.1371/journal.pone.0125553 (DOI)000353943400044 ()25942502 (PubMedID)
Available from: 2015-06-12 Created: 2015-06-12 Last updated: 2017-12-04Bibliographically approved
Li, S.-C., Khan, M., Caplin, M., Meyer, T., Öberg, K. & Giandomenico, V. (2014). Circulating microRNA detection in small intestinal neuroendocrine tumor patients treated with somatostatin analogs.
Open this publication in new window or tab >>Circulating microRNA detection in small intestinal neuroendocrine tumor patients treated with somatostatin analogs
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2014 (English)Article in journal, Meeting abstract (Refereed) Submitted
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:uu:diva-233202 (URN)
Available from: 2014-09-30 Created: 2014-09-30 Last updated: 2018-01-11Bibliographically approved
Li, S.-C., Khan, M. S., Caplin, M., Öberg, K., Meyer, T. & Giandomenico, V. (2014). MicroRNA Expression in Serum of Small Intestine Neuroendocrine Tumor Patients and miR-196a Biological Function in Neuroendocrine Tumor Cells. Paper presented at 11th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 05-07, 2014, Barcelona, SPAIN. Neuroendocrinology, 99(3-4), 228-228
Open this publication in new window or tab >>MicroRNA Expression in Serum of Small Intestine Neuroendocrine Tumor Patients and miR-196a Biological Function in Neuroendocrine Tumor Cells
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2014 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 99, no 3-4, p. 228-228Article in journal, Meeting abstract (Other academic) Published
Keywords
neuroendocrine tumors, serum mirna expression, mirna, target functions
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-237656 (URN)000343640100028 ()
Conference
11th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 05-07, 2014, Barcelona, SPAIN
Available from: 2014-12-10 Created: 2014-12-03 Last updated: 2017-12-05Bibliographically approved
Scardoni, M., Vittoria, E., Volante, M., Rusev, B., Bersani, S., Mafficini, A., . . . Scarpa, A. (2014). Mixed Adenoneuroendocrine Carcinomas of the Gastrointestinal Tract: Targeted Next-Generation Sequencing Suggests a Monoclonal Origin of the Two Components. Neuroendocrinology, 100(4), 310-316
Open this publication in new window or tab >>Mixed Adenoneuroendocrine Carcinomas of the Gastrointestinal Tract: Targeted Next-Generation Sequencing Suggests a Monoclonal Origin of the Two Components
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2014 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 100, no 4, p. 310-316Article in journal (Refereed) Published
Abstract [en]

Background: Mixed adenoneuroendocrine carcinomas (MANECs) of the gastrointestinal tract are rare neoplasms characterized by coexisting exocrine and neuroendocrine neoplastic components. MANECs' histogenetic classification and molecular characterization remain unclear, significantly affecting the identification of innovative therapeutic options for these tumors. Methods: The exocrine and neuroendocrine components of 6 gastrointestinal MANECs were microdissected and subjected to the simultaneous mutation assessment in selected regions of 54 cancer-associated genes using Ion Torrent semiconductor-based next-generation sequencing. Sanger sequencing and immunohistochemistry were used as validation of the mutational status. Results: A total of 20 driver gene somatic mutations were observed among the 12 neoplastic components investigated. In 11 of 12 (91.7%) samples, at least one mutation was detected; 7 samples (58.3%) were found to have multiple mutations. TP53 gene mutations were the most frequent genetic alterations observed in the series, occurring in 11/12 samples (91.7%). Somatic mutations in other genes were detected at lower frequencies: ATM, CTNNB1, ERBB4, JAK3, KDR, KRAS, RB1. Conclusions: Five of the 6 MANECs presented an overlapping mutational profile in both components, suggesting a monoclonal origin of the two MANEC components.

Keywords
Mixed adenoneuroendocrine carcinomas, Next-generation sequencing, WHO 2010 classification, Gastrointestinal tract
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-247355 (URN)10.1159/000369071 (DOI)000349231600006 ()25342539 (PubMedID)
Available from: 2015-03-20 Created: 2015-03-17 Last updated: 2018-01-11Bibliographically approved
Beyder, A., Strege, P., Rainey, J., Bernard, C., Giandomenico, V., Kashyap, P. & Farrugia, G. (2014). Shear sensitivity of the voltage-gated sodium selective ion channels (NaV) in the neuroendocrine cell line QGP-1. Neurogastroenterology and Motility, 26(S1), 26-26
Open this publication in new window or tab >>Shear sensitivity of the voltage-gated sodium selective ion channels (NaV) in the neuroendocrine cell line QGP-1
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2014 (English)In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 26, no S1, p. 26-26Article in journal, Meeting abstract (Other academic) Published
National Category
Gastroenterology and Hepatology Neurosciences
Identifiers
urn:nbn:se:uu:diva-235024 (URN)000341818200077 ()
Available from: 2014-10-30 Created: 2014-10-28 Last updated: 2018-01-11Bibliographically approved
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