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

Major Obstacles to Curing Cancer

Evolvability

Networked redundancy

Hanahan, D and Weinberg, RA Cell 100:57-70, 2000

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

A path forward: Altering the cellular landscape

in which cancers occur

Making proteins in cells

Hemoglobin GFP

But, function requires proper folding…

When proteins misfold…

Control Heat

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!

v-Src GAL promoter

accumulation

Wt hsp90

activity

Wt hsp90 Wt hsp90

c-Src

activity

Long exposure

Hsp90 drug reverses transformation

v-Src v-Src + drug

Signal Transduction Networks and Hsp90

HSP90 inhibition prevents antifungal drug resistance

Leah Cowen

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

Hsf1+/+

Hsf1-/-

Hsf1-deficiency dramatically suppresses skin carcinogenesis

Hsf1-deficiency reduces skin tumor burden

…and prolongs animal survival

HSF1 is activated in breast cancers

T. Ince, BWH

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

Cancer cells are “addicted” to HSF1

shRNAi-mediated knockdown

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

Acknowledgments Susan Lindquist Chengkai Dai Sandro Santagata Melissa Duquette

Whitehead Institute

Synta Pharmaceuticals David Proia

Broad Institute RNAi platform & Screening platform

Funding NIH/NCI

J&J COSAT Program Komen Foundation

Dana Farber Cancer Institute Nancy Lin