Mohamed Bentires-Alj

Transcription

1 San Antonio Breast Cancer Symposium, December 6-10, 2016 Mohamed Bentires-Alj Professor of experimental surgical oncology Department of Biomedicine University of Basel University Hospital Basel This presenta,on is the intellectual property of the author/presenter. Contact them at for permission to reprint and/or distribute

2 This presenta,on is the intellectual property of the author/presenter. Contact them at for permission to reprint and/or distribute Normal and neoplastic stem cells Genomic/proteomic landscape of breast cancer and novel targets Mechanisms of metastasis

3 This presenta,on is the intellectual property of the author/presenter. Contact them at for permission to reprint and/or distribute Normal and neoplastic stem cells Questions How is the mammary cell hierarchy organized? What mechanisms are involved in cell fate determination? What are the effects of the tumor cell-of-origin on heterogeneity, subtype, and aggressiveness of breast cancer? What are the therapeutic implications?

4 Normal mammary gland hierarchy This presenta,on is the intellectual property of the author/presenter. Contact them at for permission to reprint and/or distribute

5 Two methods: 1- Statistical analysis of multicolor lineage tracing 2- Lineage tracing at saturation to assess the fate of ALL SCs within a given lineage and the flux of cells between different lineages GENES & DEVELOPMENT 30: (2016)

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7 This presenta,on is the intellectual property of the author/presenter. Contact them at for permission to reprint and/or distribute Normal mammary gland hierarchy Therapeutic implications

8 NATURE MEDICINE VOLUME 22 NUMBER 8 AUGUST 2016

9 Model of RANKL activation of progenitor cells MaSC (BRCA1 mut/+ ) Luminal progenitor cells Basal-like tumour HR+ RANK HR RANK+ Responder cell Hormone sensor cell RANKL RANKL inhibitor Progesterone Myoepithelial cell Alveolar cell HR HR+ Ductal cells Nolan et al Nature Med 2016

10 RANK is expressed in luminal progenitors cells **** Stroma Basal/MS 102 Stroma Basal/MS CD49f LP ML LP EpCAM EpCAM ML Stroma Basal/MS Basal/MS Stroma CD49f CD49f RANK RANK LP BRCA1 100 A1mut/+5 10 LP RANK Isotype RANK Isotype RANK RANK mut/+ Basal/MS 100 Basal/MS RANK RANK p < CD49f A1mut/ Basal/MS WT BRCA1 (n = 33) (n = 22) RANK RANK Prominent RANK expression in progenitors from BRCA1 mutation carriers B R C A 2m ut at ed LP B R C A 1m ut at ed ML RANK Isotype RANK Isotype W ild -t yp e LP LP Basal/MS % RANK positive LP cells 100 ML % of%max of Max LP % of%max of Max EpCAM EpCAM -type5 10 (p < ) Normal (wildtype) -type

11 RANKL is required for progesterone-induced proliferation b BRCA1mut/+ Prog + Dmab Ki % KI67+ cells within ducts Prog % KI67+ cells within ducts Vehicle b * * * EtOH Prog Prog + EtOH Dmab Prog Prog + * 4 2 mut/+ BRCA1 0 WT BRCA1mut/+ WT Data represents mean ± s.e.m for n = 5 patient samples. *p < 0.05 c within ducts 12 * * Treatment with the RANKL inhibitor Denosumab in 3D breast organoids from prevehicle 10 neoplastic BRCA1mut/+ tissue Prog attenuated progesterone-evoked proliferation 8 Prog + Dmab

12 RANKL inhibition delays tumor development in mouse models Tumour-free survival (%) *** 100 Vehicle OPG-Fc Days (post-surgery) Vehicle OPG-Fc H & E Tumor onset delayed in mice treated with the RANKL inhibitor OPG-Fc (p = ) Median tumor onset not reached in OPG-Fc group, 6/17 (35%) mice had tumors at experimental endpoint Dramatically reduced hyperplasia in OPG-Fc treated mice at endpoint Nolan et al Nature Med 2016

13 A targetable pathway in the putative cell-of-origin population in BRCA1-mutation carriers MaSC (BRCA1 mut/+ ) Luminal progenitor cells Basal-like tumour HR+ RANK HR RANK+ Responder cell Hormone sensor cell RANKL RANKL inhibitor Progesterone Myoepithelial cell Alveolar cell HR HR+ Ductal cells Nolan et al Nature Med 2016

14 Cell Stem Cell 19, 52 65, July 7, 2016

15 Normal and neoplastic stem cells This presenta,on is the intellectual property of the author/presenter. Contact them at for permission to reprint and/or distribute

16 Science 30 SEPTEMBER 2016 VOL 353 ISSUE 6307

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18 Science 4 MARCH 2016 VOL 351 ISSUE 6277

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20 This presenta,on is the intellectual property of the author/presenter. Contact them at for permission to reprint and/or distribute Genomic/proteomic landscape of BC and novel targets Questions What are the functional genomic landscape and the repertoire of cancer genes in breast cancer (primary and metastases)? What is the effect of genetic alterations on the proteomic landscape of breast cancer? What are breast cancer vulnerabilities? Can one target epigenome regulating factors (BRD4?) and how does resistance develop? How one can target TNBC?

21 Nature 2 JUNE 2016 VOL 534

22 Cell 164, , January 14, 2016

23 N&V J. Settleman 21 JANUARY 2016 VOL 529 NATURE 289

24 Cell 164, , January 14, 2016

25 Nature 21 JANUARY 2016 VOL 52 N&V J. Settleman 21 JANUARY 2016 VOL 529 NATURE 289

26 Potent inhibitory effects of BET bromodomain inhibitors in TNBC

27 Development of specific resistance to BBI in TNBC

28 BBI-resistance is associated with increased binding of BRD4 to MED1, independently of the bromodomains (resistant to JQ1) pbrd4 binds MED1 more efficiently than BRD4

29 Nature 21 JANUARY 2016 VOL 52 N&V J. Settleman 21 JANUARY 2016 VOL 529 NATURE 289

30 Nature Medicine VOLUME 22 NUMBER 11 NOVEMBER 2016 Nature Medicine VOLUME 22 NUMBER 11 NOVEMBER 2016

31 Mechanisms of metastasis Questions What are the cell autonomous mechanisms of metastasis? What regulates prometasta,c proteins? What mediates mul,-organ site metasta,c reac,va,on? How do metasta,c cells evade innate immunity? What are the non-cell autonomous mechanisms of metastasis? How do neutrophils contribute to cancer metastasis? This presenta,on is the intellectual property of the author/presenter. Contact them at for permission to reprint and/or distribute

32 Cell 165, , June 2, 2016

33 Cell 165, 45 60, March 24, 2016

34 Nature 17 DECEMBER 2015 VO L 5 Cancer Discov; 6(6); (2016)

35 Cell 166, 47 62, June 30, 2016

36 Nature 26 MAY 2016 VOL 533