Curing Cancer

John Marshall, MD
Professor of Medicine and Oncology
Georgetown University
Lombardi Comprehensive Cancer Center

1
 The War on Cancer is Declared
Richard Nixon, 1971
 "I will also ask for an appropriation of an extra
$100 million to launch an intensive campaign to
find a cure for cancer, and I will ask later for
whatever additional funds can effectively be
used. The time has come in America when the
same kind of concentrated effort that split the
atom and took man to the moon should be
turned toward conquering this dread disease.
Let us make a total national commitment to
achieve this goal."
 NCI Funding 2005-07

The US spent $5.6 billion on cancer research in 2006

 Cancer Research –
A Super Fraud?
 "Everyone should know that most cancer
research is largely a fraud and that the
major cancer research organizations are
derelict in their duties to the people who
support them." - Linus Pauling PhD (Two-
time Nobel Prize winner).
 What went right?
 Have cured and conquered some cancers
 Leukemia
 Lymphoma
 Germ Cell cancers
 Childhood Cancers
 Screening/Early Detection/Prevention
 Breast, Colon, Cervix, Skin
 The view from 35,000 feet

Everything looks the same from up here

 What went wrong?
 Adenocarcinomas
 Progression free survival
 Declaring response rates do not correlate
with survival
 Accepting low response rates
 Health Care Costs, no sense of value
 How it happened
$$ US Industry
$$
Health Insurance/
Government Pharma

$$ $$

Patient/Consumer $$
$$

Hospitals, Services Physicians, Providers

 “Success” in the Treatment
of Colorectal Cancer
1980 1985 1990 1995 2000 2005

5-FU
Irinotecan
Capecitabine
Oxaliplatin

{
Cetuximab
Targeted therapies Bevacizumab
Therapeutic concepts Panitumumab
Palliative chemotherapy

Adjuvant chemotherapy

Neoadjuvant chemotherapy
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 NCCN Guidelines: Advanced/MCRC
First-Line Second-Line Third- or Fourth-Line
FOLFIRI or Cetuximab or panitumumab
Irinotecan or cetuximab + irinotecan
FOLFOX + BEV or
CapeOx + BEV
FOLFIRI + cetuximab or Clinical trial or best
Cetuximab + irinotecan supportive care

Good FOLFOX or CapeOx

Cetuximab or panitumumab
or cetuximab + irinotecan
Tolerance FOLFIRI + BEV
to Intensive Cetuximab or panitumumab
FOLFOX or CapeOx
Therapy or cetuximab + irinotecan

FOLFOX or CapeOx
5-FU/LV + BEV
Irinotecan or FOLFIRI
Cetuximab or panitumumab
Irinotecan
or cetuximab + irinotecan

Poor Therapy after first

Improvement in functional status progression as above
Tolerance Cape BEV or
to Intensive 5-FU + LV BEV

Therapy No improvement in functional status Best supportive care

NCCN Clinical Practice Guidelines in Oncology. Colon Cancer. v2.2007.

11
 First-Line Bevacizumab in MCRC:
Overall Survival
AVF2107g NO16966 BICC-C TREE-2

30 28.0
26.0 27.0
a b
25 23.1
20.3 19.9 21.3 20.7
19.2
20 17.6
OS (mo)

15.6
15

10

0
IF

FO

FO

FO

FO

bF

Ca
IF

IF

IF

FO
L

pe
LF

LF

LF

LF
+

LF

O
O

IR

IR
be

x
X/

X/

be

O
I

I+

be
va

+
X
Ca

Ca

va
ci

va

be
be

+
pe

pe
zu

ci

ci

va
be
va

zu
O

O
m

zu

ci
va
ci
x

x
ab

zu
zu

ci
+

ab

ab

m
zu
B

m
ev

ab
ab

m
ab
aP<0.001; bP=0.0769.

Fuchs et al. ASCO, 2007. Abstract 4027; Hochster et al. ASCO, 2006. Abstract 3510;
Hurwitz et al. N Engl J Med. 2004;350:2335; Saltz et al. J Clin Oncol. 2008;26:2013.
12
EGFR: One of Many Signaling Modules
in Cancer Cells

Hanahan, Weinberg, Cell 100:57, 2000 13

What is the Role of the Epidermal Growth Factor
Receptor (EGFR) in Cancer?

EGFR
Cell Membrane

Shc
Grb2
PI3-K Sos-1

Ras
AKT Signaling
Raf
MEKK-1 Proteins
MEK
mTOR MKK-7

ERK
JNK

Cell
Response
to Signaling
Apoptosis Proliferation Angiogenesis Metastasis
Resistance 14
Pathway vs. Network signaling

Pathway Network
“Newtonian” “Chaotic”
A. Friedman and N. Perrimon, Cell 128, January 26, 2007 15
 EGFR

Shc
Grb2
PI3-K Sos-1

Ras
AKT Signaling
Raf
MEKK-1 Proteins
MEK
mTOR MKK-7

ERK
JNK

Cell
Response
to Signaling
Apoptosis Proliferation Angiogenesis Metastasis
Resistance 16
Which Target?

Shc
Grb2
PI3-K Sos-1

Ras
AKT
Raf
MEKK-1

MEK
mTOR MKK-7

ERK
JNK

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 Sos-1
PI3-K

Ras
Grb2
Shc

Raf
MEK
MEKK-1

JNK
MKK-7
ERK
AKT

Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center

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 The EGF Receptor Interactome
Where’s the target?
Sos-1
PI3-K

Ras
Grb2
Shc

Raf
MEK
MEKK-1

JNK
MKK-7
ERK
AKT

638 Genes

Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center

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Adjuvant therapy for colon cancer fails
95% of the time in stage II colon cancer
We are under-treating

We are over-treating

Quasar Lancet. 2000 May 6;355(9215):1588-96

20
 NSABP C-08

mFF6 q2wk X 6 mo
R
Bev* q2wk X 1 yr

*5mg/K
21
 NSABP C-08
Disease Free Survival
100
80
60

%
40

Ev 3yDFS
mFF6+B 291 77.4 HR 0.89
20

mFF6 312 75.5

P 0.15
0

Yrs
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.522
Critical: Postsurgical ischemia
pmTOR-immunostaining (Ventana)

23
 Inconvenient Truths…
• Adjuvant therapy fails most of the time.
– Only a small percentage are cured with treatment
• Phase III trials are designed to detect small differences
– When PFS became acceptable, we decided we were not going to cure
cancer
• Clinical trial accrual in the US is at an all time low.
– We now “off shore” this to the lowest bidder, most in need?
• Cancer treatment adds relatively little to survival
– If you had to pay for it, would you?
• Cancer as a chronic disease is not the same as other chronic diseases
• The cost of colon cancer therapy now exceeds the cost of dialysis
• Many Pipeline drugs- not enough money, not enough patients?

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 We are in a time of change
• We now acknowledge the errors of the past
• We have better technology to support the war
– A new kind of war

• We know that success will require work, collaboration and

sacrifice
• The rewards are unimaginable
• Are our hearts in this? Do we have the stomach for it?

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A Proposal for New Drug Development in
Cancer
10 Patient Phase II Trials

Molecular
Enrichment

Molecular
Enrichment

Repeat

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 Where we are Where we need to be
Safety and Efficacy Value

Cancers are the same Cancers are different

Defining cancers by site of origin Defining cancers by molecular

profile

Phase III trials with PFS as Phase II trials with response rate as
endpoint endpoint

Only watching the tumor Watching the tumor and the host
response

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 The White House

US Capitol

My office

Pentagon

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