Imperial College London

DrSilviaOttaviani

Faculty of MedicineDepartment of Surgery & Cancer

Honorary Lecturer
 
 
 
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Contact

 

+44 (0)20 7594 2823silvia.ottaviani

 
 
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Location

 

ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

73 results found

Patel H, Periyasamy M, Sava GP, Bondke A, Slafer BW, Kroll SHB, Barbazanges M, Starkey R, Ottaviani S, Harrod A, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes RC, Ali Set al., 2023, Supplementary Figure S2. from ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

<jats:p>&lt;p&gt;Analysis of ICEC0942 treatment of MCF7 cells.&lt;/p&gt;</jats:p>

Other

Patel H, Periyasamy M, Sava GP, Bondke A, Slafer BW, Kroll SHB, Barbazanges M, Starkey R, Ottaviani S, Harrod A, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes RC, Ali Set al., 2023, Data from ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

<jats:p>&lt;div&gt;Abstract&lt;p&gt;Recent reports indicate that some cancer types are especially sensitive to transcription inhibition, suggesting that targeting the transcriptional machinery provides new approaches to cancer treatment. Cyclin-dependent kinase (CDK)7 is necessary for transcription, and acts by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (PolII) to enable transcription initiation. CDK7 additionally regulates the activities of a number of transcription factors, including estrogen receptor (ER)-α. Here we describe a new, orally bioavailable CDK7 inhibitor, ICEC0942. It selectively inhibits CDK7, with an IC&lt;sub&gt;50&lt;/sub&gt; of 40 nmol/L; IC&lt;sub&gt;50&lt;/sub&gt; values for CDK1, CDK2, CDK5, and CDK9 were 45-, 15-, 230-, and 30-fold higher. &lt;i&gt;In vitro&lt;/i&gt; studies show that a wide range of cancer types are sensitive to CDK7 inhibition with GI&lt;sub&gt;50&lt;/sub&gt; values ranging between 0.2 and 0.3 μmol/L. In xenografts of both breast and colorectal cancers, the drug has substantial antitumor effects. In addition, combination therapy with tamoxifen showed complete growth arrest of ER-positive tumor xenografts. Our findings reveal that CDK7 inhibition provides a new approach, especially for ER-positive breast cancer and identify ICEC0942 as a prototype drug with potential utility as a single agent or in combination with hormone therapies for breast cancer. ICEC0942 may also be effective in other cancers that display characteristics of transcription factor addiction, such as acute leukaemia and small-cell lung cancer. &lt;i&gt;Mol Cancer Ther; 17(6); 1156–66. ©2018 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;</jats:p>

Other

Patel H, Periyasamy M, Sava GP, Bondke A, Slafer BW, Kroll SHB, Barbazanges M, Starkey R, Ottaviani S, Harrod A, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes RC, Ali Set al., 2023, Supplementary Figure S2. from ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

<jats:p>&lt;p&gt;Analysis of ICEC0942 treatment of MCF7 cells.&lt;/p&gt;</jats:p>

Other

Patel H, Periyasamy M, Sava GP, Bondke A, Slafer BW, Kroll SHB, Barbazanges M, Starkey R, Ottaviani S, Harrod A, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes RC, Ali Set al., 2023, Supplementary Figure S1. from ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

<jats:p>&lt;p&gt;In vitro kinase assays demonstrate selectivity of ICEC0942 for CDK7.&lt;/p&gt;</jats:p>

Other

Patel H, Periyasamy M, Sava GP, Bondke A, Slafer BW, Kroll SHB, Barbazanges M, Starkey R, Ottaviani S, Harrod A, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes RC, Ali Set al., 2023, Supplementary Figure S4. from ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

<jats:p>&lt;p&gt;ADME analysis, oral bioavailability and distribution of ICEC0942.&lt;/p&gt;</jats:p>

Other

Patel H, Periyasamy M, Sava GP, Bondke A, Slafer BW, Kroll SHB, Barbazanges M, Starkey R, Ottaviani S, Harrod A, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes RC, Ali Set al., 2023, Supplementary Figure S1. from ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

<jats:p>&lt;p&gt;In vitro kinase assays demonstrate selectivity of ICEC0942 for CDK7.&lt;/p&gt;</jats:p>

Other

Patel H, Periyasamy M, Sava GP, Bondke A, Slafer BW, Kroll SHB, Barbazanges M, Starkey R, Ottaviani S, Harrod A, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes RC, Ali Set al., 2023, Supplementary Figure S4. from ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

<jats:p>&lt;p&gt;ADME analysis, oral bioavailability and distribution of ICEC0942.&lt;/p&gt;</jats:p>

Other

Patel H, Periyasamy M, Sava GP, Bondke A, Slafer BW, Kroll SHB, Barbazanges M, Starkey R, Ottaviani S, Harrod A, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes RC, Ali Set al., 2023, Supplementary Figure S6. from ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

<jats:p>&lt;p&gt;Pharmacokinetic determination of ICEC0942 plasma and tumor concentrations at different doses and over time.&lt;/p&gt;</jats:p>

Other

Patel H, Periyasamy M, Sava GP, Bondke A, Slafer BW, Kroll SHB, Barbazanges M, Starkey R, Ottaviani S, Harrod A, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes RC, Ali Set al., 2023, Supplementary Information from ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

<jats:p>&lt;p&gt;Figure legends for supplementary Figures&lt;/p&gt;</jats:p>

Other

Patel H, Periyasamy M, Sava GP, Bondke A, Slafer BW, Kroll SHB, Barbazanges M, Starkey R, Ottaviani S, Harrod A, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes RC, Ali Set al., 2023, Supplementary Figure S3. from ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

<jats:p>&lt;p&gt;Cell Cycle analysis of MCF7 cells treated with ICEC0942.&lt;/p&gt;</jats:p>

Other

Patel H, Periyasamy M, Sava GP, Bondke A, Slafer BW, Kroll SHB, Barbazanges M, Starkey R, Ottaviani S, Harrod A, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes RC, Ali Set al., 2023, Supplementary Figure S6. from ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

<jats:p>&lt;p&gt;Pharmacokinetic determination of ICEC0942 plasma and tumor concentrations at different doses and over time.&lt;/p&gt;</jats:p>

Other

Patel H, Periyasamy M, Sava GP, Bondke A, Slafer BW, Kroll SHB, Barbazanges M, Starkey R, Ottaviani S, Harrod A, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes RC, Ali Set al., 2023, Supplementary Figure S5. from ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

<jats:p>&lt;p&gt;Oral administration of ICEC0942 inhibits cyclin-dependent kinase substrate phosphorylation in mouse peripheral blood mononuclear cells.&lt;/p&gt;</jats:p>

Other

Patel H, Periyasamy M, Sava GP, Bondke A, Slafer BW, Kroll SHB, Barbazanges M, Starkey R, Ottaviani S, Harrod A, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes RC, Ali Set al., 2023, Supplementary Figure S3. from ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

<jats:p>&lt;p&gt;Cell Cycle analysis of MCF7 cells treated with ICEC0942.&lt;/p&gt;</jats:p>

Other

Patel H, Periyasamy M, Sava GP, Bondke A, Slafer BW, Kroll SHB, Barbazanges M, Starkey R, Ottaviani S, Harrod A, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes RC, Ali Set al., 2023, Supplementary Figure S5. from ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

<jats:p>&lt;p&gt;Oral administration of ICEC0942 inhibits cyclin-dependent kinase substrate phosphorylation in mouse peripheral blood mononuclear cells.&lt;/p&gt;</jats:p>

Other

Patel H, Periyasamy M, Sava GP, Bondke A, Slafer BW, Kroll SHB, Barbazanges M, Starkey R, Ottaviani S, Harrod A, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes RC, Ali Set al., 2023, Supplementary Information from ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

<jats:p>&lt;p&gt;Figure legends for supplementary Figures&lt;/p&gt;</jats:p>

Other

Patel H, Periyasamy M, Sava GP, Bondke A, Slafer BW, Kroll SHB, Barbazanges M, Starkey R, Ottaviani S, Harrod A, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes RC, Ali Set al., 2023, Supplementary Figure S7. from ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

<jats:p>&lt;p&gt;Combinatorial inhibition of breast cancer cells with a combination of ICEC0942 and anti-estrogens.&lt;/p&gt;</jats:p>

Other

Patel H, Periyasamy M, Sava GP, Bondke A, Slafer BW, Kroll SHB, Barbazanges M, Starkey R, Ottaviani S, Harrod A, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes RC, Ali Set al., 2023, Supplementary Figure S7. from ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

<jats:p>&lt;p&gt;Combinatorial inhibition of breast cancer cells with a combination of ICEC0942 and anti-estrogens.&lt;/p&gt;</jats:p>

Other

Patel H, Periyasamy M, Sava GP, Bondke A, Slafer BW, Kroll SHB, Barbazanges M, Starkey R, Ottaviani S, Harrod A, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes RC, Ali Set al., 2023, Data from ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

<jats:p>&lt;div&gt;Abstract&lt;p&gt;Recent reports indicate that some cancer types are especially sensitive to transcription inhibition, suggesting that targeting the transcriptional machinery provides new approaches to cancer treatment. Cyclin-dependent kinase (CDK)7 is necessary for transcription, and acts by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (PolII) to enable transcription initiation. CDK7 additionally regulates the activities of a number of transcription factors, including estrogen receptor (ER)-α. Here we describe a new, orally bioavailable CDK7 inhibitor, ICEC0942. It selectively inhibits CDK7, with an IC&lt;sub&gt;50&lt;/sub&gt; of 40 nmol/L; IC&lt;sub&gt;50&lt;/sub&gt; values for CDK1, CDK2, CDK5, and CDK9 were 45-, 15-, 230-, and 30-fold higher. &lt;i&gt;In vitro&lt;/i&gt; studies show that a wide range of cancer types are sensitive to CDK7 inhibition with GI&lt;sub&gt;50&lt;/sub&gt; values ranging between 0.2 and 0.3 μmol/L. In xenografts of both breast and colorectal cancers, the drug has substantial antitumor effects. In addition, combination therapy with tamoxifen showed complete growth arrest of ER-positive tumor xenografts. Our findings reveal that CDK7 inhibition provides a new approach, especially for ER-positive breast cancer and identify ICEC0942 as a prototype drug with potential utility as a single agent or in combination with hormone therapies for breast cancer. ICEC0942 may also be effective in other cancers that display characteristics of transcription factor addiction, such as acute leukaemia and small-cell lung cancer. &lt;i&gt;Mol Cancer Ther; 17(6); 1156–66. ©2018 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;</jats:p>

Other

Zagorac S, de Giorgio A, Dabrowska A, Kalisz M, Casas-Vila N, Cathcart P, Yiu A, Ottaviani S, Degani N, Lombardo Y, Tweedie A, Nissan T, Vance KW, Ulitsky I, Stebbing J, Castellano Let al., 2023, Table S2 from SCIRT lncRNA Restrains Tumorigenesis by Opposing Transcriptional Programs of Tumor-Initiating Cells

<jats:p>&lt;p&gt;Table S2. Pathway enrichment analyses for genes up- and down-regulated after growing 16h or 5d in spheres&lt;/p&gt;</jats:p>

Other

Zagorac S, de Giorgio A, Dabrowska A, Kalisz M, Casas-Vila N, Cathcart P, Yiu A, Ottaviani S, Degani N, Lombardo Y, Tweedie A, Nissan T, Vance KW, Ulitsky I, Stebbing J, Castellano Let al., 2023, Data from SCIRT lncRNA Restrains Tumorigenesis by Opposing Transcriptional Programs of Tumor-Initiating Cells

<jats:p>&lt;div&gt;Abstract&lt;p&gt;In many tumors, cells transition reversibly between slow-proliferating tumor-initiating cells (TIC) and their differentiated, faster-growing progeny. Yet, how transcriptional regulation of cell-cycle and self-renewal genes is orchestrated during these conversions remains unclear. In this study, we show that as breast TIC form, a decrease in cell-cycle gene expression and increase in self-renewal gene expression are coregulated by SOX2 and EZH2, which colocalize at CpG islands. This pattern was negatively controlled by a novel long noncoding RNA (lncRNA) that we named Stem Cell Inhibitory RNA Transcript (SCIRT), which was markedly upregulated in tumorspheres but colocalized with and counteracted EZH2 and SOX2 during cell-cycle and self-renewal regulation to restrain tumorigenesis. SCIRT specifically interacted with EZH2 to increase EZH2 affinity to FOXM1 without binding the latter. In this manner, SCIRT induced transcription at cell-cycle gene promoters by recruiting FOXM1 through EZH2 to antagonize EZH2-mediated effects at target genes. Conversely, on stemness genes, FOXM1 was absent and SCIRT antagonized EZH2 and SOX2 activity, balancing toward repression. These data suggest that the interaction of an lncRNA with EZH2 can alter the affinity of EZH2 for its protein-binding partners to regulate cancer cell state transitions.&lt;/p&gt;Significance:&lt;p&gt;These findings show that a novel lncRNA SCIRT counteracts breast tumorigenesis by opposing transcriptional networks associated with cell cycle and self-renewal.&lt;/p&gt;&lt;p&gt;&lt;i&gt;See related commentary by Pardini and Dragomir, p. 535&lt;/i&gt;&lt;/p&gt;&lt;/div&gt;</jats:p>

Other

Zagorac S, de Giorgio A, Dabrowska A, Kalisz M, Casas-Vila N, Cathcart P, Yiu A, Ottaviani S, Degani N, Lombardo Y, Tweedie A, Nissan T, Vance KW, Ulitsky I, Stebbing J, Castellano Let al., 2023, Table S3 from SCIRT lncRNA Restrains Tumorigenesis by Opposing Transcriptional Programs of Tumor-Initiating Cells

<jats:p>&lt;p&gt;Differential gene expression DESeq2 analysis for siSCIRT vs siNC using two independent siRNAs against SCIRT (Sheet #1 contains siSCIRT #1 data; Sheet #2 contains siSCIRT #2 data).&lt;/p&gt;</jats:p>

Other

Zagorac S, de Giorgio A, Dabrowska A, Kalisz M, Casas-Vila N, Cathcart P, Yiu A, Ottaviani S, Degani N, Lombardo Y, Tweedie A, Nissan T, Vance KW, Ulitsky I, Stebbing J, Castellano Let al., 2023, Table S5 from SCIRT lncRNA Restrains Tumorigenesis by Opposing Transcriptional Programs of Tumor-Initiating Cells

<jats:p>&lt;p&gt;Differential gene expression DESeq2 analysis for siEZH2 vs siNC.&lt;/p&gt;</jats:p>

Other

Zagorac S, de Giorgio A, Dabrowska A, Kalisz M, Casas-Vila N, Cathcart P, Yiu A, Ottaviani S, Degani N, Lombardo Y, Tweedie A, Nissan T, Vance KW, Ulitsky I, Stebbing J, Castellano Let al., 2023, Table S7 from SCIRT lncRNA Restrains Tumorigenesis by Opposing Transcriptional Programs of Tumor-Initiating Cells

<jats:p>&lt;p&gt;Top 100 gene significantly up-regulated upon siSCIRT treatment (Overlap between siSCIRT #1 and siSCIRT #2). Genes are ranked from the most up-regulated to the least up-regulated.&lt;/p&gt;</jats:p>

Other

Zagorac S, de Giorgio A, Dabrowska A, Kalisz M, Casas-Vila N, Cathcart P, Yiu A, Ottaviani S, Degani N, Lombardo Y, Tweedie A, Nissan T, Vance KW, Ulitsky I, Stebbing J, Castellano Let al., 2023, Table S3 from SCIRT lncRNA Restrains Tumorigenesis by Opposing Transcriptional Programs of Tumor-Initiating Cells

<jats:p>&lt;p&gt;Differential gene expression DESeq2 analysis for siSCIRT vs siNC using two independent siRNAs against SCIRT (Sheet #1 contains siSCIRT #1 data; Sheet #2 contains siSCIRT #2 data).&lt;/p&gt;</jats:p>

Other

Zagorac S, de Giorgio A, Dabrowska A, Kalisz M, Casas-Vila N, Cathcart P, Yiu A, Ottaviani S, Degani N, Lombardo Y, Tweedie A, Nissan T, Vance KW, Ulitsky I, Stebbing J, Castellano Let al., 2023, Table S1 from SCIRT lncRNA Restrains Tumorigenesis by Opposing Transcriptional Programs of Tumor-Initiating Cells

<jats:p>&lt;p&gt;Differential gene expression DESeq2 analysis for 16h Spheres vs Adh (Sheet #1) and 5d Spheres vs Adh&lt;/p&gt;</jats:p>

Other

Zagorac S, de Giorgio A, Dabrowska A, Kalisz M, Casas-Vila N, Cathcart P, Yiu A, Ottaviani S, Degani N, Lombardo Y, Tweedie A, Nissan T, Vance KW, Ulitsky I, Stebbing J, Castellano Let al., 2023, Table S2 from SCIRT lncRNA Restrains Tumorigenesis by Opposing Transcriptional Programs of Tumor-Initiating Cells

<jats:p>&lt;p&gt;Table S2. Pathway enrichment analyses for genes up- and down-regulated after growing 16h or 5d in spheres&lt;/p&gt;</jats:p>

Other

Zagorac S, de Giorgio A, Dabrowska A, Kalisz M, Casas-Vila N, Cathcart P, Yiu A, Ottaviani S, Degani N, Lombardo Y, Tweedie A, Nissan T, Vance KW, Ulitsky I, Stebbing J, Castellano Let al., 2023, Table S5 from SCIRT lncRNA Restrains Tumorigenesis by Opposing Transcriptional Programs of Tumor-Initiating Cells

<jats:p>&lt;p&gt;Differential gene expression DESeq2 analysis for siEZH2 vs siNC.&lt;/p&gt;</jats:p>

Other

Zagorac S, de Giorgio A, Dabrowska A, Kalisz M, Casas-Vila N, Cathcart P, Yiu A, Ottaviani S, Degani N, Lombardo Y, Tweedie A, Nissan T, Vance KW, Ulitsky I, Stebbing J, Castellano Let al., 2023, Table S1 from SCIRT lncRNA Restrains Tumorigenesis by Opposing Transcriptional Programs of Tumor-Initiating Cells

<jats:p>&lt;p&gt;Differential gene expression DESeq2 analysis for 16h Spheres vs Adh (Sheet #1) and 5d Spheres vs Adh&lt;/p&gt;</jats:p>

Other

Zagorac S, de Giorgio A, Dabrowska A, Kalisz M, Casas-Vila N, Cathcart P, Yiu A, Ottaviani S, Degani N, Lombardo Y, Tweedie A, Nissan T, Vance KW, Ulitsky I, Stebbing J, Castellano Let al., 2023, Supplementary Data from SCIRT lncRNA Restrains Tumorigenesis by Opposing Transcriptional Programs of Tumor-Initiating Cells

<jats:p>&lt;p&gt;Supplementary material and methods&lt;/p&gt;</jats:p>

Other

Zagorac S, de Giorgio A, Dabrowska A, Kalisz M, Casas-Vila N, Cathcart P, Yiu A, Ottaviani S, Degani N, Lombardo Y, Tweedie A, Nissan T, Vance KW, Ulitsky I, Stebbing J, Castellano Let al., 2023, Table S8 from SCIRT lncRNA Restrains Tumorigenesis by Opposing Transcriptional Programs of Tumor-Initiating Cells

<jats:p>&lt;p&gt;Sequence of primers used in the study&lt;/p&gt;</jats:p>

Other

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

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