Transcript 2 nd Annual CBTTC Investigator Meeting The Westin New Orleans

Harmonizing Bio-informatics with Clinical Reality
Michael Prados, MD
University of California San Francisco
2nd Annual CBTTC Investigator Meeting
The Westin New Orleans
May 24-25
War on Cancer
War On Cancer
September 28th 2016 | Boston
waroncancer.economist.com
Announcing this year's War On Cancer event
Following a successful inaugural War On Cancer conference attended by 260
health-care leaders, The Economist is pleased to announce its 2016 conference
for September 28th in Boston.
The event will explore how the promise of technology
allows for faster, more precise treatment and more
collaborative health care models, inching us closer
to moonshot objectives and victory. Join us to
discuss how innovation can be scaled across policy
and financing, prevention, early detection, treatment
and long-term management of this deadly disease.
Total NCI
Research Project Grants
Cancer Centers
SPOREs
Other P50s/P20s
Other Specialized Centers
Clinical Cooperative Groups
R&D Contracts
Intramural Research
Other Mechanisms*
Funding
(Dollars in Millions)
2010
2011
2012
$5,098.1 $5,058.1 $5,067.3
2,168.1
2,163.7
2,150.6
295.9
278.3
279.9
133.8
121.9
113.5
38.8
35.2
33.4
142.7
162.7
186.0
254.5
243.9
229.8
613.8
587.0
589.7
805.3
833.7
857.8
645.4
631.8
626.5
2013
$4,789.0
2,000.2
262.2
104.3
21.5
146.0
235.4
616.0
811.6
591.8
2014
$4,932.4
2,012.6
281.8
104.6
18.2
139.2
271.6
652.3
845.1
607.0
Percent Change by Mechanism
Total NCI
Research Project Grants
Cancer Centers
SPOREs
Other P50s/P20s
Specialized Centers
Clinical Cooperative Groups
R&D Contracts
Intramural Research
Other Mechanisms*
2010 to
2011
-0.8%
-0.2%
-5.9%
-8.9%
-9.3%
14.0%
-4.2%
-4.4%
3.5%
-2.1%
2011 to
2012
0.2%
-0.6%
0.6%
-6.9%
-4.9%
14.4%
-5.8%
0.5%
2.9%
-0.8%
2012 to
2013
-5.5%
-7.0%
-6.3%
-8.1%
-35.8%
-21.5%
2.4%
4.5%
-5.4%
-5.5%
2013 to
2014
-3.6%
-6.3%
-8.2%
-20.6%
-23.6%
25.4%
0.4%
1.0%
3.9%
-8.3%
2010 to
2014
-3.3%
-7.7%
-11.4%
-22.1%
-44.6%
2.3%
-7.5%
0.4%
0.8%
-8.3%
NCI Pediatric Cancer Research Portfolio
Therapeutically Applicable Research To
Generate Effective Treatments (TARGET)
The Biomarker, Imaging and Quality of Life
Studies Funding Program (BIQSFP)
The NCI-supported Childhood Cancer
Survivor Study
The Center for Cancer
Research’s Pediatric Oncology Branch
The Epidemiology and Genomics Research
Program
The Tumor Microenvironment Network (TMEN)
Pediatric CNS Tumor Funding
1. NCI gets about $4.8 Billion for cancer funding (2015; 2016
appropriations about $5.2 Billion)
2. “Total” amount for all of pediatric cancers = $185 millions (45%
treatment)
3. PBTC annual budget = $2.7million (includes the Operations Office
component, and indirect costs, so what filters down for actual clinical
trials is hard to sort out)
4. COG annual budget = $30 million; portion linked to CNS tumors is just
under $2 million (also not certain exactly how much of that supports
clinical trials per se)
5. Phase-1 consortium = $3 million
6. NCI Pediatric Branch = $3.01 million (all pediatric malignancies):
perhaps around $600,000 towards CNS tumors (small amount
towards clinical trials, more towards other research efforts)
Approximately 4% for Pediatric Cancer, < 1% for CNS Tumors
Estimated 47,631 years of potential life lost due to CNS
tumors in 2009 in the US alone
DIPG – 1996
20 years ago
Natural History
“Diffuse tumors have terrible prognosis with most
patients dead in 12 months.”
Treatment
“The most common neoplasm is the diffuse variety.
These are malignant. Can be diagnosed on basis
of MRI (pontine). Biopsy felt unnecessary.
Radiation offered as palliation.”
“MR scans should replace biopsies for the
diagnosis of diffuse brain stem gliomas: A
report from the children's cancer group”
(Albright et al, 1993)
DIPG (DFCI Protocol 10-321)
10 years ago
PBTC concept submitted 2006; declined by CTEP
New protocol structure required by Harvard Clinical Trial
Office September 14, 2009
IND submitted March 10, 2010
granted July 16 2010
Submitted for Harvard Scientific Review Oct 6, 2010
Scientific review approval March 10, 2011
IRB review March 21,2011; IRB approval Sept 1, 2011
IDE requirement as of February 2011
Submitted March 2011, IDE review end of Sept 2011
Accrual started in 2012, closed in 2015 (25 sites)
PNOC
Translational Genomics Research Institute | www.tgen.org
H3F3A
TP53
ATRX
PDGFRA
KDR
KIT
MET
PPM1D
HIST1H3B
IGF1R
BRAF
PIK3R1
PTEN
CRKL
MAPK1
79%
79%
36%
29%
21%
21%
21%
14%
7%
7%
7%
7%
7%
7%
7%
Significant Alterations & Treatment Recommendations
Treatment recommended
PNOC-003-01
Etoposide, dasatinib
PNOC-003-02
Cabozantinib, etoposide, mebendazole
PNOC-003-04
Temozolomide, sertraline
PNOC-003-05
Panobinostat, mebendazole
PNOC-003-06
Panobinostat, mebendazole
PNOC-003-07
Panobinostat, everolimus, sertraline, mebendazole
PNOC-003-08
Panobinostat
PNOC-003-09
Panobinostat
PNOC-003-10
Vemurafenib/dabrafenib, trametinib, minocycline,
panobinostat
PNOC-003-11
Etoposide, metformin, mebendazole, sertraline
PNOC-003-12
Panobinostat, everolimus, mebendazole, valproic acid
PNOC-003-13
Panobinostat, mebendazole, cabozantinib, valproic acid
PNOC-003-14
Panobinostat, cabozantinib, valproic acid, mebendazole
PNOC-003-16
Panobinostat, mebendazole, propranolol, valproic acid
Gain
Deletion
Mutation (Missense,
Nonsense, Frameshift)
PNOC Meeting Two Weeks Ago!
What really constitutes “Precision Medicine”?
Just profile and treat (is that research?)
With what “targets” (mutations, pathways,
microenvironment, altered immunity)
With how many agents (one, two, more?)
How to deliver (oral, IV, intra-nasal, intra-tumor, CED,
?others)
How to monitor response/progression (MRI, PET,
circulating tumor DNA, CSF, clinical)
How to treat at relapse
How should we prioritize: only 300-400 cases/year
What genomics platform should we use
How can we afford to do the research
DIPGs exhibit a higher mutation rate than PLGGs,
but a lower rate compared to adult cancers
DIPG
Methylation profiling reveals three molecular subgroups of DIPG
Nat Genet. 2014 May; 46(5): 451–456.
Molecular subgroups of DIPG share common clinical features and recurrent genomic events(a) Clinical and
genomic features such as gender, histology, frequency of recurrent mutations, alternative lengthening of telomeres and
copy number alterations are represented in a DIPG subgroup specific manner. (b) Probability of two mutational or
structural features of DIPG co-occurring based on odds ratio suggests statistically significant association between K27MH3.3 and PDGFRA amplifications (OR = 8.0, p = 0.0127) and between K27M-H3.1 and ACVR1 mutations (OR = 15.8, p <
0.001). (C) Probability of mutations or structural event of DIPG occurring with a clinical feature such as gender or tumor
histology based on odds ratio shows statistically significant correlation between P53 mutations and GBM histology (OR =
10.8, p < 0.005), among others.
Nat Genet. 2014 May; 46(5): 451–456.
“Google map” of glioma subtypes
Genomics Institute at UCSC has developed Tumor Map, a tool that lays out cancer
samples according to the similarity of their genomic profiles for interactive exploration,
new data overlay visualization, and statistical analysis. Tumor Map plots individual
tumors as dots that form a landscape-like topology representing genomic similarity in a
framework that will be familiar to any user of Google Maps.
Heterogeneity Exists in DIPG
Nat Genet. 2014 May; 46(5): 444–450.
Biology, Maps, Precision
How to get from point A to B to C and back
again
Translational Genomics Research Institute | www.tgen.org
Mutational Burden (Somatic Coding)
Sample
IVY-01-016
IVY-01-019
Non-hypermutated
cases
(Median, Range)
2,819
1,549
64 (40-135)
121
93
6 (3-12)
Circos Plot
Full Strexome
(~20,000 genes)
# SNV and indels
GEM Panel
~567 genes
# Mutations in Genes
Covered by Panel
ATRX
I1680T
ARHGAP33 R303Q
TNFRSF10A I38M
CDK16
I231V
Patient1
RAB8A SPLICE_SITE_ACCEPTOR
PARPBP Q59E
ARHGAP17
EGFR
TNFRSF10B
PDGFRA
P777S
A289V
T125
L1108F
EGFR
I106S
ATM
E281*
ARHGEF19 A686D
MAP3K5 E512K
SPLICE_SITE_ACCEPTOR
S229C
C2F
E495
Primary
Relapse
Post-Relapse
NOTCH3
EGFR
PIK3AP1
SLIT1
EGFR A289D
Patient 01 network analysis
‘Ideal’ Therapeutic Pipeline
biology
pre-clinical
testing
human trials
Development of Brainstem Tumor Model
NSCID
Nude
Biopsy
Rat
Brainstem injection
NSCID
SC injection
High Grade
SF8628
hTERT
Low Grade
SF7761
+
LTR
GAG
BamHI
Primary cell culture
SV40
blast
LTR
EcoRI
hTERT modification
Immortalized cells
Luciferase
modification
H3K27M Mutation in DIPG Cells
1. Levels of H3K27 di- and trimethylation (H3K27me2 and H3K27me3) are
reduced globally in H3.3K27M patient cell lines (H3.3K27M)
2. H3K27me3 and Ezh2 are dramatically increased at hundreds of gene
loci in H3.3K27M cells
3. Gain of H3K27me3 and Ezh2 at gene promoters alters the expression of
genes that are associated with various cancer pathways.
GSK-J4 Inhibits Tumor Growth in vivo
Nature Medicine 20(12):1394 (2014)
GSK-J1 – Selective JMJ Demethylase
Inhibitor
Nature 488:404-8 (2012)
Therapeutic Pipeline - Challenges
biology
• Key biologic
correlative studies
performed with
difficulty
• Pure science
(initially) may not
have a translational
link
pre-clinical
testing
• Limited emphasis
placed on model
development
• Are relevant models
used?
• Throughput?
• Role of NCI?
human trials
• Study design for
conventional phase
I trials does not
favor novel
treatment strategies
• Participation of
drug company
essential is often
limiting factor
(orphan drug)
Therapeutic Pipeline - Recommendations
biology
• Comprehensive
molecular
analyses required
• Centralized data
review and
prioritization
pre-clinical
testing
human trials
• Tightly linked to
predicted biologic
endpoints
• Standardized model
systems
• Parallel inclusion of
pharma; incentives
required
• NCI/NIH (?)
• Surgical templates
• Early inclusion of
regulatory agencies
• Most pediatric CNS
tumors should be
viewed as rare
disease problems
• Separate delivery
and efficacy
Biology, Maps, Precision
How to get from point A to B to C and back
again
Overall therapeutic approach
Newly diagnosed children (< 25 years) with
High Grade Glioma (HGG) or DIPG (n=60)
• HLA2 + and
• H3.3K27 M +
PNOC007:
K27M peptide
Vaccine trial
•
•
•
•
HGG (DIPG excluded)
Fully resected
HLA2 negative or
H3.3K27M negative
PNOC012:
Dendritic Cell
Vaccine trial
Anti-PD-1
plus XRT
• Not suitable for
PNOC012 or 07
CED
CPT11 for
DIPG
Precision
Medicine
Approach