Molecular Patient Selection KCA 2016 · HIF2-I (PT2399) inhibits proliferation & angiogenesis in...
Transcript of Molecular Patient Selection KCA 2016 · HIF2-I (PT2399) inhibits proliferation & angiogenesis in...
James Brugarolas, M.D., Ph.D.
Kidney Cancer Program Leader
Virginia Murchison Linthicum Endowed Scholar
Associate Professor of Internal Medicine
University of Texas Southwestern Medical Center
http://www.utsouthwestern.edu/kidneycancer
Molecular Patient Selection
KCA 2016
Relevant Disclosures
Peloton Therapeutics: Research Support
Patent (PCT/US2016/052118; U.S. Serial No. 62/221,527) “Biomarkers of Response to HIF-2-Alpha Inhibition in Cancer and Methods for the Use Thereof” by Brugarolas, et al.
Molecular Patient Selection
IL-2 (FDA approval 1992)
SELECT trial, PD-L1
Angiogenesis inhibitors (first FDA approval 2005)
Polymorphisms in VEGF/VEGFR genes
mTORC1 inhibitors (first FDA approval 2007)
Mutations MTOR, RHEB, TSC1, TSC2…
Checkpoint Inhibitors (Nivolumab)
PD-L1, mutation load, neoantigens
Emerging therapies:
HIF-2 inhibitor (PT2385)
Why: (i) Targets an early/truncal event; (ii) Highly specific, allosteric drug binding an uncommon feature; (iii) Variable dependency on target; (iv) Variable target expression in ccRCC; (v) Target itself may be a biomarker
– No
– No
– No
– No
Scheuermann et al.
PNAS 2009
B
A
B
A
HRE (DNA)
HIF-2a HIF-1b
HRE (DNA)
HIF-1bHIF-2a
Scheuermann et al.
Nat Chem Biol 2013
High-Throughput Screen
HIF2-I
Development of a HIF-2 inhibitor (HIF2-I)
UT Southwestern BioCenter
Sivanand et al., Sci Transl Med 2012
Unsupervised hierarchical clustering of gene expression shows similarities
between tumors and corresponding tumorgrafts
Tumorgrafts reproduce the mutations, gene expression and
drug responsiveness of human RCC
HIF2-I (PT2399) is active against
human ccRCC transplants in mice
Days
Tum
or
volu
me (
mm
3) Vehicle
Sunitinib
HIF2-I
HIF2-I is active in 50% of ccRCC
Inte
rmed
.S
en
sit
ive
Resis
tan
t
Vehicle
Sunitinib
HIF2-I
267 mice from 22 independently derived TG lines (18 ccRCC)
Chen et al., Nature 2016
HIF2-I (PT2399) has greater activity than sunitinib
and is better tolerated
Chen et al., Nature 2016EPO may serve as a PD biomarker
HIF2-I is active in 50% of ccRCC
Inte
rmed
.S
en
sit
ive
Resis
tan
t
Vehicle
Sunitinib
HIF2-I
267 mice from 22 independently derived TG lines (18 ccRCC)
Chen et al., Nature 2016
Sensitive ccRCC include tumors with rhabdoid/sarcomatoid features
Response PDX line HistologyFuhrman
GradeTissue
VHLstatus
BAP1 (IHC)
PBRM1 (IHC)
Relative GI%
(p value)
Sensitive XP26 ccRCC 2 Adrenal mut mut wt 87 (0.0003)
XP144 ccRCC 4 Kidney mut wt wt 98 (<0.0001)
XP164 ccRCC* 4 Kidney wt wt wt 134 (<0.0001)
XP165 ccRCC 3 Abd wall mut wt mut 112 (<0.0001)
XP373 ccRCC 4 Tu Thr wt¥ mut wt 103 (<0.0001)
XP374 ccRCC*# 4 Kidney mut wt wt 109 (<0.0001)
XP453 ccRCC 3 Tu Thr wt¥ wt wt 110 (<0.0001)
XP454 ccRCC 3 Kidney wt mut wt 156 (0.0032)
XP469 ccRCC 3 Kidney mut mut mut 91 (<0.0001)
XP534 ccRCC 4 Kidney mut mut n/a 129 (0.0007)
Intermediate XP237 tRCC n/a LN n/a wt wt 43 (0.0144)
XP391 ccRCC 4 Tu Thr mut wt mut 45 (0.0018)
XP426@ ccRCC# 4 Kidney mut wt wt 44 (0.0273)
XP427@ ccRCC# 4 LN mut wt wt 54 (0.0206)
XP466 ccRCC 3 Kidney wt mut n/a 67 (0.0030)
Resistant XP169 Unclassified n/a Kidney wt wt wt 0 (0.0119$)
XP258 ccRCC* 4 Kidney mut mut wt 39 (0.11)
XP296 ccRCC* 4 Kidney mut wt wt 29 (0.30)
XP462 Unclassified n/a Kidney wt wt mut 29 (0.11)
XP490 ccRCC*# 4 Kidney mut wt wt 39 (0.89)
XP506 ccRCC 3 Ascites wt wt wt 20 (0.76)
XP530 Unclassified n/a Kidney wt n/a n/a 2 (0.68)
@ Independent tumors from same patient, * Sarcomatoid differentiation, # Rhabdoid features, $ HIF2-I-treated mice
had greater relative growth than vehicle-treated mice, ¥ Promoter methylation
Chen et al., Nature 2016
HIF2-I (PT2399) inhibits proliferation &
angiogenesis in sensitive ccRCC
XP
16
4X
P4
69
XP
45
4X
P3
73
HIF2-Ivehicle
V4239 P4244
P3297V3294
V5407 P5399
V4921 P4924
HIF2-Iveh
XP
37
3X
P1
44
CD
31
H&
E
XP
37
3K
i67
veh HIF2-I
XP
16
4X
P4
90
XP
16
9X
P3
73
vehicle HIF2-I
V4237
V5239 V5229 P5231 P5240
V4236 V4241V4234
V3290 V3294 V3287 V3281
V3212 V3224 V3210 V3214
Vehicle
HIF2-I
Sunitinib
Chen et al., Nature 2016
HIF2-I (PT2399) dissociates HIF-2 in sensitive tumors
RE
SIS
TA
NT
S
EN
SIT
IVE
Chen et al., Nature 2016
Resistance mutations in HIF-2a and HIF-1b
validate HIF-2 as the drug target
P3283V3286
Fo
rwa
rdR
eve
rse
G323E
(HIF-2a)
V1849 P5123
Fo
rwa
rdR
eve
rse
F446L
(HIF-1b)
HIF-1b HIF-2a
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
-20 0 20 40 60 80 100 120 140 160 180 200
Tu
mo
r V
olu
me
(m
m3)
XP164
3283
3288
3296
3295
3299
3286Veh
Sunitinib
HIF2-I
Input
IP HIF-1b
V3
29
0
V3
29
4
V3
29
8
P3
28
3
P3
28
8
P3
29
7
V3
29
0
V3
29
4
V3
29
8
P3
28
3
P3
29
7
Tubulin
post-
resistance
HIF-2a
HIF-1b
P3
28
8
pre-resistance
vehicle HIF2-I HIF2-I
Chen et al., Nature 2016
HIF-2a and HIF-1b mutations are sufficient to
preserve HIF-2 complexes despite PT2399
FLAG-HIF-1b
Input IP FLAG (HIF-1b)
Vehicle Vehicle PT2399PT2399
+
-
+
+
-
-
-
-
-
+
+ +
+
+
- -
Tubulin
HA
FLAG
FLAG-HIF-1b (F466L)
HA-HIF-2a
HA-HIF-2a (G323E)
+
-
+
+
-
-
-
-
-
+
+ +
+
+
- - +
-
+
+
-
-
-
-
-
+
+ +
+
+
- - +
-
+
+
-
-
-
-
-
+
+ +
+
+
- -
Chen et al., Nature 2016
HIF2-I is active in 50% of ccRCC
Inte
rmed
.S
en
sit
ive
Resis
tan
t
Vehicle
Sunitinib
HIF2-I
267 mice from 22 independently derived TG lines (18 ccRCC)
Chen et al., Nature 2016
HIF2-I (PT2399) dissociates HIF-2
also in resistant tumors
RE
SIS
TA
NT
S
EN
SIT
IVE
Chen et al., Nature 2016
HIF2-I is active in 50% of ccRCC
Inte
rmed
.S
en
sit
ive
Resis
tan
t
Vehicle
Sunitinib
HIF2-I
267 mice from 22 independently derived TG lines (18 ccRCC)
Chen et al., Nature 2016
Responsiveness does not correlate with BAP1 or PBRM1 status
Response PDX line HistologyFuhrman
GradeTissue
VHLstatus
BAP1 (IHC)
PBRM1 (IHC)
Relative GI%
(p value)
Sensitive XP26 ccRCC 2 Adrenal mut mut wt 87 (0.0003)
XP144 ccRCC 4 Kidney mut wt wt 98 (<0.0001)
XP164 ccRCC* 4 Kidney wt wt wt 134 (<0.0001)
XP165 ccRCC 3 Abd wall mut wt mut 112 (<0.0001)
XP373 ccRCC 4 Tu Thr wt¥ mut wt 103 (<0.0001)
XP374 ccRCC*# 4 Kidney mut wt wt 109 (<0.0001)
XP453 ccRCC 3 Tu Thr wt¥ wt wt 110 (<0.0001)
XP454 ccRCC 3 Kidney wt mut wt 156 (0.0032)
XP469 ccRCC 3 Kidney mut mut mut 91 (<0.0001)
XP534 ccRCC 4 Kidney mut mut n/a 129 (0.0007)
Intermediate XP237 tRCC n/a LN n/a wt wt 43 (0.0144)
XP391 ccRCC 4 Tu Thr mut wt mut 45 (0.0018)
XP426@ ccRCC# 4 Kidney mut wt wt 44 (0.0273)
XP427@ ccRCC# 4 LN mut wt wt 54 (0.0206)
XP466 ccRCC 3 Kidney wt mut n/a 67 (0.0030)
Resistant XP169 Unclassified n/a Kidney wt wt wt 0 (0.0119$)
XP258 ccRCC* 4 Kidney mut mut wt 39 (0.11)
XP296 ccRCC* 4 Kidney mut wt wt 29 (0.30)
XP462 Unclassified n/a Kidney wt wt mut 29 (0.11)
XP490 ccRCC*# 4 Kidney mut wt wt 39 (0.89)
XP506 ccRCC 3 Ascites wt wt wt 20 (0.76)
XP530 Unclassified n/a Kidney wt n/a n/a 2 (0.68)
@ Independent tumors from same patient, * Sarcomatoid differentiation, # Rhabdoid features, $ HIF2-I-treated mice
had greater relative growth than vehicle-treated mice, ¥ Promoter methylation
PBRM1+ BAP1+
PBRM1- BAP1+
PBRM1+ BAP1-
PBRM1- BAP1-
Joseph, R.* and Kapur, P.* et al., J. Urol. 2015
Kapur et al., Lancet Oncology 2013
Chen et al., Nature 2016
HIF2-I is active in 50% of ccRCC
Inte
rmed
.S
en
sit
ive
Resis
tan
t
Vehicle
Sunitinib
HIF2-I
267 mice from 22 independently derived TG lines (18 ccRCC)
Chen et al., Nature 2016
Inhibition of HIF-2-regulated genes
in sensitive but not resistant tumors
Veh HIF2-I Veh HIF2-I
Sensitive Resistant
Vehicle
HIF2-I
Sunitinib
Up 195 0
Down 297 0
Total 492 0
Differential Gene Expression
Sensitive Resistant
Veh v HIF2-I Veh v HIF2-I
pg
/ml
hVEGF
Rela
tive
mR
NA
ex
pre
ss
ion
Rela
tive
mR
NA
ex
pre
ss
ion
CCND1 TGFA
hVEGF SERPINE1 IGFBP3
SLC2A1
Chen et al., Nature 2016
Sensitive tumors have higher levels of HIF-2a
HIF-2α HIF-1αHIF-2αHIF-1α
XP
469
XP
374
XP
164
XP
490
XP
530
XP
462
HIF2-a
Pe
rce
nta
ge
po
sitiv
e c
ells
Chen et al., Nature 2016
Sensitive
Differential dependency on HIF-2 in ccRCC
HIF2-I
VEGF VEGF
Resistant
HIF2-I
?
Gene expression
75-gene Nanostring signature distinguishes
sensitive & resistant tumorgrafts
(different tumors and cohorts)
Demographics and Baseline Treatment Characteristics
Escalation/Expansion
n = 51
Age, years, median (range) 65 (29-80)
Gender, n
Female
Male
15
36
ECOG PS, n (%)
0
1
16 (31%)
35 (69%)
Number of prior therapies, median (range) 4 (1-7)
Prior systemic therapies, n (%)
1
2
3
4
> 5
7 (14%)
9 (18%)
8 (16%)
12 (24%)
15 (29%)
Prior anti-cancer therapies, n (%)
VEGF / VEGFR inhibitor
mTORC1 inhibitor
Cytokine
Other Immunotherapy
Investigational/Other
51 (100%)
31 (61%)
9 (18%)
10 (20%)
13 (25%)
Adapted from Courtney
et al., ASCO 2016
Phase 1 Clinical Trial of HIF2-I (PT2385)
Pharmacodynamics: Decrease in
HIF-2a target EPO
• Rapid reduction of erythropoietin observed at all doses
• No further reduction observed above 800 mg b.i.d.
800 mg b.i.d. Recommended Phase 2 Dose
Adapted from Courtney et al., ASCO 2016
No DLT
002 041 016 035 026 047 001 028 020 036 055 033 034 054 048 043 004 003 012 049 045 029 053 023 021 010 007 019 022 027 005 030 038 046 042 037 009 057 013 011 015 018 052 025 039 040 017 008 006
-1 0 0
-9 0
-8 0
-7 0
-6 0
-5 0
-4 0
-3 0
-2 0
-1 0
0
1 0
2 0
3 0
4 0
5 0
Ma
xim
um
S
LD
R
ed
uc
tio
n fro
m B
as
eli
ne
(%
)
M a x im u m S L D - A ll P a tie n ts
Maximum Radiographic Response
PD
SD
PR
CR
Data cutoff: May 18, 2016
1 CR, 3 PR, and 16 pts with SD > 16 weeks
100 mg, b.i.d.200 mg, b.i.d.400 mg, b.i.d.800 mg, b.i.d.1,200 mg, b.i.d.1,800 mg, b.i.d.
Adapted from Courtney et al., ASCO 2016
Ongoing treatmentPartial ResponseComplete Response
Data cutoff: May 18, 2016
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0 5 5 6 0 6 5
024
019
012
044
030
043
034
048
016
041
001
003
010
022
026
054
035
036
047
055
004
005
033
057
023
007
028
020
002
037
053
052
021
049
046
045
018
040
042
029
038
039
027
025
017
015
013
011
009
008
006
W e e k s o n T re a tm e n t
Pa
tie
nt
100 mg, b.i.d.200 mg, b.i.d.400 mg, b.i.d.800 mg, b.i.d.1,200 mg, b.i.d.1,800 mg, b.i.d.
Duration of Treatment
Adapted from Courtney et al., ASCO 2016
SPORE: Translating Discovery
& Innovation at UTSW
Project 1: Targeting HIF-2 for the Treatment of ccRCC (Brugarolas, Courtney, Pedrosa)
Project 2: Evaluation of the Functional and Clinical Significance of the Novel Tumor Suppressor Gene BAP1 (Kapur, Carroll, Yu)
Project 3: Clinically Actionable Biomarkers from RCC Metabolism and Imaging (DeBerardinis, Margulis, Pedrosa)
Project 4: Prognostic Significance and Therapeutic Potential of DROSHA Mutations in Wilms Tumor (Amatruda, Mendell)
Cores: Admin, Pathology (Kapur, Rakheja), Imaging (Pedrosa, Lenkiski), Data Analytics (Xie, Xie, Hwang).
30%55%
3%
12%
wt PBRM1 BAP1 & PBRM1 BAP1
30%
12%
55%3%
wt BAP1 PBRM1 BAP1/PBRM1
30%
12%
55%3%
wt BAP1 PBRM1 BAP1/PBRM1
30%
12%
55%3%
wt BAP1 PBRM1 BAP1/PBRM1
30%
12%
55%3%
wt BAP1 PBRM1 BAP1/PBRM1
VHL
HIF-2
ccRCC is not one tumor type – HIF-2 and BAP1/PBRM1 define distinct
subtypes with different dependencies and biology.
This may impact drug responsiveness, in particular to drugs targeting
pathways other than VEGF.
Molecular subtypes of ccRCC
Brugarolas Lab
Brinda Chellappan
Yifeng Gu
Allison Joyce
Meghan Konda
Eric Ma
Renee McKay
Tiffani McKenzie
Neville Wang
Nick C. Wolff
Juan Yang
Hui Ye
Anum Yousuf
Alana Christie
Min Kim
Tao Wang
Xian-Jin Xie
Yang Xie
Wenfang Chen
Shannon Cohn
Haley Hill
Eboni Holloman
Farrah Homayoun
Blanka Kucejova
Andrea Pavia-Jimenez
Samuel Peña-Llopis
Sharanya Sivanand
Vanina Toffessi
Tram Anh Tran
Silvia Vega-Rubin de Celis
Shanshan Wang
Toshinari Yamasaki
Jenny Chang
Deni Von Merveldt
Vincy Alex
Debbie Harvey
Funding
Virginia Murchison Linthicum Endowment
Cancer Prevention and Research Institute of Texas
NIH, National Cancer Institute
Kidney Cancer Program
Urology
Jeff Cadeddu
Jeff Gahan
Yair Lotan
Vitaly Margulis
Ganesh Raj
Arthur I. Sagalowsky
Medical Oncology
Yull Arriaga
Kevin Courtney
Eugene Frenkel
Hans Hammers
Radiation Oncology
Raquibul Hannan
Nathan Kim
David Pistenmaa
Robert Timmerman
Pathology
Payal Kapur
Dinesh Rakheja
Radiology
Ivan Pedrosa
Lori Watumull
Clinical Genetics
Megan Farley
Illumina Inc.
Arnold Liao
Nan Leng
Christian Haudenschild
Mark Ross
David Bentley
Mayo Clinic
Richard W. Joseph
Daniel J. Serie
Jeanette Eckel-Passow
Thai Ho
John C. Cheville
Alexander Parker
Genentech
Anwesha Dey
Steffen Durinck
Eric W. Stawiski
Zora Modrusan
Sekar Seshagiri
NCI
Laura Schmidt
Marston Linehan
Other Collaborators
Thomas Carroll
Ralph DeBerardinis
Robert E. Hammer
Bruce Posner
Dipti Ranganathan
Noelle Williams
Jin Ye
Yonghao Yu
Phase 1 Trial
Kevin Courtney
Jeffrey R. Infante
Elaine T. Lam
Robert A. Figlin
Brian I. Rini
Naseem J. Zojwalla
Keshi Wang
Eli M. Wallace
John A. Josey
Toni K. Choueiri
Bioniformatics
Min Kim
Dipti Ranganathan
Phillip Reeder
Tao Wang
Yang Xie
He Zhang