Lombardi Cancer Center Georgetown University Washington, DC

Transcription

1 Lombardi Cancer Center Georgetown University Washington, DC

2 Lombardi Cancer Center Georgetown University Washington, DC microrna and other nucleic acids analysis in liquid biopsies Anton Wellstein World CDx Boston, Sept 8-11, 2015

3 Disclosures: Inventor on Georgetown University filed patents related to the topic Member of the Scientific Advisory Board of Indivumed Inc.

4 DNA mrnas + 3 x 10 4 genes mrnas Proteins > modified Metabolites + 5 x 10 3 Phenotype

5 DNA mrnas + 3 x 10 4 genes mrnas micrornas Proteins > modified Metabolites + 5 x 10 3 Phenotype

6 microrna = mir 1993 two reports that a small (= micro) RNA modulates expression of a protein in the nematode C. elegans 2002 initial reports of a potential role of micrornas in cancer

7 mirna genes: Human 1,424 Mouse 720 Zebrafish 358 Berezikov Nat Rev Genetics 2011

8 micrornas microrna expression patterns in normal vs cancer tissues Colon Pros Brst ColonCa ProCa BrCa normal tissues cancer tissues Lu et al. Nature 435:834, 2005

9 microrna versus mrna expression patterns in normal human tissues ( 89 different epithelial tissues) Lu et al. Nature 435:834, 2005

10 2008

11 2008

12 Nature Methods 2011

13 2007; Vol. 9:654-9

14 2011; Vol. 13: ; Vol. 9:654-9

15 What is in a liquid biopsy? plasma buffy coat (leukocytes) erythrocytes, platelets cell-free: DNA microrna proteins metabolites Vietsch et al Pancreat Disord Ther 5:22; 2015

16 What is in a liquid biopsy? plasma buffy coat (leukocytes) erythrocytes, platelets cell-free: DNA microrna proteins metabolites + cancer cells cancer cells stroma Vietsch et al Pancreat Disord Ther 5:22; 2015

17 Detect metastatic disease in early stage cancer? plasma buffy coat (leukocytes) erythrocytes, platelets cell-free: DNA microrna proteins metabolites + cancer cells cancer cells stroma Vietsch et al Pancreat Disord Ther 5:22; 2015

18 serum before the initial surgery of stage I/II colon cancer Shivapurkar et al PLoS One 2014 e84686

19 Shivapurkar et al PLoS One 2014 e84686

20 The usual suspects approach... Shivapurkar et al PLoS One 2014 e84686

21 B Genome wide mir serum profile one patient with one without recurrent disease RC NRC hsa-mi-378 hsa-mir-92a hsa-mir-185 hsa-mir-1979 hsa-mir-25 hsa-mir-1977 hsa-mir-320a hsa-mir-1246 hsa-mir-320b hsa-mir-1974 hsa-mir-424 hsa-mir-374a hsa-mir-486-5p hsa-mir-223 hsa-mir-1274b hsa-mir-20b hsa-mir-126 hsa-mir-195 hsa-mir-451 hsa-mir-16 hsa-mir-103 hsa-mir-17 hsa-mir-140-3p hsa-mir-191 hsa-let-7c hsa-mir-15a hsa-mir-135a hsa-mir-1290 hsa-mir-1307 hsa-mir-30e hsa-mir-376a hsa-mir-26b hsa-mir-425 hsa-mir-29c hsa-mir-106b hsa-mir-107 hsa-mir-23b hsa-mir-494 hsa-mir-92b hsa-mir-192 hsa-mir-151-3p hsa-mir-320c hsa-mir-342-5p hsa-mir-122 hsa-mir-320d hsa-mir-30d hsa-mir-142-3p hsa-mir-150 hsa-mir-1975 hsa-mir-106a hsa-mir-19a hsa-mir-19b hsa-mir-374b hsa-mir-30a hsa-mir-135b hsa-mir-1274a hsa-mir-93 hsa-let-7b hsa-mir-15b hsa-mir-532-3p hsa-mir-221 hsa-mir-125a-5p hsa-mir-615-5p hsa-mir-1260 hsa-mir-596 hsa-mir-1287 hsa-mir-1915 hsa-mir-23a hsa-mir-21 hsa-mir-101 Shivapurkar et al PLoS One 2014 e84686

22 Shivapurkar et al PLoS One 2014 e84686

23 Shivapurkar et al PLoS One 2014 e84686

24 Shivapurkar et al PLoS One 2014 e84686

25 Shivapurkar et al PLoS One 2014 e84686

26 Monitor treatment response? plasma buffy coat (leukocytes) erythrocytes, platelets cell-free: DNA microrna proteins metabolites + cancer cells cancer cells stroma Vietsch et al Pancreat Disord Ther 5:22; 2015

27 LaConti et al PLoS One e20687

28 Analysis of micrornas during PanCa progression ( Kras mutant model ) micrornas qrt-pcr animal model P48Cre x LSL/KrasG12D patients pancreatic cancer initiation and progression

29 Analysis of micrornas during PanCa progression ( Kras mutant model ) LaConti et al PLoS One e20687

30 Analysis of micrornas during PanCa progression ( Kras mutant model ) LaConti et al PLoS One e20687

31 micrornas in the circulation & gemcitabine treatment mouse mutant K-ras Panc Ca model blood samples diagnosis profile treatment blood samples response profile micrornas

32 micrornas in the circulation & gemcitabine treatment mouse mutant K-ras Panc Ca model LaConti et al PLoS One e20687

33 micrornas in the circulation & gemcitabine treatment mouse mutant K-ras Panc Ca model LaConti et al PLoS One e20687

34 Shivapurkar et al Int J Colorectal Dis

35 Circulating mir patterns in patients with pancreatic cancer treatment with capecitabine & lapatinib different times of treatment ( n=8 ) Tian, Shivapurkar et al Oncology Letters in press

36 Circulating mir patterns in patients with pancreatic cancer treatment with capecitabine & lapatinib different times of treatment ( n=8 ) Tian, Shivapurkar et al Oncology Letters in press

37 Evolutionary selection of cancer cell populations with distinct drivers of malignant progression

38 Evolutionary selection of cancer cell populations with distinct drivers of malignant progression from: Yates, Nature Rev Genetics 2012

39 Monitor the evolutionary selection of cancer cell populations / treatment response plasma buffy coat (leukocytes) erythrocytes, platelets cell-free: DNA microrna proteins metabolites + cancer cells cancer cells stroma Vietsch et al Pancreat Disord Ther 5:22; 2015

40 Food for Thought: Bad Tumor Markers Are Equal to Bad Drugs Daniel F. Hayes, MD U Mich, Ann Arbor

41 Ivana Peran Eveline Vietsch Anne Deslattes Joe LaConti Anna T Riegel Narayan Shivapurkar John Marshall Louis Weiner Claudine Isaacs Ruth A He Hartmut Juhl, Indivumed Hamburg, Germany Casper van Eijck, Erasmus U Rotterdam, Netherlands

42 Ivana Peran Eveline Vietsch