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Cancer Chemotherapy: An Unfolding Story
Luke Whitesell Whitehead Institute
“Crab” Origami Zoo Robert J. Lang
April 2, 2012
Disclosure/Disclaimer
Scientific American
Luke Whitesell declares no competing
financial interests
The information presented is intended for educational
purposes only, not the diagnosis or treatment of
any individual
Current State of the Art
Childhood Leukemia
High Risk Neuroblastoma
Pro
babi
lity
of S
urvi
val (
%)
Pro
babi
lity
of S
urvi
val (
%)
Pui et al. SJCRH
Bagatell et al. CHOP
Overview 1) A brief history of cancer chemotherapy Where we have come from 2) Obstacles to a “cure” Why we’re not there yet 3) New insights and ways forward How we might get there
1940 1950 1980 2000 2004 2008 1970 1960 1990
Nitrogen
Mustard
Anti-
Metabolites
First cures of childhood leukem
ia & lym
phomas:
Com
bination therapy A
djuvant and multi-m
odality treatm
ent approaches
Large scale involvement
of pharmaceutical industry
Oncogene-targeted drugs
Angiogenesis inhibitors
Exploiting “non-oncogene”
addiction
Cancer chemotherapy: Timeline Cancer mortality begins to decline for first time
Clinical Advances
1940 1950 1980 2000 2004 2008 1970 1960 1990
Nitrogen
Mustard
Anti-
Metabolites
First cures of childhood leukem
ia & lym
phomas
Adjuvant and m
ulti-modality
treatment approaches
Large scale involvement
of pharmaceutical industry
Oncogene-targeted drugs
Angiogenesis inhibitors
Exploiting “non-oncogene”
addiction
Clinical Advances
Cytotoxicity-based Disease-oriented Target-based Phenotypic
Evolving drug discovery approaches
1940 1950 1980 2000 2004 2008 1970 1960 1990
Nitrogen
Mustard
Anti-
Metabolites
First cures of childhood leukem
ia & lym
phomas
Adjuvant and m
ulti-modality
treatment approaches
Large scale involvement
of pharmaceutical industry
Oncogene-targeted drugs
Angiogenesis inhibitors
Exploiting “non-oncogene”
addiction
Clinical Advances
Cytotoxicity-based Disease-oriented Target-based Phenotypic
Tumor biology Molecular biology Systems biology
Drug discovery approaches
Enabling scientific insights/technologies
Take Home Messages • In little more than 60 years, safe and
effective drug treatments have been developed that reliably cure some widely metastatic, previously lethal
cancers • Much of this progress has been a
history of “doing the right things for the wrong reasons”
• Clinical advances have been driven by basic scientific and technological
achievements, typically decades earlier
• Decline in U.S. cancer mortality has largely been driven by factors other
than better chemotherapy (Don’t smoke!!!)
• A generic “cure” is highly unlikely
Tumor heterogeneity
The Cancer Genome Anatomy Project, Nature 2008
88%
78% 86%
71%
Genetic alterations detected by sequencing a series of glioblastoma tumors
Tumor evolvability • Heterogeneity
• Genetic instability
• Selection pressure
Breast cancer metastasis to lung
Cancer BIOLOGY is the key obstacle-- Not the ability to make drugs
Oncogene Activation
Tumor Suppressor Loss
Targeted Drugs
Networked Robustness
Effective Therapy
Heat-shock proteins help other proteins fold
Whitesell, L & Lindquist, SL. 2005. Nature Reviews Cancer 5:761-72
HSP
HSP
Normal vs. Oncogenic Src Kinase
Self-inhibited wild-type c-Src
P mutation
Active mutant v-Src
P
P
P
P
GROW!
GROW!
GROW! P
GROW!
GROW!
PharmaDD Online 2006
Vernalis Novartis* Conforma Biogen-Idec* Serenex Pfizer* Kosan BMS* Kyowa Hakko Kogyo* Synta* Infinity AstraZeneca* Sanofi-Aventis Merck Others
2012
Hsp 90 Inhibitors: Rapid Progress
in Clinical Development
* Phase I/II clinical trials in progress
Response in a lung
metastasis Geldanamycin R = OCH3
17-AAG R = NHCH2CH=CH2
17-DMAG R = NHCH2CH2N(CH3)2
O
O
R
Me
MeOOH
Me
NH
OMe
Me
MeO
OCONH2
Hormone-refractory breast cancer
• 200,000 women diagnosed with breast cancer in US per year
• 40,000 women die of their disease • 2/3 of all breast cancers in US are ER+ • Hormonal therapy reduces risk of recurrence • Clinical benefit rate (CR+PR+SD >6 mo.) is 40-
60% in metastatic disease setting, but almost all women eventually progress
Control
GA
Tam
T+G
Outgrowth of tamoxifen-resistant clones is blocked Hsp90 inhibitor
MCF-7 Cells were grown For 1 month in the continuous presence of the indicated drugs Tamoxifen (Tam): 1 uM Geldanamycin (GA): 20 nM
Mouse Treatment Study Im
plan
t MC
F-7
Cel
ls
Impl
ant E
2 pe
llets
Ass
ign
to T
reat
men
t Arm
s Tamoxifen SQ daily
Tamoxifen SQ daily
Vehicle SQ daily
Vehicle SQ daily
STA-1474 2X Week X8
STA-1474 2X Week X8
Vehicle 2X Week X8
Vehicle 2X Week X8
Hormonal Rx Hsp90i Rx
HSP90
HSP70 HSF1 HSF1 HSF1 HSF1
HSE
Heat Shock Proteins Chaperones
Stress Heat shock factor 1 (HSF1)
HSP27 HSP40 HSP70 HSP90 “Heat-shock Response”
A genome wide transcriptional program to support malignancy
Hsf1+/+
Hsf1-/-
Resistance to transformation by oncogenic Ha-RAS
0
5
10
15
20
25
30
Ras+GFP LacZ+GFP LacZ Only
(+/+)(-/-)
Cell Type %
Pos
itive
Cel
ls
Transfection Conditions
Focus formation Transfection efficiency
Hsf1+/+
Hsf1-/-
Chemical Skin Carcinogenesis Model
Normal skin Papilloma Squamous cell
carcinoma
DMBA
TPA
mut
atio
ns
Ras <5%
Initiation Progression Maintenance
Lung Carcinoma
Non-neoplastic Lung
Prostate Carcinoma
Non-neoplastic Prostate
Colon Carcinoma
Non-neoplastic Colon
Breast Carcinoma
Non-neoplastic Breast
…and a broad range of other human cancers
HSE GFP
HSE GFP Only
+ Heat Shock
HSE GFP
Inhibitors
Screening strategy: Reporter based – Phenotypic screen Test molecules
Test molecules
HSE GFP
ON
OFF
Inducers
Broad screen (2008) – 80,000 molecules
MLPCN screen (2010) – 301,000 molecules
Phenotypic screens for selective HSF1 inhibitors
Slide #15
Rocaglamide selectively inhibit heat-shock reporter
• Large family of natural product benzofurans isolated from mahogany trees of Malaysia (Aglaia)
• Insecticidal and anticancer activities
• Total synthesis has been achieved enabling medicinal chemistry efforts
(Collaborator: John Porco, BU)
Aglaia elyptica
Rocaglamide A
Heat-shock Reporter
Control reporter
Protein folding as an anticancer target
-HSF1 can be used as a biosensor to screen for compounds that modulate protein folding in cells
-Targeting HSF1 function appears a promising anticancer strategy
-The protein folding system in cells shapes the landscape to make cancer possible -Inhibiting HSP90 can limit the development of drug-resistance in cancer cells