what’s on the horizon for cancer imaging · phase 2 for others astrazeneca (london) olaparib...

HARVARDMEDICAL SCHOOL

Ralph Weissleder, MD, PhD

What’s on the horizon for cancer imaging ?

Tuesday, October 18, 11

Cancer incidence and mortality

Lung cancerBreast cancer

Colorectal cancer


1/19/11

2/23/11


Number of cancer patients rising≤19 yrs: 1%

20-39 yrs: 4%

40-64 yrs of age35%

65+ yrs of age60%

Source: SEER Data

World 2011 (population of 7B): 2.17 billion cancer patientsWorld 2020: 50% rise in cancer numbers (WHO)

US cancer cases

60,000,000

66,666,667

73,333,333

80,000,000

86,666,667

93,333,333

100,000,000

1970 1980 1990 2000 2010YEAR

95 M

2,000,000

3,666,667

5,333,333

7,000,000

8,666,667

10,333,333

12,000,000

1971 1978 1985 1992 1999 2006YEAR

Survivors (US)

12 M


Cancer imaging

Clinical realities• reimbursement going down• Imaging “too expensive”• Competition from outside• Not “business as usual”

any longer• Have to become more

creative• Adapt to new realities and

clinical questionsMR-PET Whole body DW MRI

University of Homburg/SaarSiemens


Questions for imaging/dx• Is cancer present ?

• Where is it ?

• What it is relationship to neighboring structures ?

• What is the total tumor volume ?

• How well does/will it respond to treatment ?

• What kind of mutations and do they predilect to tx ?

• Is the treatment optimized in a given patient ?

• How fast will it grow/metastasize ? Has it recurred ?

What new technologies/biomarkers are on the horizon to help answering the above ?


Two stories on measuring treatment response

BIND chemistry (PET)

RASSOS

RAF

MEK

RAF inhibitors

MEK inhibitors

ERK

GRB2SHC

GRB2

Transcription factors

PP

P

PI3K

PTEN

PDK

PIP3 PIP2

mTOR

S6K1 4E-BP1

elF4E

IKK I!B

NF-!BFKHR

BAD

AAAA

Growth factorRTK

RTK inhibitors

AKT

TSC1 TSC2

RHEB

Proteasomeinhibitors

ApoptosisProtein translation

PI3Kinhibitors

Transcription factors

Cell-cycle progressionSurvivalMigration

Rapamycinderivatives

Many of the signalling pathways involved intumour-cell development are initiated by theinteraction between growth factors and their

lead to the nuclear translocation of the FKHR

transcription of genes that encode pro-apoptoticfactors such as BIM and FAS ligand. Second, AKTsignalling regulates the activity of mitochondrialproteins such as BAD, which promotes apoptosis. Theseinhibitors, as well as rapamycin derivatives that inhibitmammalian target of rapamycin (mTOR), can also slow cancer-cell protein translation, mediated by factors such as S6K1,eukaryotic translation initiation factor 4E (eIF4e) and eIF4E-binding

• Angew Chem Int Edit 2011;50:1922-5• ChemMedChem 2011;6:424-7• Chembiochem 2010;11:2374-2377• Angew Chem 2009;48:7013-6 • Bioconj Chem 2008; 19: 2297-2299

FNA profiling (IR)

• Science Transl Med. 2011;3(71):71ra16• IEEE J Solid-ST Circ. 2011;46(1):342-352• Nature Nanotechnol. 2010;5(9):660-5• P Natl Acad Sci U S A. 2009;106 (30):12459-12464• Nature Med. 2008;14(8):869-74


http://ieeexplore.ieee.org/xpl/freeabs_all.jsp?arnumber=5604668

http://ieeexplore.ieee.org/xpl/freeabs_all.jsp?arnumber=5604668

20102007

Pharma industry

• TCO modification• modular Tz imaging reporters

In vivo imaging2011

Imaging O

18F

Cl

NN

NH

OSOO

S OOF3C

NH

NO

S

Tz +

Cold drug Universal 18F tag

Molecular “Velcro”


PARP inhibitors

Nat Biotech 2011; 29:373-4

Scientists at Dana-Farber Cancer Institute have uncovered the mechanism behind a promising new approach to cancer treatment: damaging cancer cells’ DNA with potent drugs while simultaneously preventing the cells from repairing themselves.


PARP-1 inhibitors in clinical trialsCompany Compound Indication Status

Sanofi-aventis (BiPar Sciences subsidiary, S. San Francisco)

Iniparib (BSI-201; 4-iodo- 3-nitrobenzamide)

Trials in squamous non–small cell lung cancer (NSCLC), ovarian cancer and uterine carcinosarcoma

Phase 3 for NSCLC; phase 2 for others

AstraZeneca (London)

Olaparib (AZD-2281; KU-59436)

Serous ovarian cancer Phase 2

Pfizer (New York) PF-01367338 (AG-014699)

Trials in triple-negative breast cancer (TNBC) or BRCA1- and BRCA2-deficient breast or ovarian cancer

Phase 2

Abbott Laboratories (Abbott Park, Illinois)

Veliparib (ABT-888)

Trials in serous ovarian cancer, BRCA1 and BRCA2-deficient breast cancer, advanced breast cancer, melanoma, colorectal cancer, HCC, cervical cancer

Phase 2

Cephalon (Frazer, Pennsylvania) CEP-9722 Trials in NSCLC and DNA repair

mismatch tumors Phase 2

Nat Biotech 2011; 29:373-4Tuesday, October 18, 11

Summary of clinical trials• Initial success in BRCA breast cancer with BRCA

mutations (phase 1 of Olaparib, Astra Zeneca) NEJM 2009;361:123-34

• Considerable hype in NEJM (from Dana Farber) and lay press

• 2011 large trials fail to meet primary survival endpoints in TNBC (Sanofi-Aventis; note that these are not BRCAneg) - stopped trials (can’t make enough $)

• Search for other subpopulations in which it works

• Search for combinations (e.g. CDK1i; Nat Med 2011;17:875-883)

• Search for new applications (ovarian ca)Tuesday, October 18, 11

Cold AZD2281 inhibitor added to cells

0

0.3

0.6

0.9

1.2

0 2 mg 4 mg

Cold AZD2281 inhibitor added in vivo

AZD

2281

-18F

SU

V

Baseline

12 hrs after inhibition

Bilateral MD-MB436 tumors (hind legs)18F-AZD2281

Chembiochem 2010;11:2374-2377; ChemMedChem 2011, 6, 424-427; Angew Chem 2011, 50, 1922-1925;

AZD2281

-1 0 1 2 30

25

50

75

100

Legend

0 1 2 3-1-20

25

50

75

100

log conc (inhibitor) [nM]

% in

hibi

tion

AZD2281AZD2281-Tz18F-AZD2281

IC50 = 8.4 ± 1.3 nMIC50 = 17.9 ± 1.1 nM

IC50 = 1.7 ± 1.4 nMNNH

O

F

N

O

N

O

18F-TCO

18F-AZD2281AZD2281-Tz

NNH

O

F

N

O

N

O

HN

O

N N

NNO

18F

NNH

O

F

N

O

N

O

HN

O

N N

18F


Other 18F-PET drugs• Taxol (microtubule inhibitor)• PLK1 inhibitors (BI2536)• AKA inhibitors (MLN)• EGFR inhibitors (Tarceva)• HDAC inhibitors (SAHA, MS275)• Bcl2 inhibitors (Navitoclax)• GLPR1 inhibitors (Exenatide)• Various therapeutic antibodies

Herceptin (Trastuzumab)AvastinErbituxanti-CTLA-4anti-TGFb anti-CD40anti-4-1BB

Bioconj Chem, 2008;19:2297-2299 Angew Chem 2009;48:7013-6 Nature Nano 2010;5:660-5 J Am Chem Soc. 2010;132:7838-9Angew Chem 2011; epub Jan 22Angew Chem 2011; in pressBioconj Chem 2011; in pressPNAS 2011; in press


Network Diagram of FDA Approved Drugs and their Targets (Human Gene Products)Tuesday, October 18, 11

Biopsy frustrations ...

Waited for path ?

Wasted time with

unnecessary biospies ?

High rebiopsy rate ?


Nat Rev Canc 2008;8:329

Venous access or tumor FNA

Affinity purification

Nat Rev Canc 2008;8:329

Molecular cancer diagnostics

Current limitations: • Enrichment and purification slow• Proteins/cells have short half-lives (hrs)• Sensitivity (thousands of cells, FACS)• Limited multiplex capability• Limited POC applications

Needle aspirates


Ham et al; IEEE 2009

World smallest NMR


How does it work ?

(n)

2. Novel reagents/assays (BOND)

Nature Nanotech. 2010;5(9):660-50 250 500 750 1000

10-1

100

101

102

103 Fe@MnFe2O4

Fe@Fe3O4

Fe@FeO

MION

CLIO

Fe3O4

Fe3O4

Diameter (nm)

6 8 10 12 14 16

Fe3O4

Saturation magnetization (kA/m)

r 2 (×

10-1

6 s-1

[par

ticle

/l]-1

)

B0 = 0.47 T

1. Sample collection

4 channel sensors

Mini magnet

Electronics

5 cm

3. On chip measurement

Integrated microfluidics15 min

TumorsTumors Normal host cellsExtracellularExtracellular IntracellularIntracellular Normal host cells

A33 Glypican-3 α-fetoprotein phospho-EGFR anti-FibroblastB7H3 Hepsin CK5 phospho-p53 Calretinin A (Mesothelial

cell)B7-H4 HER2 CK7 phospho-S6rpCalretinin A (Mesothelial cell)

CA125 HER3 CK8 PSA CD11bCD63 Mesothelin CK14 PSMA (Monocytes)CD133 MET CK18 s100A2 CD11cCEA Mucin1 CK19 s100A4 CD14Claudin-1 Mucin16 CK20 s100A6 CD15Claudin-3 Mucin18 EGFR s100A11 CD16Claudin-7 NRP1 (cytoplasmic) s100B CD19E-cadherin P-cadherin gp100 S6rp CD41EGFR PCSA Ki-67 TTF-1 CD45EGFRv3 PDGFR MAGE-1 Tyrosinase (Leukocyte)EMMPRIN Podoplanin Melan-A Vimentin CD56 (NK cell)EpCAM PSMA p53 WT1 CD68EPHA2 PSAP panCK PARP1 MCHIIFOLR1 TfR pH2AX Cleaved PARPFSH-R TSPAN8 Cleaved CASP3

uPAR


Blood

Sputum Tissue

Biospies

• Tissue penetrating

• No major sample preparation

• Fast (<1 min; total: <20 min)

• Quantitative

• Measurements in 1-100 cells (not tens of thousands

• Inherent amplification (MNP → H2O)

• Different 2nd amplification strategies

• Multiplexed sensing

• Multiple target types (DNA, protein)

• Point of care

Nat. Biotechnol. 20, 816-820 (2002); Angew. Chem. Int. Ed. Engl. 47, 4119-4121 (2008); Nat. Med. 14, 869-874 (2008);Sci Trans Med 2011;epub

Advantages


† Visceral sites include: lungs, liver, brain, adrenal glands, pancreas, and kidney. Non-visceral sites include lymph nodes, abdominal wall, breast, bones, and skin.

CD45

10 markers

Characteristic Original diagnostic setOriginal diagnostic set Independent test setIndependent test setNumber % Number %

Number of patients 50 20Age Median 64 63 Range 29-86 24-90Gender Male 24 48% 7 35% Female 26 52% 13 65%Lesion type Malignant 44 88% 14 70% Benign 6 12% 6 30%Tumor Subtypes Breast 2 4.5% 2 14% Gastrointestinal 13 30% 4 28% Genitourinary 3 6.5% 1 7% Gynecologic 4 9% 3 22% Lung 8 18% 1 7% Pancreatic 7 16% 3 22% Undifferentiated 7 16% 0 0%History Prior history of cancer 30 60% 4 20% No prior therapies 20 42% 7 35% Active treatment 11 22% 9 45%Biopsy Site†

Visceral 36 72% 9 45% Non-visceral 14 28% 11 55%Lesion Size (axial diameter)Lesion Size (axial diameter) < 1 cm 3 6% 10 50% 1-3 cm 25 50% 6 30% > 3 cm 22 44% 4 20%Biopsy Modality Ultrasound 14 28% 16 80% CT 36 72% 4 20%

Science Transl Med. 2011;3(71):71ra16


0123

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49

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1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49

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1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49

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1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49

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1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49

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1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49

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1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49

0123

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49

EpCAM

B7-H3

HER2

EGFR

Muc1

CK18

Vimentin

p53

Ki-67

NM

R s

igna

l

Patient

Marker



Technique n Diagnostic Non-diagnostic Misdiagnosis Sensitivity Specificity AccuracyFine needle aspirate 49 36 13 11 70% 100% 74%Core biopsy 50 45 5 8 82% 100% 84%DMR 50 50 0 2 100% 67% 96%

How do markers compare ?

Type Marker DMR SensitivitySpecificityAccuracy

Single

Muc1 0.25 66% 83% 68%

Single

EGFR 0.20 64% 83% 66%

Single

B7-H3 0.11 68% 67% 68%

SingleHER2 0.24 64% 100% 68%

Single Ki-67 0.10 68% 67% 68%SingleEpCam 0.21 59% 67% 60%

Single

Vimentin 0.08 59% 67% 60%

Single

CK18 0.06 73% 50% 70%

Single

p53 0.38 41% 83% 46%

Dual EpCam + CK18 (unweighted) 0.27 84% 50% 80%DualEpCam + CK18 (weighted) 0.65 73% 67% 72%

Triple Muc1 + HER2 + EGFR (weighted) 1.23 95% 67% 92%Quad Muc1 + HER2 + EGFR + EpCAM (weighted)1.6 100% 67% 96%



Follow-up (6 mo)Biopsy (2 mo)Pre-biopsy diagnostic scan

Game changing technology

0

1

2

3

MUC-1 EGFR B7-H3 Her2 Ki-67 EpCAM Vimentin CK18 p53

0.43

0

0.9

1.25

00

0.5

0.05

1.03

NM

R S

igna

l

Q4 (>1.6)Tuesday, October 18, 11


• Detection accuracy (96%) higher than for core bx (84%) or cytology (74%)

• Need for repeat bx (non-diagnostic specimen) reduced from 15/50 pt to 0 patients

• Showed real management change in individual patients

• New insight into stats of marker expression (“quad”) which will improve CTC diagnostics

• Insight into temporal markera expression and heterogeneity

• Insight into sample preparation• Several ongoing clinical trials


what’s on the horizon for cancer imaging · phase 2 for others astrazeneca (london) olaparib...

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