Molecular and morphological changes induced by ivosidenib correlate with efficacy in mutant-IDH1 cholangiocarcinoma

被引：20

作者：

Aguado-Fraile, Elia ^{[1
]}

Tassinari, Ania ^{[1
]}

Ishii, Yuko ^{[1
]}

Sigel, Carlie ^{[2
]}

Lowery, Maeve A. ^{[3
]}

Goyal, Lipika ^{[4
]}

Gliser, Camelia ^{[1
]}

Jiang, Liewen ^{[1
]}

Pandya, Shuchi S. ^{[1
]}

Wu, Bin ^{[1
]}

Bardeesy, Nabeel ^{[4
]}

Choe, Sung ^{[1
]}

Deshpande, Vikram ^{[4
,5
]}

机构：

[1] Agios Pharmaceut Inc, Cambridge, MA 02139 USA

[2] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[3] Trinity Coll Dublin, Trinity St James Canc Inst, Dublin D02, Ireland

[4] Harvard Med Sch, Massachusetts Gen Hosp, Canc Ctr, Dept Med, Boston, MA 02114 USA

[5] Harvard Med Sch, Massachusetts Gen Hosp, Canc Ctr, Dept Pathol, Boston, MA 02114 USA

来源：

FUTURE ONCOLOGY | 2021年 / 17卷 / 16期

关键词：

cholangiocarcinoma; drug mechanisms; gastrointestinal cancers; genetic profiling; hepatic differentiation; isocitrate dehydrogenase; ivosidenib; tumor biopsy; SET ENRICHMENT ANALYSIS; ONCOMETABOLITE; 2-HYDROXYGLUTARATE; INTRAHEPATIC CHOLANGIOCARCINOMAS; GENE-EXPRESSION; IDH MUTATION; DIFFERENTIATION; (R)-2-HYDROXYGLUTARATE; REGENERATION; HEPATOCYTES; IDH1-MUTANT;

D O I：

10.2217/fon-2020-1274

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: IDH1 mutations occur in approximately 13% of intrahepatic cholangiocarcinomas (IHCCs). The oral, targeted, mutant IDH1 (mIDH1) inhibitor ivosidenib (AG-120) suppresses production of the oncometabolite D-2-hydroxyglutarate, promoting disease stabilization and improved progression-free survival (PFS) in mIDH1 IHCC. Materials & methods: Harnessing matched baseline and on-treatment biopsies, we investigate the potential mechanisms underlying ivosidenib's efficacy. Results: mIDH1 inhibition leads to decreased cytoplasm and expression of hepatocyte lineage markers in patients with prolonged PFS. These findings are accompanied by downregulation of biliary fate, cell cycle progression and AKT pathway activity. Conclusion: Ivosidenib stimulates a hepatocyte differentiation program in mIDH1 IHCC, a phenotype associated with clinical benefit. mIDH1 inhibition could be a paradigm for differentiation-based therapy in solid tumors.

引用

页码：2057 / 2074

页数：18

共 84 条

[1] Ivosidenib in IDH1-mutant, chemotherapy-refractory Croatia& cholangiocarcinoma (ClarlDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study [J].

Abou-Alfa, Ghassan K. ;

Macarulla, Teresa ;

Javle, Milind M. ;

Kelley, Robin K. ;

Lubner, Sam J. ;

Adeva, Jorge ;

Cleary, James M. ;

Catenacci, Daniel V. ;

Borad, Mitesh J. ;

Bridgewater, John ;

Harris, William P. ;

Murphy, Adrian G. ;

Oh, Do-Youn ;

Whisenant, Jonathan ;

Lowery, Maeve A. ;

Goyal, Lipika ;

Shroff, Rachna T. ;

El-Khoueiry, Anthony B. ;

Fan, Bin ;

Wu, Bin ;

Chamberlain, Christina X. ;

Jiang, Liewen ;

Gliser, Camelia ;

Pandya, Shuchi S. ;

Valle, Juan W. ;

Zhu, Andrew X. .

LANCET ONCOLOGY, 2020, 21 (06) :796-807

[2] A human liver cell atlas reveals heterogeneity and epithelial progenitors [J].

Aizarani, Nadim ;

Saviano, Antonio ;

Sagar ;

Mailly, Laurent ;

Durand, Sarah ;

Herman, Josip S. ;

Pessaux, Patrick ;

Baumert, Thomas F. ;

Gruen, Dominic .

NATURE, 2019, 572 (7768) :199-204

[3] Dichotomy in intrahepatic cholangiocarcinomas based on histologic similarities to hilar cholangiocarcinomas [J].

Akita, Masayuki ;

Fujikura, Kohei ;

Ajiki, Tetsuo ;

Fukumoto, Takumi ;

Otani, Kyoko ;

Azuma, Takeshi ;

Itoh, Tomoo ;

Ku, Yonson ;

Zen, Yoh .

MODERN PATHOLOGY, 2017, 30 (07) :986-997

[4] Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response [J].

Amatangelo, Michael D. ;

Quek, Lynn ;

Shih, Alan ;

Stein, Eytan M. ;

Roshal, Mikhail ;

David, Muriel D. ;

Marteyn, Benoit ;

Farnoud, Noushin Rahnamay ;

de Botton, Stephane ;

Bernard, Olivier A. ;

Wu, Bin ;

Yen, Katharine E. ;

Tallman, Martin S. ;

Papaemmanuil, Elli ;

Penard-Lacronique, Virginie ;

Thakurta, Anjan ;

Vyas, Paresh ;

Levine, Ross L. .

BLOOD, 2017, 130 (06) :732-741

[5] A Roadmap for Human Liver Differentiation from Pluripotent Stem Cells [J].

Ang, Lay Teng ;

Tan, Antson Kiat Yee ;

Autio, Matias I. ;

Goh, Su Hua ;

Choo, Siew Hua ;

Lee, Kian Leong ;

Tan, Jianmin ;

Pan, Bangfen ;

Lee, Jane Jia Hui ;

Lum, Jen Jen ;

Lim, Christina Ying Yan ;

Yeo, Isabelle Kai Xin ;

Wong, Chloe Jin Yee ;

Liu, Min ;

Oh, Jueween Ling Li ;

Chia, Cheryl Pei Lynn ;

Loh, Chet Hong ;

Chen, Angela ;

Chen, Qingfeng ;

Weissman, Irving L. ;

Loh, Kyle M. ;

Lim, Bing .

CELL REPORTS, 2018, 22 (08) :2190-2205

[6]

Bates, 2019, R PROJECT STAT COMPU

[7] Correlation of immune phenotype with IDH mutation in diffuse glioma [J].

Berghoff, Anna Sophie ;

Kiesel, Barbara ;

Widhalm, Georg ;

Wilhelm, Dorothee ;

Rajky, Orsolya ;

Kurscheid, Sebastian ;

Kresl, Philip ;

Woehrer, Adelheid ;

Marosi, Christine ;

Hegi, Monika E. ;

Preusser, Matthias .

NEURO-ONCOLOGY, 2017, 19 (11) :1460-1468

[8] Frequent Mutation of Isocitrate Dehydrogenase (IDH)1 and IDH2 in Cholangiocarcinoma Identified Through Broad-Based Tumor Genotyping [J].

Borger, Darrell R. ;

Tanabe, Kenneth K. ;

Fan, Kenneth C. ;

Lopez, Hector U. ;

Fantin, Valeria R. ;

Straley, Kimberly S. ;

Schenkein, David P. ;

Hezel, Aram F. ;

Ancukiewicz, Marek ;

Liebman, Hannah M. ;

Kwak, Eunice L. ;

Clark, Jeffrey W. ;

Ryan, David P. ;

Deshpande, Vikram ;

Dias-Santagata, Dora ;

Ellisen, Leif W. ;

Zhu, Andrew X. ;

Iafrate, A. John .

ONCOLOGIST, 2012, 17 (01) :72-79

[9] Frequency and prognostic significance of isocitrate dehydrogenase 1 mutations in cholangiocarcinoma: a systematic literature review [J].

Boscoe, Audra N. ;

Rolland, Catherine ;

Kelley, Robin Kate .

JOURNAL OF GASTROINTESTINAL ONCOLOGY, 2019, 10 (04) :751-+

[10] Cholangiolar pattern and albumin in situ hybridisation enable a diagnosis of intrahepatic cholangiocarcinoma [J].

Brackett, Diane G. ;

Neyaz, Azfar ;

Arora, Kshitij ;

Masia, Ricard ;

Mattia, Anthony ;

Zukerberg, Lawerence ;

Misdraji, Joseph ;

Goyal, Lipika ;

Zhu, Andrew X. ;

Ferrone, Cristina R. ;

Yilmaz, Omer H. ;

Deshpande, Vikram .

JOURNAL OF CLINICAL PATHOLOGY, 2020, 73 (01) :23-29

← 1 2 3 4 5 6 7 8 9 →