Genetic Basis of Kidney Cancer. W. Marston Linehan, M.D. Urologic Oncology Branch National Cancer Institute
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1 Genetic Basis of Kidney Cancer W. Marston Linehan, M.D. Urologic Oncology Branch National Cancer Institute
2 Genitourinary Malignancies Organ Site Cases/Year* Deaths/Year* Prostate 238,590 29,720 Urothelial 75,280 18,910 Kidney 65,150 13,680 Testis 7, Penile 1, ,510 62,990 U.S. 1,660,290 (23.4%) 580,350 (11%) *Estimated U.S. 2013
3 Renal Carcinoma 271,000 are diagnosed worldwide annually 116,000 deaths worldwide annually 65,000 are diagnosed in the U.S. annually 13,000 die in the U.S. each year There are over 200,000 alive with kidney cancer in the U.S. Ca Cancer J Clin 62:2012 Int J Cancer 127:2010
4 Stage I Tumor < 7 cm, within the renal capsule T1; N0; M0 95% 5 year survival AJCC 7 Cancer Staging Manual 2010
5 Stage IV Adjacent organs or distant metastasis T4; M1 19% 2 year survival AJCC 7 Cancer Staging Manual 2010
6 Human Renal Epithelial Neoplasms Clear Cell Papillary Type 1 Chromophobe Hybrid Oncocytoma Papillary Type 2 TFE3 Angiomyolipoma Oncocytic Clear/Chromophobe
7 Human Renal Epithelial Neoplasms Clear Cell Papillary Type 1 Chromophobe Hybrid Oncocytoma VHL Met FLCN Papillary Type 2 FH TFE3 Angiomyolipoma Oncocytic Clear/Chromophobe TFE3, TFEB, MITF TSC1, TSC2 SDHB, SDHC, SDHD PTEN
8 Studying cancer families to identify renal carcinoma genes
9 Inherited Forms of Renal Carcinoma 1. Von Hippel Lindau Clear Cell 2. Hereditary Papillary Renal Carcinoma Papillary Type 1 3. Birt Hogg Dubé: Chromophobe/Oncocytoma 4. Hereditary Leiomyomatosis RCC Papillary Type 2 5. Succinate Dehydrogenase Clear Cell/Chromophobe
10 Clear Cell Renal Carcinoma von Hippel Lindau (VHL)
11 VHL Clinical Features Tumors develop in: Both Kidneys Adrenal Glands Pancreas Brain or Spine Eyes Inner Ears
12 VHL Clinical Features Tumors develop in: Both Kidneys Adrenal Glands Pancreas Brain or Spine Eyes Inner Ears
13 VHL: Renal Cell Carcinoma CT Scan: Bilateral, Multifocal RCC VHL Kidney: Multifocal RCC
14 von Hippel-Lindau (VHL) Multiple Clear Cell Renal Carcinomas Multiple Renal Cysts Containing RCC Clear Cell RCC J Urol 153:1995
15 VHL-Associated RCC High Persistence Rate Microscopic Tumors VHL 600 clear cell RCC/kidney 1300 cysts/kidney J Urol 154:1995
16 VHL: Advanced RCC
17 NCI VHL Kindreds N= patients (684 affected) from 369 VHL families have been evaluated 338 nephrectomies/partial nephrectomies
18 Surgical Management of VHL-Associated Renal Carcinoma 3 3 cm rule Delay surgery until diameter of largest renal tumor = 3 cm Surgery = nephron sparing enucleation Radiology 174: 1990 J Urol: 153:1995 J Urol 165:2001 J Urol 165:2001 J Urol 172:2004 J Urol
19 Robotic Assisted Partial Nephrectomy
20 Robotic Assisted Partial Nephrectomy
21 NIH Clinical Center
22 VHL-26 VHL-27 VHL-28 VHL-29 VHL-33 VHL-30 VHL-31 VHL-32 VHL-34 VHL-35 VHL-36 VHL-37 VHL-38 VHL-39 VHL-40 VHL-41
23 VHL 3 VHL Gene: Clear Cell RCC
24 VHL Gene Localization Map Latif, et al Science 260; 1993
25 Human VHL Gene Exon Science 260:1993
26 Germline VHL Mutations 365/365 Families Human Mutation 5:1995 Corbin et al. In Prep
27
28 VHL Gene: Sporadic RCC Tumor tissues from patients with renal cell carcinoma were evaluated for: 1. VHL gene mutation 2. VHL gene deletion (loss)
29 Sporadic Clear Cell RCC VHL Gene Mutations Science 260:1993 Nature Genetics 7:1994 Clin Cancer Res 14:2008
30 Clear Cell Renal Carcinoma
31 Papillary Renal Carcinoma Type 1 Type 2
32 Mutated Deleted * Chromosome 3 Clear Cell Kidney Cancer
33 PNAS 93:1996 Athymic Nude Mouse Bearing Clear Cell RCC (VHL -/-)
34 Mouse With RCC + VHL Gene PNAS 93:1996
35 How Does the VHL Gene Function?
36 HIFα is targeted for degradation in normoxic, Normoxia VHL HIF-α β-domain OH OH Elongin B Elongin C α-domain UB UB CULLIN 2 Rbx1 E2 UB HIF-α Degradation Maxwell, et al Nature 399:1999 Ohh, et al. Nat Cell Biol 2:2000
37 HIFα is targeted for degradation in normoxic, but not hypoxic cells Normoxia Hypoxia VHL HIF-α β-domain OH OH Elongin B Elongin C α-domain UB UB CULLIN 2 Rbx1 E2 UB HIF-α β-domain Elongin B Elongin C α-domain CULLIN 2 Rbx1 E2 UB HIF-α Degradation HIF-α Accumulation Maxwell, et al Nature 399:1999 Ohh, et al. Nat Cell Biol 2:2000 VEGF Glut 1 PDGF
38 Downstream effects of VHL mutation VHL Gene Mutation VHL Protein VHL Complex Disrupted HIF-α Accumulation VEGF PDGF TGF-α/EGFR Angiogenesis Paracrine Growth Stimulation Autocrine Growth Stimulation
39 Targeting VHL/HIF in Clear Cell RCC VHL Antibody HIF VEGF PDGF TGF-α
40 Targeting VHL/HIF in Clear Cell RCC VHL HIF VEGF VEGFR PDGF PDGFR TGF-α EGFR Tyrosine Kinase Inhibitor (TKI)
41 Targeting VHL/HIF in Clear Cell RCC VHL Bevacizumab (Antibody) HIF mtor VEGF PDGF TGF-α Temsirolimus Everolimus VEGFR PDGFR EGFR Pazopanib Axitinib Sunitinib Sorafenib
42 Clear Cell Renal Carcinoma
43 TCGA Clear Cell Kidney Cancer Nature: 2013
44 Intratumor Heterogeneity Gerlinger et al NEJM 366:2012
45 Intratumor Heterogeneity Gerlinger et al NEJM 366:2012
46 Nature: 2013
47 Kidney Cancer is a Metabolic Disease Nature Rev Urol:
48 Non-Clear Cell RCC What possible approaches are there for developing therapeutic approaches for patients with: 1. Type 1 Papillary RCC 2. Chromophobe RCC 3. Type 2 Papillary RCC 4. Granular-Clear Cell RCC
49 Locally Advanced Kidney Cancer Surgery 4/21/87 11 cm T3A 21 Year Old Female
50 Non-Clear Cell Kidney Cancer Patient 1 Surgery 4/21/87 Died 1/08/88 11 cm T3A 21 Year Old Female
51 Papillary Kidney Cancer: Patient 1 Papillary Kidney Cancer
52 Non-Clear Cell Kidney Cancer: Patient 2 5/23/89 2/01/90 18 Year Old Female
53 Papillary Kidney Cancer: Patient 2 Papillary Kidney Cancer
54 Non-Clear Cell Kidney Cancer: Patient 3A 3/3/92 71 year old man
55 Non-Clear Cell Kidney Cancer: Patient 3B 4/28/92 68 year old female
56 Non-Clear Cell Kidney Cancer: Patient 3C 3/31/92 42 year old male
57 Papillary Kidney Cancer Patient 3 Papillary Kidney Cancer
58 Inherited Renal Carcinoma
59 Hereditary Papillary Renal Carcinoma (HPRC) J. Urol 151: 1994 J. Urol 153: 1995
60 HPRC: Renal Tumors
61 Hereditary Papillary Renal Carcinoma Type 1 papillary renal carcinoma
62 Hereditary Papillary Renal Carcinoma High Persistence Rate Microscopic Tumors Type 1 Papillary RCC 1100 basophilic papillary J Urol: 163, 2000
63 Surgical Management of HPRC-Associated Renal Carcinoma 3 3 cm rule Delay surgery until diameter of largest renal tumor = 3 cm Surgery = nephron sparing enucleation W J Urol 13: 1995 J Urol: 153:1995 J Urol 165:2001 J Urol 165:2001 J Urol 172:2004 J Urol
64 NIH Clinical Center
65 7 MET MET Gene: Type 1 Papillary RCC
66 Location of the HPRC Gene
67 MET is the HPRC Gene Met Receptor Nature Genetics 16:1997
68 HGF HGF Met Receptor Nature Genetics 16:1997
69 HPRC: Activating Mutations in the Tyrosine Kinase Domain of MET Met Receptor Activating Mutation Proliferation- Papillary Kidney Cancer
70 Location of Met Mutations in the HPRC patients β α codon 1112, 1110, 1124 (exon 16) codon 1149 (exon 17) codons 1206, 1213 (exon 18) codons 1238, 1246, 1248, 1268 (exon 19) Nature Genetics 16:1997 Cancer Res 58:1998
71 NCI HPRC Kindreds N= patients (66 affected) from 22 HPRC families have been evaluated Germline MET mutations have been detected in 22/22 (100%) HPRC kindreds. In Preparation Nature Genetics 16:1997 Cancer Res 58:1998
72 Early Onset HPRC 38 year old male 27 year old female J Urol: 172, 2004
73 Targeting MET RCC Gene Pathway CT Scan: Bilateral, Multifocal RCC HPRC Kidney: Multifocal RCC
74 Targeting Met Gene Pathway: Hereditary Papillary Renal Carcinoma MET Pathway: RCC Met Receptor Tyrosine Kinase Inhibition Activating Mutation No Proliferation Hereditary Papillary Renal Cell Carcinoma (HPRC)
75 GSK 089: Dual VEGFR and MET Inhibitor Met Receptor Foretinib Activating Mutation No Proliferation
76 Hereditary Papillary Renal Carcinoma (HPRC) Type 1
77 Regression of a renal tumor in a patient with HPRC treated with Foretinib Pre-Treatment J Clin Oncol 10:2012
78 Regression of a renal tumor in a patient with HPRC treated with Foretinib 1.4cm Pre-Treatment Following 49 cycles of therapy GSK 089 J Clin Oncol 10:2012
79 Patient #2 Baseline Following 28 cycles J Clin Oncol 10:2012
80 Patient #2 Baseline Following 28 cycles J Clin Oncol 10:2012
81 Hereditary Papillary Renal Cell Carcinoma: Foretinib 39 Target Lesions from 9 Patients J Clin Oncol 10:2012
82 Kidney Cancer is a Metabolic Disease Nature Rev Urol:
83 Locally Advanced Kidney Cancer Surgery 4/21/87 Died 1/08/88 11 cm T3A 21 Year Old Female
84 Locally Advanced Kidney Cancer Papillary Kidney Cancer
85 UOK124 t(x;1)(p11.2;q21.2) Translocation Papillary Kidney Cancer Cytogenet Cell Genet 71:1995
86 UOK124, UOK120, UOK 146 TFE3 Kidney Cancer + Cell lines UOK 120, UOK146 Cell line UOK 124 Human Mol Genetics 5:1966
87 TFE3 t(x;1)(p11.2;q21.2) Translocation Papillary Kidney Cancer 2 cm 23 Year Old Female
88 TFE3 t(x;1)(p11.2;q21.2) Translocation Papillary Kidney Cancer Positive Hilar node 23 Year Old Female
89 TFE3 Kidney Cancer 1-1.6% All renal tumors 15% RCC patients <45 years of age 20-45% RCC in children and young adults
90 Micropthalmia Transcription Factor (MITF) Kidney Cancer TFE3 kidney cancer TFEB kidney cancer MITF kidney cancer Kidney cancer and melanoma families
91 TFEB Kidney Cancer t(6:11)(p21;q13) Pulmonary and Osseous metastases 18 Year Old Female
92 TFEB Kidney Cancer t(6:11)(p21;q13) 14 Year Old Female
93 MITF Kidney Cancer Nature 480:2011
94 Kidney Cancer is a Metabolic Disease Nature Rev Urol:
95 Inherited Renal Carcinoma Birt-Hogg-Dubé (BHD)
96 Birt Hogg Dubé Cutaneous Manifestations
97 Birt Hogg Dubé Cutaneous Manifestations
98 Kidney Tumors in BHD: Risk of Renal and Colonic Neoplasms and Spontaneous Pneumothorax in the Birt-Hogg- Dubé Syndrome B Zbar, G Alford, G Glenn, M Turner, C Pavlovich, L. Schmidt, M Walther, P Choyke, F Gabril, C Greenberg, M Merino, J Toro and W M Linehan Cancer Epi, Biomarkers & Prev 11:2002
99 Kidney Tumors in Birt Hogg Dubé
100 Kidney Tumors in Birt Hogg Dubé
101 Kidney Tumors in Birt Hogg Dubé
102 Birt Hogg Dubé Renal Tumors Chromophobe RCC Hybrid RCC Clear Cell RCC Oncocytoma
103 BHD Renal Tumor Pathology Chromophobe Oncocytoma Oncocytic RCC
104 High Persistence Rate Microscopic Tumors BHD 3,000 Chromophobe, Chromo-Hybrid
105 Surgical Management of BHD-Associated Renal Carcinoma 3 3 cm rule Delay surgery until diameter of largest renal tumor = 3 cm Surgery = nephron sparing enucleation J Urol Am J Hum Genet 76: 2005
106 Identification of the BHD Gene lung skin kidney l-1 l-2 ll-1 ll-2 ll-3 ll-4 ll-5 ll-6 ll-7 ll-8 ll-9 lll-1 lll-2 lll-3 lll-4 lll-5 lll-6 lll-7
107 NIH Clinical Center
108 Cutaneous Fibrofolliculomas
109 BHD 17 BHD Gene: Chromophobe RCC Am J Hum Genetics 69:2001
110 BHD1 Gene Locus Chromosome 17 Am J Hum Genetics 69:2001
111 BHD Protein Sequence Cancer Cell: 2002
112 FLCN mutation spectrum FLCN mutations across the entire gene 97% detection rate in 176 NCI BHD families Type of mutation Frameshift Nonsense Splice site Missense c.1087delaginsc c.1092delt c.1126delca c.1733insc / c.1733delc HOT SPOT MUTATION In >50% affecteds c.1670c>g c.1707delc c.1741insa c.1755 G>A c.1755g>c EXON c.707delc c.751dela c.774delgtinscac c.802insa c.513delt c.602dela c.1036delg c.1039delg c.1065delg CinsTA c dup c dup c.1468delg c.1473delc c.1758delt c.1834deltc c.1844c>g c.1881insg c.1884c>t c.1945insctgt c.1978a>g c.2034c>t J Med Gen 45:2008 Am J Hum Gen 76:2005 Cancer Cell 2:2002 ATG IVS4-1 G> A IVS4-2A>G IVS7+1G>T IVS9 +l G>A IVS9+2 T>G IVS12+1G>A
113 BHD Lung Cysts
114 BHD Lung Cysts
115 BHD Lung Cysts
116 Therapeutic Approach: What Kind of Gene is FLCN?
117 BHD Gene Analysis in BHD-Associated RCC Tumor tissues from patients with BHD renal cell carcinoma were evaluated for: 1. BHD gene mutation 2. BHD gene deletion (loss)
118 Somatic mutations in renal tumors from BHD patients 2nd hit mutation rate(70%) Intragenic change 41/77 tumors, 53% LOH rate 13/77 tumors, 17% C 1733 Ci1733 Ci1733 Ai1742 Type of mutation frameshift intronic del termination del aa C 875 TTC 924 Ci36bpdup956 11bp 998 Ai1591 C 497 C 544 GG 653 C 656 C 733 C 801 TG 841 C bp 1398 TC 1452 TCi1494 CA 1508 G 1262 C 1779 Ti1859 5bp 2039 G2043T G2082T EXON ATG intron G>A intron TCC intron TCC intron TCC intron G>A intron 14bp
119 Somatic mutations in tumors from a single BHD patient
120 UOK 257, BHD -/- RCC cell line, is tumorigenic UOK257
121 UOK 257-2, BHD restored RCC cell line, is not tumorigenic UOK257-2
122 How Does the FLCN Gene Function?
123 Folliculin-FNIP1/2-AMPK Interactions PNAS 103:2006 Gene 415:2008
124 mtorc1/mtorc2 Activation: FLCN-Deficient Kidney Cancer PNAS 106:2009 PNAS 103:2006
125 Tumors from BHD d/+ mice show histology and LOH at BHD locus similar to human BHD tumors Clear cell, oncocytic hybrid and oncocytoma histology Southern blot shows loss of BHD wt allele WB & Duolink immunostaining show loss of FLCN expression
126 Tumor development in a BHD heterozygous null mouse model Aged BHD d/+ mice develop renal tumors by 24 months Hasumi Y et al. (2009) PNAS 106:
127 BHD Deletion Specifically in the Kidney Baba, JNCI 100:2008
128 BHDf/d/KSPCre Mouse Kidney Histology Baba, JNCI 100:2008
129 BHD f/d /KSPCre Mouse Microscopic Kidney Histology Baba, JNCI 100:2008
130 BHD Deletion Specifically in the Kidney Baba, JNCI 100:2008
131 BHD Flox/Delete KspCre Renal Phenotype & Survival +/- Rapamycin G BHD f/d / KSPCre, Buffer H BHD f/d / KSPCre, R apa Baba, JNCI 100:2008
132 mtorc1/mtorc2 Activation: FLCN-Deficient Kidney Cancer Rapamycin JNCI 100:2008
133 mtorc1/mtorc2 Activation: FLCN-Deficient Kidney Cancer Dual Kinase Inhibitor In preparation
134 HLRCC Kidney Cancer 18 y.o. Female Germline FH Mutation: c.240dupa, NT 110, p.ile81aspfsx14, AA# 38, Exon 1, Frameshift
135 Hereditary Leiomyomatosis Renal Cell Carcinoma: HLRCC Cutaneous leiomyomas Uterine leiomyomas (fibroids) Renal cell carcinoma
136 HLRCC Kindred J Urol:
137 HLRCC: Cutaneous Manifestations
138 HLRCC: Cutaneous Manifestations
139 HLRCC: Uterine leiomyomas Am J Hum Genet 71:2003
140 HLRCC Kidney Cancer Lymph Nodes 18 y.o. Female Kidney Tumor Germline FH Mutation: c.240dupa, NT 110, p.ile81aspfsx14, AA# 38, Exon 1, Frameshift
141 HLRCC Kidney Cancer Germline FH Mutation: c.240dupa, NT 110, p.ile81aspfsx14, AA# 38, Exon 1, Frameshift
142 HLRCC Kidney Cancer 21 Year Old Male
143 HLRCC Patient 32 Year Old Male J Urol:
144 2.5 Cm Renal Cyst HLRCC Renal Mass 2/22/02
145 HLRCC Renal Mass 2/22/ Cm Renal Cyst ½ cm Renal Tumor
146 HLRCC Renal Mass 2/22/ Cm Renal Cyst 2 cm Hilar Node
147 HLRCC Kidney Cancer: Orangophilic Nucleoli + Perinucleolar Halos 40X 100X Am J Surg Path 31:2007
148 HLRCC Kidney Cancer 10 Year Old Female Tumors Cysts
149 HLRCC Kidney Cancer 77 Year Old Male Tumor
150 24 Year Old Female HLRCC Patient 4/11/2007
151 24 Year Old Female HLRCC Patient 07/18/07
152 24 Year Old Female HLRCC Patient 04/09/08
153 24 Year Old Female HLRCC Patient 04/09/08
154 24 Year Old Female HLRCC Patient 04/09/08
155 24 Year Old Female HLRCC Patient 06/06/08
156 24 Year Old Female HLRCC Patient 06/06/08
157 46 Year Old Female HLRCC Patient September 2006 FH: T>G, NT 602, Leu201Arg, Exon 4, Missense
158 50 Year Old Female HLRCC Patient December 2010 Lymph nodes Renal tumor FH: T>G, NT 602, Leu201Arg, Exon 4, Missense
159 50 Year Old Female HLRCC Patient December 2010 FH: T>G, NT 602, Leu201Arg, Exon 4, Missense
160 50 Year Old Female HLRCC Patient 9 cm Type 2 Papillary Renal Cancer 10/59 lymph nodes positive FH: T>G, NT 602, Leu201Arg, Exon 4, Missense
161 Surgical Management of HLRCC-Associated Renal Carcinoma 3 3 cm rule Delay surgery until diameter of largest renal tumor = 3 cm Surgical management should NOT be delayed Wide Surgical Margins Mostly Open Procedures Can be bilateral and multifocal Nature CPU 3:2007 J Urol 177:2007
162 FH 1 Fumarate Hydratase Gene: HLRCC
163 Fumarate Hydratase (FH): HLRCC Gene FH catalyzes the conversion of fumarate to malate L-Malate MDH Acetyl-CoA citrate synthase OAA Citrate Fumarate fumarate hydratase (FH) aconitase H 2 O Succinate succinate dehydrogenase succinate thiokinase Isocitrate IDH Succinyl-CoA α-ketoglutarate CO 2 α-kgdh Tomlinson, et al. Nature Genetics:
164 Succinate Dehydrogenase: CBT Gene L-Malate MDH Acetyl-CoA citrate synthase OAA Citrate Subunit B,C,D Succinate Dehydrogenase Mutations Fumarate Succinate fumarate hydratase (FH) succinate dehydrogenase succinate thiokinase H 2 O aconitase Isocitrate IDH Succinyl-CoA α-ketoglutarate CO 2 α-kgdh Benn, et al. Oncogene 22:2003
165
166 NCI HLRCC Kindreds N= affected individuals from 141 families have been evaluated Germline FH mutations have been detected in 135/138 (98%) HLRCC kindreds. Am J Hum Genet 71:2003 J. Med Genet 6: 2005
167 Mutated * Deleted Chromosome 1 Fumarate Hydratase-Deficient Kidney Cancer
168 Cancer Cell 20:2011 UOK-262 EV (Empty Vector)
169 UOK-262 FHWT (Wild-type replaced) Cancer Cell 20:2011
170 How Does Loss of a Krebs Cycle Enzyme Lead to Kidney Cancer?
171 HLRCC Kidney Cancer Glucose Dependent- Warburg Effect Glucose Glucose Glycolysis ATP NADH Pyruvate Acetyl-CoA Lactate Oxaloacetate Malate Citrate Fumarate Hydratase (FH) Fumarate Isocitrate Succinate α-ketoglutarate Succinyl-CoA Cancer Cell 20:2011 Cancer Cell: 2005 Citric Acid Cycle
172 HLRCC-Renal Cancer: Glucose-Dependent Cancer Gen Cytogenet 196:2010
173 HLRCC Tumors In Vivo are Readily Detected by [18]Fluoro-deoxyglucose-based PET Scan
174 HLRCC Tumors In Vivo are Readily Detected by [18]Fluoro-deoxyglucose-based PET Scan
175 HLRCC Liver Tumor: CT Scan
176 HLRCC Tumors In Vivo are Readily Detected by [18]Fluoro-deoxyglucose-based PET Scan
177 HLRCC Retroperitonal Tumor: PET Scan
178 HLRCC Retroperitonal Tumor: PET Scan
179 HLRCC Chest Tumor: PET Scan Chest CT
180 HLRCC Chest Tumor: PET Scan Chest CT FDG PET
181 HLRCC Patient J Urol:
182 Cutaneous Leioymyomas In Vivo are Readily Detected by [18]Fluoro-deoxyglucose-based PET Scan Cutaneous leiomyomas
183 Uterine Leiomyomas
184 HLRCC Fumarate Increases Glucose Glucose Glycolysis ATP NADH Pyruvate Acetyl-CoA Lactate Oxaloacetate Malate Fumarate Fumarate Hydratase (FH) Citrate Isocitrate Succinate α-ketoglutarate Succinyl-CoA Cancer Cell 20:2011 Cancer Cell: 2005 Citric Acid Cycle
185 HLRCC Fumarate Increases Glucose Glucose Glycolysis ATP NADH Pyruvate Acetyl-CoA Lactate Oxaloacetate Fum Fum Fum Malate Fumarate Fumarate Hydratase (FH) Citrate Isocitrate Succinate α-ketoglutarate Succinyl-CoA Cancer Cell 20:2011 Cancer Cell: 2005 Citric Acid Cycle
186 HIF Accumulates Glucose Glucose Glycolysis ATP NADH Pyruvate Acetyl-CoA Lactate HIF-α Oxaloacetate Malate Citrate PHD 2 Fum Fumarate Hydratase (FH) 2-OG 2-OG Fum Fum Fum Fum Fumarate Isocitrate VHL Succinate α-ketoglutarate Succinyl-CoA Cancer Cell 20:2011 Cancer Cell: 2005 Citric Acid Cycle
187 HIF Accumulates Glucose HIF-α Accumulation Glucose Glycolysis ATP NADH Pyruvate Acetyl-CoA Lactate HIF-α Oxaloacetate Malate Citrate PHD 2 Fum Fumarate Hydratase (FH) 2-OG 2-OG Fum Fum Fum Fum Fumarate Isocitrate VHL Succinate α-ketoglutarate Succinyl-CoA Cancer Cell 20:2011 Cancer Cell: 2005 Citric Acid Cycle
188 VEGF Glucose HIF-α Accumulation GLUT1 GLUT4 Glucose Glycolysis ATP NADH Pyruvate Acetyl-CoA Lactate HIF-α Oxaloacetate Malate Citrate PHD 2 Fum Fumarate Hydratase (FH) 2-OG 2-OG Fum Fum Fum Fumarate Isocitrate VHL Succinate α-ketoglutarate Succinyl-CoA Cancer Cell 20:2011 Cancer Cell: 2005 Citric Acid Cycle
189 Targeting VEGF/EGFR in HLRCC VHL Fumarate Bevacizumab (Antibody) HIF VEGF VEGFR PDGF PDGFR TGF-α EGFR Erlotinib
190 Pre-Therapy A partial response following 18 months of therapy with bevacizumab + erlotinib
191 HLRCC Germline FH Mutation: Del TC, NT , AA# 449, Exon 9, Frameshift
192 HLRCC Patient with Metastatic RCC Pre-Therapy
193 Complete Response Following 3 Months Following Bevacizumab and Erlotinib
194 Complete Response Following 3 Months Following Bevacizumab and Erlotinib On Therapy 9/05 Complete Response 12/05 Continued CR as of 4/12 6 years
195 Kidney Cancer is a Metabolic Disease Nature Rev Urol:
196 SDH-RCC Succinate Dehydrogenase Kidney Cancer Pheochromocytoma Paraganglioma Renal cell carcinoma
197 SDH-RCC Succinate Dehydrogenase Kidney Cancer L-Malate MDH Acetyl-CoA citrate synthase OAA Citrate Subunit B Succinate Dehydrogenase Mutations Fumarate Succinate fumarate hydratase (FH) succinate dehydrogenase succinate thiokinase H 2 O aconitase Isocitrate IDH Succinyl-CoA α-ketoglutarate CO 2 α-kgdh Benn, et al. Oncogene 22:2003
198 Succinate Dehydrogenase
199 SDH-RCC Succinate Dehydrogenase B
200 SDH-RCC Succinate Dehydrogenase B
201 SDHB-RCC
202 SDH-RCC Succinate Dehydrogenase B 19 y.o. female SDHB Mutation: c.541-2a>g, IVS5-2A>G, Splice Acceptor
203 SDH-RCC Succinate Dehydrogenase B 19 y.o. female Oncocytic + mitochondria SDHB Mutation: c.541-2a>g, IVS5-2A>G, Splice Acceptor
204 SDH-RCC Succinate Dehydrogenase B 17 y.o. Male Germline SDHB mutation: c.137g>a
205 SDH-RCC Succinate Dehydrogenase B 17 y.o. Male Oncocytic Kidney Cancer Germline SDHB mutation: c.137g>a
206 SDH-RCC Succinate Dehydrogenase B 17 y.o. Male Oncocytic Kidney Cancer With Spindle Features Germline SDHB mutation: c.137g>a
207 SDH-RCC Succinate Dehydrogenase B 27 y.o. female SDHB Mutation: Partial Deletion
208 SDH-RCC Succinate Dehydrogenase B 27 y.o. female Oncocytic Kidney Cancer SDHB Mutation: Partial Deletion
209 SDH-RCC Succinate Dehydrogenase B 27 y.o. female Carotid body Tumor (CBT) SDHB Mutation: Partial Deletion
210 SDH-RCC Succinate Dehydrogenase B 33 y.o. female SDHB Mutation: G>A, NT 137, Arg46Gln, Missense
211 SDH-RCC Succinate Dehydrogenase B 33 y.o. female Oncocytic Kidney Cancer UOK269 SDHB -/- RCC cell line SDHB Mutation: G>A, NT 137, Arg46Gln, Missense
212 SDH-RCC Succinate Dehydrogenase B 55 y.o. female 1.8 cm tumor SDHB Mutation: G>A, NT 286, Gly96Ser, Missense
213 SDH-RCC Succinate Dehydrogenase B 55 y.o. female Hepatic Metastases SDHB Mutation: G>A, NT 286, Gly96Ser, Missense
214 SDH-RCC Succinate Dehydrogenase B 55 y.o. female Hepatic Metastases SDHB Mutation: G>A, NT 286, Gly96Ser, Missense
215 SDH-RCC Succinate Dehydrogenase B 61 y.o. male Pheochromocytoma SDHB Mutation: C>T, NT 268, p.arg90x, AA# = 90, Nonsense
216 SDHB-RCC Glucose Uptake: FDG PET Scan Pheo RCC CT SCAN FDG PET SCAN
217 Familial Renal Carcinoma Succinate Dehydrogenase B Oxaloacetate Malate Citrate Fumarate Succinate Dehydrogenase (SDH) Succinate Isocitrate α-ketoglutarate Succinyl-CoA Benn, et al. Oncogene 22:2003 Citric Acid Cycle
218 SDH-deficient Kidney Cancer (UOK-269) Characterized by Aerobic Glycolysis O2 Consumption Rate (OCR) Extracellular Acidification Rate (ECAR- Glycolysis)
219 SDH-RCC Glucose HIF-α Accumulation GLUT1 Glucose ATP Glycolysis NADH Pyruvate Acetyl-CoA Lactate HIF-α Oxaloacetate Malate Citrate PHD 2 Suc 2-OG 2-OG Suc Fumarate Succinate Dehydrogenase (SDH) Isocitrate VHL Suc Suc Suc Succinate Succinyl-CoA α-ketoglutarate Yang, et al. In prep Citric Acid Cycle
220 Kidney Cancer is a Metabolic Disease Nature Rev Urol:
221 Human Renal Epithelial Neoplasms Clear Cell Papillary Type 1 Papillary Type 2 Chromophobe Oncocytoma VHL Met FH FLCN Angiomyolipoma TFE3 Oncocytic Clear/Chromophobe TSC1, TSC2 TFE3, TFEB, MITF SDHB, SDHC, SDHD PTEN
222 Kidney Cancer is a Metabolic Disease Nature Rev Urol:
223 Kidney Cancer is a Metabolic Disease Nature Rev Urol:
224 Kidney Cancer is a Metabolic Disease Nature Rev Urol:
225 Kidney Cancer is a Metabolic Disease Nature Rev Urol:
226 Kidney Cancer is a Metabolic Disease Nature Rev Urol:
227 Kidney Cancer is a Metabolic Disease Nature Rev Urol:
228 Kidney Cancer is a Metabolic Disease Citric Acid Cycle Nature Rev Urol:
229 Peter A. Pinto, M.D. Prostate Cancer Surgical & minimally invasive management of localized prostate cancer MRI/image guided biopsy localized prostate cancer Molecular therapeutic approaches localized prostate cancer
230 Adam Metwalli, M.D. Kidney Cancer Surgical & minimally invasive management of localized/advanced kidney cancer Molecular therapeutic approaches kidney cancer
231 Piyush Agarwal, M.D. Bladder Cancer Surgical & minimally invasive management of localized/advanced bladder cancer Molecular therapeutic approaches bladder cancer
232 Ramaprasad Srinivasan, MD,Ph.D Molecular therapeutic trials, hereditary and sporadic kidney cancer Small molecule natural products targeting the kidney cancer gene pathways
233 Urologic Oncology Fellows Brain Shuch, M.D. Srinivas Vourganti, M.D. Armine Smith, M.D. Anthony Huang, M.D. Jeffery Nix, M.D. Soroush Rais Bahrami, M.D. Minhaj Siddiqui, M.D. Lambros Stamatakis, M.D.
234 Family 166 I 1 2 II III Urologic Oncology Branch National Cancer Institute
235
236 Inherited Renal Carcinoma: Tuberous Sclerosis Complex (TSC)
237 TSC: Angiomyolipoma 49 Year Old Male
238 TSC: Fat Poor AML 49 Year Old Male
239 TSC: Fat Poor AML 49 Year Old Male
240 Familial Renal Cancer (FRC) I:2 I:1 Kidney Ca. II:1 II:2 Kidney Ca. II:3 Kidney Ca. Presented with Kidney Cancer III:1 Bilateral Kidney Ca. II:2 Kidney Ca.
241 Familial RCC Bilateral, Multifocal 5 cm 3.6 cm 3.5 cm 1.9 cm 44 Year Old Female
242 Familial RCC Bilateral, Multifocal Clear cell with papillary RCC Chromophobe RCC Oncocytosis Leiomyoma 44 Year Old Female
243 Tuberous Sclerosis Complex (TSC) I:2 I:1 Kidney Ca. II:1 II:2 Kidney Ca. II:3 Kidney Ca. Presented with Kidney Cancer Genetically Proven TSC2 Mutation III:1 Bilateral Kidney Ca. II:2 Kidney Ca. TSC2: c.3598c>t, p.arg1200trp, Missense
244 Tuberous Sclerosis Complex (TSC) RCC with clear cell and tubular features 47 Year Old Female TSC2: c.1946t>c, p.met649thr
245 Tuberous Sclerosis Complex (TSC) RCC with clear cell and tubular features Capsular leiomyoma 51 Year Old Female TSC1: del 4 bp (GAGA), Frameshift
246 Kidney Cancer is a Metabolic Disease Nature Rev Urol:
247 Inherited Renal Carcinoma: Cowden s Disease
248 Cowden s Disease 56 Year Old Male PTEN: 388 C>T, R130X
249 Cowden s Disease 32 Year Old Female PTEN: 210-1G>A
250 Kidney Cancer is a Metabolic Disease Nature Rev Urol:
251 Familial Renal Cancer Mol Cancer Res: In Press
252 Familial Renal Cancer Mol Cancer Res: In Press
253 Familial Renal Cancer Mol Cancer Res: In Press
254 Familial Renal Cancer Mol Cancer Res: In Press
255 FRC: Renal Cyst Mol Cancer Res: In Press
256 FRC: Cystic Clear Cell RCC Mol Cancer Res: In Press
257 FRC: High Grade Clear Cell RCC Mol Cancer Res: In Press
258 BAP1 Familial Renal Cancer Mol Cancer Res: In Press
259 Germline BAP1 p.l14h Mutation Familial Renal Cancer Mol Cancer Res: In Press
260 Clear Cell Kidney Cancer VHL SETD2 BAP1 PBRM1 Chromosome 3 Nature: In Press
261 BAP1 Staining Normal (positive) Tumor (negative) Mol Cancer Res: In Press
262 BAP1 Familial Renal Cancer Mol Cancer Res: In Press
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