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Third Annual New Frontiers in Urology
Moffitt Cancer Center
James J. Hsieh, M.D. Ph.D.
Associate Member, MSK
The Panoramic View and
Clinical Implications of Large
Scale Kidney Cancer Global
Metabolomics
Histological Subtypes of Kidney Cancer
Hsieh, Tickoo et al
3
Current Signaling Targets in ccRCC
RAS
RAF
MEK
MAPK
HIF1/2
Target Genes
PI3K
AKT
mTORC1
Tumor Cell
Nucleus
HIF-1/2α
PTEN
Everolimus
Temsirolimus
Endothelial Cell
TIE2
Bevacizumab
FGF
PDGF
VEGF Sunitinib, Sorafenib,
Pazopanib, Axitinib
FGFR
PDGFR
VEGFR
Angiogenesis
mTORC2
TSC1/2
S6K
4EBP1
Rheb
HIF-1/2α
VHL
MET
Tumor Microenvironment
1992-2005
Treatment for ccRCC (Past, Now, Future)
Sorafenib
Sunitinib
Temsirolimus
High dose
interleukin-2
2005 2006 2007 2008 2009
Bevacizumab + IFN
Axitinib Interferon- Everolimus
2010
Pazopanib
2012 2014
Nivolumab
2015-2016
Dark Age Modern Age Golden Age
• Ipilimumab etc.
• Precision
• Combination Sequence
• Immunization
• Prevention
• Detection
Hsieh, Aug 2016
Cabozantinib
Single Arm Targeted Therapy 2005-2014
Lenvatinib
Cancer Hallmarks
Hanahan & Weinberg
Cell, 2011, 44, 646
Challenges of Precision Medicine
Layers of Complexity
Pan-Omics of Three Major Kidney Cancer Types
Creighton et al. Cell Reports 2016
Cancer Metabolism:
Blind Men & The Elephant
Nature, 2013
Biochemical Extraction
Metabolyzer™ UHPLC-MS/MS (+ESI)
GC-MS (+EI)
UHPLC-MS/MS (-ESI)
Instrumentation
Biochemical Analysis
Global Metabolomics Platform For Human Biospecimens
Peak Detection
Peak Integration
Library Search RT, Mass, MS/MS
QA/QC
In Collaboration with Metabolon
13
tryptophan 984,812
glutamic acid 23,387
histidine 32,597
leucine 117,683,785
cholesterol 197,866
asparagine 1,245,744
creatinine 127,611
cytidine 721,266
lactate 2,111,697
alpha-keto-glutarate 14,105,654
4-hydroxyphenylacetate 444,817
3-hydroxybutanoic acid 1,639,392
cytosine 106,032
arabinose 778,911
fructose 2,519,658
X-3370 1,101,581
mannose 2,833,397
pyruvate 250,670
uridine 135,807
Cholic acid 26,394,344
allantoin 208,938
isocitrate 5,825,474
heptadecanoic acid 913,112
inosine 1,115,331
isoleucine 452,549
alanine 462,648
threonine 208,938
tyrosine 67,989
lysine 296,740
methionine 49,879
malic acid 156,499
X-3697 46,230
n-hexadecanoic acid 298,590
octadecanoic acid 240,570
trans-4-hydroxyproline 132,151
X-9043 13,989,172
2-deoxyguanosine 5,913,519
3-hydroxyphenylacetate 7,214,406
3-phospho-d-glycerate 8,649,644
Kynurenic acid 468,663
5-s-methyl-5-thioadenosine 14,569,292
(p-Hydroxyphenyl)lactic acid 1,303,643
alphahydroxybenzeneacetic acid 450,807
ornithine 326,949
5-oxoproline 890,753
orotic acid 97,674
palmitoleic acid 4,036,188
pantothenic acid 94,772,385
salicylic acid 379,417
alpha-tocopherol 766,717
citric acid 4,245,654
X-6270 228,209
glyceric acid 8,267,905
histamine 912,667
N-acetyl-L-leucine 45,949
N-acetylneuraminic acid 2,178,243
uric acid 312,025
arginine 364,344
ascorbic acid 584,247
fumaric acid 4,459,712
n-dodecanoate 370,805
glutamine 109,597
serine 321,078
valine 2,241,354
pyridoxal 78,842
urea 437,094
riboflavine 2,520,194
proline 901,738
pyrophosphate 1,045,231
taurine 101,103,133
X-3030 5,726,735
citrulline 1,243,836
biliverdin 420,511
pyridoxamine 218,468
serotonin 5,105,113
gamma-L-glutamyl-L-glutamine 174,652
gamma-L-glutamyl-L-tyrosine 8,854,738
guanosine-5-monophosphate 82,682
3-indoxyl-sulfate 369,207
X-3100 135,999
phosphate 35,095
glycine 6,209,638
nonanate 1,936,241
DL-homocysteine 418,561
L-kynurenine 3,451,095
tartaric acid 631,615
sn-Glycerol-3-phosphate 282,554
carnitine 76,307
2-methylhippuric acid 462,487
3-methyl-2-oxovaleric acid 395,839
4-Guanidinobutanoic acid 73,352,989
4-methyl-2-oxopentanoate 272,564,647
beta-hydroxypyruvic acid 431,358
X-1656 118,271
hippuric acid 7,724,959
ethylmalonic acid 182,320
D-lyxose 267,189
maltose 27,024
S-5-adenosyl-L-methionine 216,405
2-deoxycytidine 1,151,739
L-alpha-glycerophosphorylcholine 992,513
aspartate 6,520,826
p-hydroxybenzaldehyde 106,124
X-1962 147,926
D-sphingosine 289,530
cortodoxone 58,939
DL-indole-3-lactic acid 281,085
gamma-glu-leu 177,587
glycocholic acid 725,542
taurocholic acid 3,281,189
X-10381 231,486
phenylalanine 118,902,022
taurodeoxycholic acid 29,443,151
inositol 146,593
X-10419 554,814
D-glucose 65,293,846
1,5-anhydro-D-glucitol 5,183,545
meso-erythritol 1,151,739
X-3026 992,513
2-hydroxybutyric acid 6,520,826
digalacturonic acid 106,124
3-methyl-2-oxobutyric 147,926
monopalmitin 289,530
1-stearoyl-rac-glycerol 58,939
21-hydroxyprogesterone 147,926
3-hydroxyoctanoic acid 289,530
1-methylguanidine-hydrochloride 58,939
3-hydroxydecanoic acid 281,085
3-indoleacrylic acid 177,587
DL-3-phenyllactic acid 3,281,189
DL-alpha-hydroxyisocaproic acid 231,486
DL-hexanoyl-carnitine 118,902,022
O-acetyl-L-carnitine-hydrochloride 29,443,151
EDTA 992,513
l-aspartyl-l-phenylalanine 6,520,826
Metabolyzer Software
4 5 6 7 8 9 10 11 12 13 14
Time (min)
4.01 14.43
5.84
4.38 10.66
8.46
10.18
11.76 4.55 6.52 6.73 7.74
9.34 11.79
11.03
13.05 9.47 7.50
11.21 5.34 12.89 3.17 13.30
8.01
Mass spectrum
3.17 min
Biochemical Amount
cholesterol 143,789
Database
Of
Standards
cholesterol
Biochemical ID
Automated Biochemical Identification
MSK TKCRP N=138 T/N Global Metabolomics Cohort
Hakimi et al. Cancer Cell 2016
KEGG Metabolic Pathway Analysis (T vs N)
Immunesuppressivemetabolites
5-Hydroxy-L-Tryptophan
Serotonin
5-Hydroxykynurenamine
0.00
0.50
1.00
1.50
NG1G2G3G4
Foldchange
Grade
DDC
Tryptamine Indole-3-acetaldehyde
0.00
0.50
1.00
1.50
N G1 G2 G3 G4
Foldchan
ge
Grade
MAOA
0.00
2.00
4.00
6.00
N G1 G2 G3 G4
Foldchan
ge
Grade
MAOB
0.00
0.50
1.00
1.50
NG1G2G3G4
Foldchan
ge
Grade
DDC
0.00
0.50
1.00
1.50
NG1G2G3G4
Foldchange
Grade
ALDH2
Indolepyruvate
Indoleacetamide
N-Formyl-Kynurenine
IDO
TDO
Immune suppression
0
0.5
1
1.5
N G2 G3 G4
Foldchange
Grade
Indoleacetate
0
0.5
1
1.5
N G2 G3 G4
Foldchange
Grade
Tryptophan
0
1
2
3
N G2 G3 G4
Foldchan
ge
Grade
Indolelactate
0
10
20
N G2 G3 G4
Foldchan
ge
Grade
Kynurenine
0
5
10
N G2 G3 G4
Foldchange
Grade
Quinolinate
H. Wettersten et al. Cancer Research 2015 75, 2542
0.00
0.20
0.40
0.60
0.80
1.00
1.20
N G2 G3 G4
Fold
ch
ange
Grade
L-Tryptophan
Central Carbon Metabolism of ccRCC (Tumor versus Normal)
Hakimi et al. Cancer Cell 2016
Metabolic Progression of ccRCC (Supervised)
Dipeptides
Glutathione Pathway
Hakimi et al. Cancer Cell 2016
Interconnected Metabolic Progression in ccRCC
ccRCC Pathogenesis (T vs N)
Hakimi et al. Cancer Cell 2016
Unsupervised NMF Consensus Clusteringof ccRCC
Based on Metabolites
Hakimi et al. Cancer Cell 2016
mCluster 2 (high glutathione) & mCluster 3 (high dipeptide)
have worse survival (higher metastasis)
The Lack of Clear Concordance between Transcriptomics & Metabolomics:
Based on Metabolic Pathways
RNA
Metabolites
IsoEnzymes, Allosteric Regulation, Substrate, Rx Condition
RNA
Metabologram
Integrative Metabolic Analysis to
Highlight Prominent Metabolic Shifts
http://kidneymetab.chenghsiehlab.org/
Volume 29
Number 1
Jan 11
2016
Cancer
Cell
An Integrated Metabolic Atlas of Clear Cell Renal Cell Carcinoma
Unsupervised RNA Clusters (rCluster) Based on Metabolic Genes Expression Based on KIRC TCGA RNA-Seq Data
A C B D
Hakimi et al. Cancer Cell 2016
Conclusion ccRCC exhibits broad shifts in central carbon metabolism,
one carbon metabolism, and antioxidant response
Clinical progression of ccRCC manifested with elevated
glutathione and dipeptides
Metabolomic clustering of human ccRCC identified
distinct high- and low-risk subsets
Lack of correlation between enzyme expression levels and
abundance of metabolites in ccRCC
Metabolograms visualize metabolomic, transcriptomic,
and clinical data of ccRCC
Pan-Omics including metabolomics provides integrated
insights that could be exploited for prognostic and
therapeutic purposes in ccRCC
MSKCC
TKCRP
7/2016
MSK Kidney
Cancer Core Lab
James Hsieh Dina Djesevic
Jianing Xu
Amrita Nargund
Toshinao Oyama
Jozefina Casucelli
Chelsea Ray
Maria Becerra
Yiyu Dong
Smrutiben Mehta
Emily Cheng Toru Wakamatsu
Yogesh Ganesan
Song Han
Yuchen Xie
Metabolomics Metabolon
Genomics
NYGC
Antibodies
Eureka
Cores
IGO/CMO
Metabolomics
Proteomics Surgery
Paul Russo
Ari Hakimi
J. Coleman
Brandon Manley
Comp Bio Chris Sander
Nils Weinhold Edward Reznik John Chodera
Steven Albanese Christina Leslie
Hatice Osmangeyoglu
Radiology
Hedi Hricak
Kayvan Keshari
Evis Sala
Omer Aras
Jeremy Durack
Biostatistics
Mithat Gonen
Irina Ostrovnaya
Elli Papaemmanuil
Venkat Seshan
Emily Zabor
Medicine
Bob Motzer
James Hsieh
Martin Voss
Darren Feldman
Joe Lee
Maria Carlo
Pathology
Victor Reuter
Ying-Bei Chen
Satish Tickoo
Chris Iacobuzio
Mike Berger
Lu Wang
TCGA
& KCA
& ACKC
& Rare KCA
Immunology
Ming Li