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Pancreatic Cancer Research
Jonathan Brody, Ph.D.
Co-director of the Jefferson Pancreatic,
Biliary, andRelated Cancer Center
Director of Surgical Research
Kimmel Cancer Center Member
Wallace Davis Professor of Surgery
Thomas Jefferson University
Pancreatic Cancer Action Network
Educational Session
04/14/2016
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May 25, 1961
“I believe we should go to the moon…
It is a most important decision that we
make as a nation.”
And 8 years later…
July 20, 1969
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1. Genetic mutations: We know a lot about the
genes involved or mutated in pancreatic.
2. Treat every aspect of the tumor (the complex
TME): We know that this is a complex tumor
compared to other tumor systems.
3. Update on early detection, monitoring disease
4. Optimize agents with existing and proven
activity (even gemcitabine)
5. Understand and identify new targets beyond
genetic lesions
Key facts, concerns, and hope in the field of
pancreatic cancer research
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Knudsen ES, O'Reilly EM, Brody JR, Witkiewicz AK. Gastroenterology. 2015 Sep 15.
1. Personalized
approach
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The progression model has not changed…. August, 2008
PanIN-1 PanIN-2 PanIN-3 Normal ductal epithelium
KRAS mutations Telomere shortening
CDKN2A loss TP53 loss SMAD4 loss BRCA2 loss
Winter, Yeo, Brody: Devita, Rosenberg: Cancer Principles & Practice of Oncology
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Gleevec
Philadelphia chromosome (P. Nowell & D. Hungerford)
Novartis
(High Throughput Screen)
Game changer:
CML, GIST
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Average development time: 15 years
Average cost: approximately $1 billion
*Studies in humans
6 years 7 years
2 years
+ +
Preclinical
Research
Preclinical
Development
Pivotal
Trials*
Clinical
Research*
FDA Review
and Approval*
Developing a targeted therapy against these mutated pathways takes time and money….
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Single-dose
treatment with
MMC (5 mg/kg)
Complemented
Empty vector
Clin Cancer Res 2005;11:7508-7515
Best example….
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Case study: BRCA2
• Mrs. Smith: Prior tongue cancer;
uterine cancer and breast cancer
• Surgery—pancreatic ductal
adenocarcinoma (PDA) by Dr. Yeo
early January 2007
Platinum-based adjuvant therapy
Patient alive and well today (~8 years)
BRCA2 (mutation, inactivation)
1. The cause of her tumor:
via a defect in genome
maintenance
2. An Achilles Heal of the tumor:
giving Mrs. Smith a great response
Team: Charles Yeo, MD,
Sarah Charles, Ph.D.
An example (rare)
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Gemcitabine
Radiation
FOLFORINOX
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0 20 40 600
20
40
60
80
100
Days
Clin
ical
ben
efit
World with no biomarkers….
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World with an effective Biomarker….
0 20 40 60 800
20
40
60
80
100
+ Biomarker A
negative biomarker A
Days
Clin
ical b
en
efit
Surgery or
Biopsy Laboratory work:
analysis to predict patient therapy
Predictive biomarkers
Optimized
adjuvant therapy
Early detection
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Sequence:
BRCA2 mutation Immunohistochemistry Expression Heatmap
Long survival Short survival
What are Biomarkers?
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Future of medicine: Personalized Medicine
WE HAVE BANKED >400 specimens to date!
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Roa et al, Under Review Cancer Research Subha Madhavan
ERCC1 and
RRM1
might be
Useful…
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Chemotherapy Predictive Markers
• Pilot Trial in Pancreatic Cancer • Patient “Tailored” Therapy (*2000 version)
Tumor Biopsy
Low RRM1
Gem - Based
High RRM1
No Gem
Low ERCC1
Platinum - Based
High ERCC1
No Platinum
Low ERCC1
GemOX
High ERCC1
No Platinum
Predictive Markers
Gemcitabine
RRM1
Platinum
ERCC1
5-FU
TS Low TS
Gem 5FU
High TS
Gem Tax
Low TS
FOLFOX
High TS
Ox - Tax
Low TS
5 - FU Tax
High TS
Tax - Iri
Michael Pishvaian, MD, Ph.D., LCC, Georgetown University
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Clinical trial over 4 institutions: TJU the lead institution
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Is the pancreatic cancer field ready for “personalized” therapy?
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Multi-Omic analysis
• NGS (DNA)
• Expression (RNA)
• Immunohistochemistry
• Phosphoprotein
Biopsy while on Front line therapy (prior to progression)
(Overview of the grant) Patient chronology: Metastatic pancreatic cancer patients
1st Disease
progression
R
A
N
D
O
M
I
Z
E
Physician’s discretion (SOC)
Molecular Tailored Therapy
2nd line
therapy
Aim 1: Clinical trial
Aim 2: V 2.0
Biopsy Biopsy upon
Progression
ORGs
ORGs
O
U
T
C
O
M
E
S
Molecular Tailored Therapy
Version 2.0 for Phase III trial
Aim 3: Resistance Pathways
ORGs
ORGs
Resistant CRCs
Additional Omic analysis
• Focused genomic sequencing
• RNA seq
• Phosphoprotein
• Post-transcriptional
New targets and Resistance pathways
Front line
therapy
Systems Biology
2nd Disease
progression
Multi-Omic Analysis
*2016
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5 core Biopsies
• Validate sequencing • SNPs
• Drug sensitivity • MOP
• Protein • RNA • NGS
Develop CRCs 2D
• Orthotopic
mouse
• Xenograft
• Zebratars
David Tuveson, Cold Spring
Harbor
Correlative science
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Sue Chand, a graduate student,
actively plating cancer cells for
organoid growth
On top of the 1 million dollar grant we raised >500K for the organoid lab.
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SURGICAL
BIOPSY
GENERATE
ORGANOIDS
WHOLE
EXOME
SEQUENCE
FOCUSED DRUG
SCREENING
PERTHERA TESTING
PERTHERA & Organoids: Trial Design (stage I & 2)
Jordan Winter
Talar Tatarian
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SURGICAL
RESECTION
GENERATE
ORGANOIDS
DRUG SCREENING
DEVELOP A
LIVE BIOBANK
Organoids and
Pharmacologic Tailored
Therapy (PTT) PTT
Jordan Winter
Talar Tatarian
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KYT-Perthera Workflow
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Patient 576: IDH1 Mutation
• 48 year-old female diagnosed with metastatic pancreatic cancer
• Started FOLFIRINOX – progression after nine months
• Started on a clinical trial of gemcitabine plus nab-paclitaxel plus
pembrolizumab
• Biopsy of a liver metastasis was performed while on study
FM identified an established IDH1 R132H mutation in found in GBMs
(frequency of 12% in GBM - Cosmic)
From a separate sample from the tumor we confirmed via
targeted next-generation sequencing pan cancer panel
Mutant IDH1 specific Ab H & E
IHC confirmation with an Ab against mutant IDH1
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Part II: Treat every aspect of the tumor (the
complex TME): We know that this is a
complex tumor compared to other tumor
systems.
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Fibroblasts
Collagen and elastic fibers
T cells
The many facets of targeting pancreatic cancer...
Weinberg BA, Yabar CS, Brody JR, Pishvaian MJ.
Oncology (Williston Park). 2015 Nov;29(11):809-20, 886.
2. Know your entire tumor
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IDO
IDO
T cells
T cells Regs
T cells
Cancer cells
T cells
T cells
T cells
Genotyping and expression analysis of IDO2 in human pancreatic
cancer: a novel, active target.
Witkiewicz AK1, Costantino CL, Metz R, Muller AJ, Prendergast GC,
Yeo CJ, Brody JR.
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IDO2 cooperates with Kras
IDO2 -/- genotype
Wild type genotype
IDO2-null genotype
aids therapy
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Part III: early detection and monitoring
T1 T2 T3
-5 -10 -15 -20
yrs
interval
clinical relevance
histologic progression
Death
t3 t2 t1 t0
Surgical intervention
Detectable By CT
Disseminated pancreatic
cancer
Nature. 2010; 467; 1114 Canc Res. 2000; 60: 2002. Clin Can Res. 2008; 14: 412. Clin Im. 2010; 34:277.
X
T1: tumor initiation to parental clone T2: parental clone to metastastic clone T3: dissemination to death Nature 2010; 467: 1114.
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KRAS TP53
Genetic events
Pancreatic tumorigenesis Infiltrating/metastasis
Treatment/ tumor microenvironment
Lethality
microRNAs/Chromatin changes
Darwinian selection
12 years 2 years
Nature. 2010; 467; 1114 Canc Res. 2000; 60: 2002. Clin Can Res. 2008; 14: 412. Clin Im. 2010; 34:277.
Disseminated pancreatic
cancer
Part IV: Optimize agents with existing
and proven activity (even gemcitabine)
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Pencil sketch of the DNA double helix
by Francis Crick in 1953
>RNA>Protein
Central Dogma
13104 publications
80
publications
RNA processing
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2001
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Microscopic Chronic Pancreatitis* (Non-Smoker) (Smoker) Any Fam. Hx of Cancer (Non-Smoker) (Smoker) Fam. Hx of Colon Cancer* (Non-Smoker)§ (Smoker) Fam. Hx of Prostate Cancer (Non-Smoker) (Smoker)
N/A
N/A
Fam. Hx of Breast Cancer (Non-Smoker) (Smoker) Fam. Hx of Pancreas Cancer (Non-Smoker) (Smoker)
Group 1* (Non-Smoker) (Smoker) Group 2§ (Non-Smoker)§ (Smoker)
Fam. Hx of Lung Cancer (Non-Smoker)
(Smoker) N/A
0.06 0.25 1.00 4.00 16.00
Odds Ratio (95% CI)
Risks Associated with WEE1 INDEL vs. WEE1 WT (N=99)
Smokers (N=37), Non-Smokers(N=51).
Risk of Cancer in 1st degree relatives, Odds Ratio (95% Confidence Interval).
* P < 0.05; § P = 0.06
Group 1: Colon, Rectal, Gastric, Endometrial, Ovarian
Group 2: Colon, Rectal, Gastric, Breast, Hepatobiliary, Pancreas, Endometrial, Ovary, Melanoma, Brain, Urinary
OR P
Microscopic Chronic Pancreatitis 2.403846 0.042
Microscopic Chronic Pancreatitis (Non-
Smoker) 2.285714 0.178
Microscopic Chronic Pancreatitis (Smoker) 2.428571 0.21
Familial History of Colon Cancer 6.323529 0.012
Familial History of Colon Cancer (Non-
Smoker) 5.294118 0.057
Familial History of Colon Cancer (Smoker) 0.144
Group 1 4.298387 0.016
Group 1 (Non-Smoker) 3.733333 0.095
Group 1 (Smoker) 0.132
Group 2 2.384868 0.057
Group 2 (Non-Smoker) 3.340659 0.055
Avi Nevler, MD
Struan Grant, Ph.D. (CHOP)
James Eshleman, MD/PhD (Johns
Hopkins)
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Blo
od
ve
ss
el
Tumor cells
pO2
0.1%
Hypoxia
pO2 Drug Resistance
Poor Prognosis Nature, 379 (1996),
Cancer Res, 60 (2000)
1. Lower microvessel density: drug penetration
2. Hypoxic niches: Arrested or quiescent cells become
refractory to agents targeting rapidly-dividing cells
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The Hypoxia-Inducible Proto-Oncogene PIM1
Promotes Chemoresistance
PIM1
a-Tubulin
0 6 12 24
MiaPaCa2 cells
PIM1 is a serine-threonine kinase that regulates DNA repair and therapeutic response
PIM1
Hypoxia
Inhibition of
apoptosis
e.g., BAD
Cell Cycle
Arrest
DNA Repair
Chemoresistance
The role of PIM1 expression in hypoxia-induced
chemoresistance to Oxaliplatin
0
20
40
60
80
100
120
0.01 0.1 1 10 100
Oxaliplatin (mM)
Rela
tive
Cell
Su
rviv
al (%
)
Normoxia
0
20
40
60
80
100
120
0.01 0.1 1 10 100
Oxaliplatin (mM)
Hypoxia
Hours in Hypoxia, 1%O2:
Blanco et al Oncogene 2015
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Sensitivity to Oxaliplatin in Normoxia and Hypoxia
Blanco et al Oncogene 2015
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HuR PIM1
Nuclear/cytoplasmic
Blanco et al Oncogene 2015
In patient samples cyto HuR correlates with PIM1 levels
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Nat Chem Biol. 2007 Aug;3(8):508-15.
Blanco et al Oncogene 2015
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Phase I/II Trial ofvABT-888 in
Pancreatic Cancer • Phase I – ABT-888 dose escalation
• Mixture of untreated and previously treated patients
• Phase II - two strata • Untreated vs. previously treated
Georgetown Lombardi
TJU
1 2 3 4 5 6 7 29 15 43 56
Cycle 4 Cycle 1 Cycle 3 Cycle 2
Day
Response
Assessment
5-FU CI
2400mg/m2
ABT-888
Orally BID
5-FU CI
2400mg/m2
ABT-888
Orally BID
5-FU CI
2400mg/m2
ABT-888
Orally BID
Oxaliplatin
85mg/m2
Leucovorin
400mg/m2
Oxaliplatin
85mg/m2
Leucovorin
400mg/m2
Oxaliplatin
85mg/m2
Leucovorin
400mg/m2
Oxaliplatin
85mg/m2
Leucovorin
400mg/m2
5-FU CI
2400mg/m2
ABT-888
Orally BID
Based on some of
the preliminary data
obtained from the
Pascal collaboration
Pishvaian MJ, Brody JR…. PARP inhibitor + mFOLFOX for the treatment of
pancreatic cancer, GI ASCO and ASCO presentations
Cancer Res. 2015 Sep 29;6(29):27312-31.
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PARP inhibitors translocate HuR
Untreated Veliparib Olaparib Rucaparib Niraparib Talazoparib
HuR HuR HuR HuR HuR HuR
DAPI
HuR
DAPI
HuR
DAPI
HuR
DAPI
HuR
DAPI
HuR
DAPI
HuR
Cyto
pla
sm
ic
Nucle
ar
Lamin A/C
α-Tubulin
HuR
Tota
l
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Xenograft studies with Mia.sh290 and Olaparib treatment
Vehicle only shHuR + Olap + Olap,
shHuR
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PARP1 PARP1
Trapped PARP1
PARP1
PARP1
DNA damage repair
PARP1 released
HuR cytoplamic expression
(expression and function)
Targeting HuR
Chand et al., unpublished
HuR regulates Poly ADPribose Glycohydrolase (PARG) to
modulate PARPi resistance
Veliparib Olaparib Untreated
PARP1
Histone H3
PAR
GAPDH
CH
RO
MA
TIN
-BO
UN
D F
RA
CT
ION
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Abdelmohsen and Gorospe, WIRES Res 2010
Chemotherapeutic
Efficacy:
PIM1, PARG, WEE1
TME:
PIM1, IDH1
A novel, alternative non-genetic target
for pancreatic cancer.
Part V: Understand and identify new targets beyond genetic lesions
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Would targeting RNA regulation be more effective than targeting DNA?
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A Global Synthetic Lethal approach: Multiple targets at once
Chemotherapeutic
Efficacy:
PIM1, PARG, WEE1
TME:
PIM1, IDH1
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• Discovered in bacteria as a key part of a precise immune
reaction
• Short DNA sequences are recognized and put back together
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) system
Wave of the future: Latest in DNA/RNA tech
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CRISPR plasmid was transfected into MiaPaCa2 cells in 6-well plate
48 h later GFP
positive cells were
single sorted by FACS in 96-well
plate
2-3 weeks later single cell
colonies were expanded into 24-well plate
Cells were then expanded into T-75 flask
Cells were then expanded into
6-well plate
Expanded colonies were assessed for mutations with sequencing, qPCR and Western
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CRISPR
Technology
Shruti Lal, Ph.D.
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N/A
No Tumor
N/A
No Tumor
HuR -/- cells
Xenograft lethality
Lal et al, unpublished Novartis, HuR inhibitor (Nature 2007)
Univ. of Kansas, HuR inhibitor
Genisphere, DNA dendrimer (Cancer Research, In press, Ovarian)
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Take home points
• High throughput DNA sequencing of pancreatic cancer
genomes has provided us with some validating pearls,
BRCAness: Best example for personalized therapy
• Alternative approach: Post-transcriptional gene
regulation can provide us with information about the
biology of the tumor now (not yesterday but when the
tumor is treated): Personalized therapy=Present focus
Therapy: “Pancreatic cancer Transcriptionally
addicted”
• Understanding these acute, stress response mechanisms
by tumor cells will allow us to NOW:
• 1: Optimize current therapies
• 2: Attack and find new targets
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How to make a difference against this foe?
• Multi-disciplinary conferences (surgeons, PhDs, medical
oncologists, Radiation Oncology, nutrition, geneticists, basic
scientists, medicinal chemists, bioinformatics): patient
centric
• Programmatic initiatives with authentic questions: think out
of the box type strategies
• Development/philanthropic strategies to support pilot
awards and bridge funding
• LiveBiobank: How many important questions have been
answered from a frozen BioBank (except for genetics)
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Summary of key concepts
1. Genetic mutations: We know a lot about the
genes involved or mutated in pancreatic.
2. Treat every aspect of the tumor (the complex
TME): We know that this is a complex tumor
compared to other tumor systems.
3. Update on early detection, monitoring disease
4. Optimize agents with existing and proven
activity (even gemcitabine)
5. Understand and identify new targets beyond
genetic lesions
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4/14/2016 61
Lab Members
Mahsa Zarei
Saswati Chand
Joseph Cozzitorto
Rick Burkhart
Carmella Romeo
Masaya Jimbo
Kevin O’Hayer
Shruti Lal
Fernando Blanco
Edwin Cheung
Amanda Grigoli
Avinoam Nevler
Nava Azimzadeh
Cinthya Yabar
Collaborators
Michael Pishvaian (GU)
Chip Albanese (GU)
Peter Kozuch (MS) Dan Dixon (Kansas)
George Prendergast(LIMR)-R01
Janet Sawicki (LIMR)
David Tuveson (Cold Spring)
Jonathan Sachs (Minn)- R01
Struan Grant (CHOP)
Jim Eshleman (JHU)
Tim Yen (FC)
Igor Astsaturov (FC)
TJU
Jordan Winter
Charles J. Yeo
Mark Tykocinski
Isidore Rigoutsos
Scott Waldman
Matt Weber
Ashwin Sama
Peter McCue
Paolo Fortina
John Pascal
Wei Jiang
Theresa Yeo
Support from: NCI; NIH; PanCAN-AACR; American Cancer Society; WW Smith; Fund A
Cure, Sarah Parvin Foundation; Hirshberg; Fund A CURE; Mary Halinski Pancreatic
Cancer Research Fund ; Linda Katz; Van Vance