1845-1923

High Spatial ResolutionHigh Spatial ResolutionCT, MRI, Optical, & USCT, MRI, Optical, & US MRI ImagingMRI Imaging

– High Density, Internalizing ReceptorsHigh Density, Internalizing Receptors Transferrin receptor w. Transferrin Transferrin receptor w. Transferrin

MIONMION Optical ImagingOptical Imaging

– Physiologic measurementsPhysiologic measurements Volume, flow, Hb OVolume, flow, Hb O22

– Fluorescent-labeled ligandsFluorescent-labeled ligands Ultrasound ImagingUltrasound Imaging

– Physiologic measurementsPhysiologic measurements– Targeting with a single, site-directed Targeting with a single, site-directed

bubble.bubble.

The Advantage of Radionuclides The Advantage of Radionuclides for Targeted Imaging, especially for Targeted Imaging, especially

Low Density Sites (<20 nM)Low Density Sites (<20 nM)

If 10 mCi at a specific activity of >1000 If 10 mCi at a specific activity of >1000 µCi/nmol: 10 nmol/70 Kg µCi/nmol: 10 nmol/70 Kg

<0.2 nM<0.2 nM

For Gd MRI:.For Gd MRI:.

Iron oxide (T2) increases sensitivity.Iron oxide (T2) increases sensitivity.

10-100 µM10-100 µM

For iodinated contrast mediaFor iodinated contrast media >100 µM>100 µM

Optical imaging and UltrasoundOptical imaging and Ultrasound ??

George Charles de HevesyGeorge Charles de Hevesy The first to identify the radioisotope tracer

principle. In 1923, he used 10.6 hour lead-212 to

study the uptake of solutions in bean plants, noninvasively. Used small, non-toxic amounts given the sensitivity of the radioactivity techniques.

The first experiment in animals used Bi-210 to label and follow the circulation of Bi-containing antisyphilitic drugs in rabbits.

In a later book with Fritz Paneth, the tracer method was introduced as the use of radioelements as indicators.

•The first practical application of a radioisotope was made by George de Hevesy in 1911.

•He suspected that meals that appeared regularly might be made from leftovers.

•To confirm these suspicions de Hevesy put a small amount of radioactive material into the remains of a meal.

•When the same meal was served, it was radioactive!

History has forgotten the landlady, but George de Hevesy went on to win the Nobel prize in 1943 and the Atoms for Peace award in 1959.

Imaging the In Vivo Imaging the In Vivo Distribution of a Gamma Distribution of a Gamma

Emitting RadioisotopeEmitting Radioisotope

Unprecedented ProgressUnprecedented Progress 1937 Discovery of the element Tc1937 Discovery of the element Tc 1947 Isolation of Tc-991947 Isolation of Tc-99 1958 Technetium Generator1958 Technetium Generator 1970 Instant DTPA, HSA, & RBC Kits1970 Instant DTPA, HSA, & RBC Kits 1978 Crystal structures of potential Tc 1978 Crystal structures of potential Tc

radiopharmaceuticalsradiopharmaceuticals 2002-present2002-present

– Smaller, neutral, more polar inert chelatesSmaller, neutral, more polar inert chelates– Maximal effective specific activityMaximal effective specific activity– Tc labeled molecules ~300 MWTc labeled molecules ~300 MW

1934 photo of Livingston and 1934 photo of Livingston and Lawrence with the 27” cyclotron at Lawrence with the 27” cyclotron at

LBLLBL

In 1938, Glenn Seaborg and Emilio In 1938, Glenn Seaborg and Emilio Segre discovered Technetium-Segre discovered Technetium-

99m.99m.

Walter Tucker Walter Tucker Powell RichardsPowell Richards

Mechanism: TcOMechanism: TcO44-- + stannous ion = reduced Tc + stannous ion = reduced Tc

+ chelating agent or particle = + chelating agent or particle = final product final product

Kit components = stannous salt (reducing agent) & chelating agent or particle

RS-[RS-[123123I]IQNB on 5/11/83I]IQNB on 5/11/83

Market Analysis and Future ProspectsMarket Analysis and Future Prospects

U.S. sales of diagnostic radiopharmaceuticals reached $1.53 billion in 2004 and are expected to rise to $3.20 billion by 2010. – This growth will be based on introduction of new

products, strong demand for cardiology procedures and increased sales of oncology products, particularly FDG for PET imaging.

Nuclear cardiology sales of $1.06 billion in 2004 will increase to $1.89 billion by 2010.

FDG sales for oncology as well as cardiology and neurology will increase from $249 million in 2004 to $522 million by 2010. – In addition, new PET radiopharmaceuticals in the

pipeline for specialized applications should add to these sales estimates.

Market Analysis and Future Market Analysis and Future ProspectsProspects

U.S. sales of therapeutic radiopharmaceuticals were still on the threshold in 2005, with total sales of $57 million. – Rapid growth is anticipated over the next 5-6 years.

By 2012, therapeutic product sales should reach $1.9 billion, with high continuing growth beyond that time.

– This will be based on the introduction of new therapeutic radiopharmaceuticals for treating lymphoma, colon cancer, lung cancer, prostate cancer, bone cancer and other persistent cancers. These agents will be used in conjunction with traditional therapies, enhancing their effectiveness, with better specificity and reduced side effects. Individualized Medicine!

DEVELOPMENT OF DEVELOPMENT OF Enzyme/Receptor Targeting in Enzyme/Receptor Targeting in

humanshumans

DATEDATE PETPET SPECTSPECT

19771977 [[1818F]FDGF]FDG

19831983 [[1111C]N-MeSpipC]N-MeSpip[[123123I]IQNBI]IQNB

1984*1984* [[1818F]CyclofoxyF]Cyclofoxy

19851985 [[1111C]RacloprideC]Raclopride[[99m99mTc]NGATc]NGA

19851985 [[1111C]CarfentanilC]Carfentanil

19851985 [[1111C]FlumazenilC]FlumazenilHow many radiotracers have changed clinical care?

How many have been used in combination with pharmaceuticals?

The Principle of PET: Coincidence Detection of Two 511 KeV Gamma

Rays is Used to Determine the Position

PET RADIONUCLIDE PET RADIONUCLIDE PRODUCTIONPRODUCTION

TT1/2 1/2 ((minmin)) EE+ + (kev)(kev) Nuclear ReactionNuclear Reaction

8282RbRb 1.31.3 33503350 8282Sr generatorSr generator1111CC 20 20 960960 1414N (p,N (p,)) w. 6 ppm Ow. 6 ppm O22

1313NN 10 10 11901190 1616O (p,O (p,))1515OO 2.05 2.05 17201720 1414N (d,n) N (d,n) w. 2% Ow. 2% O22

1818FF 109.6 109.6 635635 2020Ne (d,Ne (d,) ) w. 0.5%Fw. 0.5%F22

1818FF 109.6109.6 635635 1818O (p,n)O (p,n)

7676BrBr 966966 39803980 7575As (As (,3n),3n)6464CuCu 762762 571571 6464Ni (p,n)Ni (p,n)124124II 59765976 21342134 124124Te (p,n)Te (p,n)

FDG:1976 to FDG:1976 to 20022002

Imaging Saturable Sites Imaging Saturable Sites with MRIwith MRI

Relatively High Capacity, Internalizing Sites.Relatively High Capacity, Internalizing Sites.– Mion-TransferrinMion-Transferrin

Substrates For Enzymes.Substrates For Enzymes.– FDGFDG

High Capacity, Non-internalizing Binding Sites.High Capacity, Non-internalizing Binding Sites.– A Gd complex of polyDTPA polyneogalactosyl dextran.A Gd complex of polyDTPA polyneogalactosyl dextran.

Low Capacity, Non-internalizing Binding Sites.Low Capacity, Non-internalizing Binding Sites.– Gd antibodies targeted to solid tumors.Gd antibodies targeted to solid tumors.– Gd labeled antibodies targeted to endothelial sites.Gd labeled antibodies targeted to endothelial sites.

In Vivo MR Imaging: In Vivo MR Imaging: MR image of a MR image of a mouse with TfR+ and TfR- flank tumorsmouse with TfR+ and TfR- flank tumors

(a) The T1-weighted coronal SE image (3.5 min; 0.3x0.3x3 mm3 resolution). TfR- tumors (right arrowhead) and TfR+ tumors (left arrowhead) have similar signal intensity. (b) Corresponding T2-weighted gradient echo image showing significant difference (8 min; same resolution). TfR-mediated cellular accumulation of the superparamagnetic probe decreases signal intensity as expected using T2- and T2*-weighted imaging pulse sequences on cellular internalization. (c) Composite of a T1-weighted spin echo image obtained for anatomic detail with superimposed R2 changes after Tf-MION administration displayed in a color map.

Other Imaging Modalities for desialylated Other Imaging Modalities for desialylated glycoproteins binding to the high capacity glycoproteins binding to the high capacity

(~500 nM) hepatic binding protein(~500 nM) hepatic binding protein

[Gd]DTPA-galactosyl-Dextran

Post-injection: 3.8 minLiver: 66 % Enhancement

How can targeted imaging How can targeted imaging accelerate drug discovery?accelerate drug discovery?

William C Eckelman PhDWilliam C Eckelman PhD

Bethesda MDBethesda MD

Definitions: Molecular ImagingDefinitions: Molecular Imaging

The term molecular imaging can be broadly defined as The term molecular imaging can be broadly defined as the in vivo characterization and measurement of the in vivo characterization and measurement of biologic processes at the cellular and molecular level. biologic processes at the cellular and molecular level. [Weissleder & Mahmood, Radiology 2001].[Weissleder & Mahmood, Radiology 2001].

MI techniques directly or indirectly monitor and record MI techniques directly or indirectly monitor and record the spatiotemporal distribution of molecular or cellular the spatiotemporal distribution of molecular or cellular processes for biochemical, biologic, diagnostic, or processes for biochemical, biologic, diagnostic, or therapeutic applications [Thakur & Lentle, Radiology therapeutic applications [Thakur & Lentle, Radiology 2005].2005].

Targeting ProteinsTargeting ProteinsThe Magic BulletThe Magic Bullet

Paul Ehrlich used the English expression Paul Ehrlich used the English expression “magic bullet” for the first time in his “magic bullet” for the first time in his Harben Lectures. The German word Harben Lectures. The German word “Zauberkugel” appears earlier in his “Zauberkugel” appears earlier in his thoughts and publications, based on his thoughts and publications, based on his view of “sidechains”, the precursor of our view of “sidechains”, the precursor of our concept of receptors, and on the desirable concept of receptors, and on the desirable property of drugs that must not harm the property of drugs that must not harm the host, but attach the parasitic invader.host, but attach the parasitic invader.

Royal Institute of Public Health (London:Lewis, 1908), Experimental Royal Institute of Public Health (London:Lewis, 1908), Experimental Researches on Specific therapy. On immunity with special references to the Researches on Specific therapy. On immunity with special references to the relationship between distribution and action of antigens, 107.relationship between distribution and action of antigens, 107.

The Magic BulletThe Magic Bullet

Ehrlich’s first magic bullet was Ehrlich’s first magic bullet was Salvarsan or arsphenamine, discovered Salvarsan or arsphenamine, discovered in 1909, which provided the only cure for in 1909, which provided the only cure for syphilis. syphilis. Ehrlich also thought of attaching toxins Ehrlich also thought of attaching toxins to antibodies whereby the antibody to antibodies whereby the antibody would carry the deadly freight to the site would carry the deadly freight to the site of the invading parasite. His idea lives on of the invading parasite. His idea lives on in the development of immunotoxins.in the development of immunotoxins.

Both the lock and the key are Both the lock and the key are necessary in Targeted Imagingnecessary in Targeted Imaging

99m99mTcDTPA or GdDTPA in GFR measurements is a key TcDTPA or GdDTPA in GFR measurements is a key without a specific target (lock). GFR is a nontargeted without a specific target (lock). GFR is a nontargeted process.process.

[[1818F]FP-TZTP is a M2 muscarinic agonist, which is F]FP-TZTP is a M2 muscarinic agonist, which is transported non specifically across the BBB, but binds transported non specifically across the BBB, but binds specifically to the M2 receptor (the lock).specifically to the M2 receptor (the lock).

Doxorubicin in liposomes is not a targeted drug Doxorubicin in liposomes is not a targeted drug although the therapeutic effect is increased by although the therapeutic effect is increased by improvement in liver tox profile.improvement in liver tox profile.

Emil Fischer, 1894

Imaging & “Molecular TargetingImaging & “Molecular Targeting””

Interactions between a probe and a protein Interactions between a probe and a protein target using pre-genomic techniques.target using pre-genomic techniques.– ““Biochemical probes” such as iodide (~50 years), Biochemical probes” such as iodide (~50 years),

receptor binding radiotracers and monoclonal receptor binding radiotracers and monoclonal antibodies (~25 years) from autopsy, linkage and antibodies (~25 years) from autopsy, linkage and drug efficacy, etc.drug efficacy, etc.

Interactions between a probe and a protein Interactions between a probe and a protein target using post-genomic techniques.target using post-genomic techniques.– Molecular biology, proteomics, genomics, Molecular biology, proteomics, genomics,

antisense, reporter genes, protein-protein antisense, reporter genes, protein-protein interactions. More targets (500 2000-3000) interactions. More targets (500 2000-3000)

Why is Targeted Imaging Why is Targeted Imaging becoming more important in Drug becoming more important in Drug

Development?Development? As the pharmaceutical industry turns As the pharmaceutical industry turns

to targeted drugs, targeted imaging is to targeted drugs, targeted imaging is well positioned to “biomark” the drug well positioned to “biomark” the drug potential.potential.

Target identification is dependent Target identification is dependent upon clinical research, i.e., upon clinical research, i.e., “humanomics” should be the study of “humanomics” should be the study of choice.choice.

Lindsay MA. Finding new drug targets in the 21st century. DDT 2005: 23/24: 1683.

The Druggable genomeThe Druggable genome

Russ & Lampel. The Druggable genone: an update. DDT 2005: 23/24: 1607.

Nucl Horm R

Measuring Targeting Measuring Targeting with Imagingwith Imaging for targets of for targets of

differing densitydiffering density

In Vitro B/F = BIn Vitro B/F = Bmaxmax/K/Kii

Imaging requires B/F ratio ~5, Drugs Imaging requires B/F ratio ~5, Drugs

do notdo not

Measuring the In Vivo Binding Parameters Measuring the In Vivo Binding Parameters of [of [1818F]-Fallypride in Monkeys Using a PET F]-Fallypride in Monkeys Using a PET

Multiple-Injection Protocol.Multiple-Injection Protocol.Bmax Bmax (nM)(nM)

Bmax/KBmax/KDD

(theory)(theory)

LRR LRR (DVR)(DVR)

DA OCCDA OCC

AMPAMPKKoffoff

minmin-1-1

putameputamenn

2727 900900 2222 19%19% 0.0430.043

0.0280.028

caudatecaudate 2323 767767 2424 18%18% 0.0430.043

0.0290.029

v. v. striatumstriatum

1414 467467 44 18%18% 0.0300.030

0.0250.025

0.0260.026

thalamuthalamuss

1.81.8 6060 22 24%24% 0.0560.056

0.0350.035

0.0540.054

amygdalamygdalaa

0.90.9 3030 22 39%39% 0.0420.042

0.0360.036

0.0520.052

Mukherjee 2005

Measuring Measuring occupancyoccupancy

with Imagingwith Imaging for a successful for a successful

treatmenttreatment

NormalControl

MethadoneMaintained

Patient

Specific binding of [18F]Cyclofoxy was lower by 29 to 32% in Methadone Maintained Patients.

Kling et al., J Pharm Exp Therap, 295: 1070-1076, 2000

Thalamus 32  ± 15Amygdala 24  ± 30Caudate 24  ± 19Ant. cingulate cortex 29  ± 20

Measuring Measuring OccupancyOccupancy with Imaging with Imaging

for Multi-target drugsfor Multi-target drugs

A single target drug with a multi-A single target drug with a multi-target radiotracer.target radiotracer.

A multi-target drug with a single A multi-target drug with a single target radiotracer.target radiotracer.

M100907 as measured M100907 as measured using [using [1111C]NMSP PET in C]NMSP PET in

humans humans

Measure possible 5-HTMeasure possible 5-HT2A2A receptor receptor occupancy by measuring frontal cortex to occupancy by measuring frontal cortex to cerebellum ratio.cerebellum ratio.

Measure possible D2 receptor occupancy Measure possible D2 receptor occupancy by measuring striatum to cerebellum ratio.by measuring striatum to cerebellum ratio.

Is the Occupancy related to plasma Is the Occupancy related to plasma concentration?concentration?

Is the Occupancy time course related to Is the Occupancy time course related to plasma concentration?plasma concentration?

[[1111C]NMSP Binding at C]NMSP Binding at 5-HT5-HT2A2A & D2 receptors & D2 receptors

Schizophrenia and Schizophrenia and Antipsychotic DrugsAntipsychotic Drugs

M100907 (aka MDL 100907) is a M100907 (aka MDL 100907) is a potent and selective 5-HTpotent and selective 5-HT2A2A receptor receptor antagonist, but does not bind to the antagonist, but does not bind to the D2 receptor.D2 receptor.

Therefore, it has the profile of an Therefore, it has the profile of an atypical antipsychotic agent.atypical antipsychotic agent.

[[1111C]NMSP can be used to monitor 5-C]NMSP can be used to monitor 5-HTHT2A2A and D2 receptor density and D2 receptor density changes.changes. J Clin Pharmacol Suppl 1999

Sensitivity/Sensitivity/IdentifiabilityIdentifiability

for Drug Changesfor Drug Changes

Measuring endogenous Measuring endogenous transmitter changestransmitter changes

Measuring increased Measuring increased

dopaminedopamine..

22.3% (±2.7) in 22.3% (±2.7) in schizophrenia vs. schizophrenia vs. 15.5% (±1.8) in 15.5% (±1.8) in

controls.controls.

Schizophrenia is Schizophrenia is associated with elevated associated with elevated amphetamine-induced amphetamine-induced

synaptic dopamine.synaptic dopamine.Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A, Weinberger DR, Weisenfeld N, Malhotra AK, Eckelman WC, Pickar D.

Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2569-74.

Measuring Measuring increased increased

acetylcholine.acetylcholine.

[[1818F]FP-TZTP as a F]FP-TZTP as a probe for AChE probe for AChE

inhibitors such as inhibitors such as donepezil, donepezil,

rivastigmine, & rivastigmine, & tacrine. tacrine.

Increased ACh and 15%

decrease of [18F]FP-TZTP in

Ctx.

Control Physostigmine

Carson RE, Kiesewetter DO, Jagoda E, Der MG, Herscovitch P, Eckelman WC. Muscarinic with [18F]FP-TZTP: control and competition studies.J Cereb Blood Flow Metab. 1998 Oct;18(10):1130-42.

Individualized Individualized MedicineMedicine

Current Individualized Current Individualized MedicineMedicine

Metastatic pheochromocytoma (Pheo) can be detected using [123I]MIBG (or it that is not available [131I]MIBG can be used) prior to therapy with [131I]MIBG. The mechanism of localization is based on the neuroendocrine character of this disease with the the norepinephrine transporter (NET) being the key biochemical parameter. Up to 73% of PHEO cells in vitro express somatostatin receptors so patients with Pheo have been assessed with somatostatin receptor imaging (with either [123I]Tyr3-octreotide or [111In]DTPA-octreotide). Since the presence of NET and SSR appear to be inversely related and dependent on cell differentiation, imaging both pathways can be instrumental in choosing therapy.

Current Individualized Current Individualized MedicineMedicine

The American College of Radiology has recently set practice guidelines for [90Y]ibritumomab tiuxetan (Zevalin) and [131I]tositumomab (Bexxar), which are approved by the FDA for radioimmunotherapy of non-Hodgkin’s lymphoma.

Both antibodies are directed against the CD20 antigen, which is found on the surface of normal and malignant B lymphocytes.

The preliminary imaging studies are to determine dosimetry or assess biodistribution before the radiotherapeutic is administered. The package insert for these two radiotherapeutics has guidelines for interpreting the imaging study and these guidelines must be met before the therapy can commence.

Targeted Drugs Targeted Drugs Targeted ImagingTargeted Imaging

Trastuzumab for HER2 (aka ErbB2 & Neu)– A cell surface glycoprotein with TK activity– HER2 amplification/over-expression is

predictive for response in breast caner.– Overexpression became an entry criteria

and higher objective response was related to level of overexpression.

Imaging study was developed with Ab fragment to match the Ga-68 half life.

tra STUH zoo mab; Herceptin

Imaging HER2 Receptor in Imaging HER2 Receptor in response to HSp90 Inhibitorsresponse to HSp90 Inhibitors

17-allylaminogeldanamycin (17-AAG) is the first Hsp90 inhibitor to be tested in a clinical trial.

Induce proteasomal degradation of HER2 by binding to Hsp90 chaperone protein.

Label the F(ab’)2 of the anti-HER2 antibody Herceptin with Ga-68.

Smith-Jones et al. Nat Biotech 2004

MicroPET images (coronal) of mice with MicroPET images (coronal) of mice with BT-474 tumors with Ga-68-DOTABT-474 tumors with Ga-68-DOTAccHF at 3 HF at 3

h before and 24 h after 17-AAGh before and 24 h after 17-AAG

Tu

mor

& k

idn

ey

Taken from Smith-Jones et al. Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors. Nat Biotechnol. 2004;22:701-6

Targeted DrugsTargeted Drugs Imatinib is an inhibitor of BCR-ABL Imatinib is an inhibitor of BCR-ABL

TK.TK. The Philadelphia chromosome and The Philadelphia chromosome and

BCR-ABL have prognostic BCR-ABL have prognostic significance for chronic myeloid significance for chronic myeloid leukemia (CML).leukemia (CML).

Also, inhibits TK of the oncogene c-Also, inhibits TK of the oncogene c-KIT in GIST.KIT in GIST.

Imatinib-resistant mutants led to BMS Imatinib-resistant mutants led to BMS 354825.354825.

im MA ta nib; Gleevec

In Vivo Proteomics:In Vivo Proteomics:FDG: Before and after GleevecFDG: Before and after Gleevec

Taken from Demetri et al.

Cancer is not a single gene Cancer is not a single gene disease, yet …..disease, yet …..

Imatinib (Gleevec)-effective in GIST and CML. Mutants appeared, but further TK inhibitors have high affinity for all mutants.

Trastuzumab (Herceptin)-best in high expressors of HER2.

Gefitinib (Iressa)-EGFR TK.– Shrinks tumor, but no change in survival

in NSCLC. Population specific.– Erlotinib (Tarceva) & Cetuximab (Erbitux)-

MAb Angiogenesis Inhibitors

DDT 2004:9:1042-1044

Golsteyn RM. DDT 2005 10(6):381.

Drivers for Targeted Drivers for Targeted ImagingImaging

Expansion of SPECT/CT complementing Expansion of SPECT/CT complementing the continued expansion of PET/CT.the continued expansion of PET/CT.

Development of the parallel field of Development of the parallel field of small animal imaging. small animal imaging.

The pharmaceutical company’s need to The pharmaceutical company’s need to increase their success rate from 17% for increase their success rate from 17% for established targets and 3% for post-established targets and 3% for post-genomic targets.genomic targets.

The FDA’s need to encourage biomarker The FDA’s need to encourage biomarker development, especially for human use.development, especially for human use.

Magnitude of the Magnitude of the opportunitiesopportunities

Failures in Phase II or Phase III are often due to Failures in Phase II or Phase III are often due to newly identified toxicity or absence of targeting.newly identified toxicity or absence of targeting.

2000 drugs have failed to target sufficiently and 2000 drugs have failed to target sufficiently and are accumulating at a rate of 150-200 per year.are accumulating at a rate of 150-200 per year.

Kola & Landis Nat Rev DD 2004:3:711-716

Arth CV CNS Inf Oncol Eye Metab Uro Women ALL

Perc

en

tag

e o

f su

ccess

Efficient “Molecular Targeting”Efficient “Molecular Targeting” Discovery & Development Discovery & Development

Streamlining drug discovery: finding Streamlining drug discovery: finding the right drug against the right the right drug against the right target to treat the right disease.target to treat the right disease.

For Targeted Imaging probes: finding For Targeted Imaging probes: finding the right molecular probe against the the right molecular probe against the right target to monitor the right right target to monitor the right disease.disease.

Molecular Probe DesignMolecular Probe Design Develop Molecular Imaging Probes that Develop Molecular Imaging Probes that

target a protein that changes early in the target a protein that changes early in the disease.disease.

Develop molecular tracers that are based on Develop molecular tracers that are based on a reductionist concept where the drug-a reductionist concept where the drug-organism interplay can be reduced to a drug-organism interplay can be reduced to a drug-target interplay.target interplay.

Collaborate with or join the Pharmaceutical Collaborate with or join the Pharmaceutical IndustryIndustry

OpportunitiesOpportunities

University FacultyUniversity Faculty– Chemistry deptChemistry dept– Pharmacology deptPharmacology dept– Radiology deptRadiology dept

Radiopharmaceutical companiesRadiopharmaceutical companies Pharmaceutical companiesPharmaceutical companies

– Drug development using imagingDrug development using imaging

Target-based drug discovery: Target-based drug discovery: Is something wrong? Is something wrong?

Physiologic targetsPhysiologic targets– For example, blood pressure measurements For example, blood pressure measurements in vivo in vivo

using potential drugs, e.g., the ACE inhibitors.using potential drugs, e.g., the ACE inhibitors. Targeted DrugsTargeted Drugs

– Gene Targets, e.g., single gene diseaseGene Targets, e.g., single gene disease– Mechanistic Targets (receptors, enzymes)Mechanistic Targets (receptors, enzymes)

Combitorial chemisty, HTS, rationale drug discoveryCombitorial chemisty, HTS, rationale drug discovery Underestimation of the complexity of the physiology Underestimation of the complexity of the physiology

and lack of relevant disease model.and lack of relevant disease model.

Targeted Imaging could play a major role.Targeted Imaging could play a major role.

Sams-Dodd, DDT 2005:10:139

Other Imaging Modalities for desialylated Other Imaging Modalities for desialylated glycoproteins binding to the high capacity glycoproteins binding to the high capacity

(~500 nM) hepatic binding protein(~500 nM) hepatic binding protein

[Gd]DTPA-galactosyl-Dextran

Post-injection: 3.8 minLiver: 66 % Enhancement

Mattrey, Hall Vera UCSD

Comparison of HER2 status between primary tumor and disseminated

tumor cells in primary breast cancer patients.

RESULTS: In 46 of 137 (34%) breast cancer patients, CK-positive cells were detectable in BM. DTC with HER2 positivity were found in 20 (43%) of these patients.

The HER2 expression on DTC was heterogeneous in 7 of 17 (41%) patients.

Concordance rate of HER2 status between primary tumor and DTC was 62%. In 12 of 20 patients with HER2 negative tumors HER2 positive DTC were detected.

HER2 positive DTC can be detected in patients with

HER2 negative primary tumors.

Solomayer EF et al. Breast Cancer Res Treat. 2006 Mar 22; [Epub ahead of print]

HER2-positive circulating tumor cells (CTC) indicate poor clinical outcome in

stage I to III breast cancer patients.

We detected one to eight CTCs in the peripheral blood of 17 of 35 patients (48.6%) presenting no overt metastasis.

As a positive control, 7 of 7 (100%) patients with metastatic disease presented positive.

The presence and frequency of HER2-positive CTCs correlated with a significantly decreased disease-free survival (P < 0.005) and overall survival (P < 0.05).

Interestingly, in 12 patients with HER2-positive CTCs, the primary tumor was negative for HER2 as assessed by immunohistochemical score and fluorescence in situ hybridization.

This study provides some evidence of a prognostic effect of HER2-positive CTCs in stage I to III breast cancer.

Wulfing P et al. Clin Cancer Res. 2006 Mar 15;12(6):1715-20.

Predictive Factors for Outcome in a Phase II Study of Gefitinib in Second-

Line Treatment of Advanced Esophageal Cancer Patients.

Gefitinib has a modest activity in second-line Gefitinib has a modest activity in second-line treatment of advanced esophageal cancer. treatment of advanced esophageal cancer.

However, the patient outcome was However, the patient outcome was significantly better in female patients and in significantly better in female patients and in patients demonstrating high EGFR patients demonstrating high EGFR expression or SCC histology. expression or SCC histology.

The selection of esophageal cancer patients The selection of esophageal cancer patients for future studies with EGFR-TKIs based on for future studies with EGFR-TKIs based on the level of EGFR expression in their tumors the level of EGFR expression in their tumors or SCC histology should be considered. or SCC histology should be considered.

Janmaat ML et al. J Clin Oncol. 2006 Apr 1;24(10):1612-9.

What makes a probe a What makes a probe a targeted molecule?targeted molecule?

Does the probe bind to the target?Does the probe bind to the target?– If there are a limited number of sites, If there are a limited number of sites,

increased mass should decrease probe increased mass should decrease probe binding.binding.

Is the delivery dependent on flow, Is the delivery dependent on flow, permeability, or permeability, or protein concentrationprotein concentration??– What does flow dependence look like?What does flow dependence look like?– What does permeability dependence look?What does permeability dependence look?

Is the probe sensitive to target change? Is the probe sensitive to target change?

Epidermal growth factor receptor Epidermal growth factor receptor inhibitors in cancer treatment.inhibitors in cancer treatment.

The epidermal growth factor receptor (EGFR) is a cellular transmembrane receptor with tyrosine kinase enzymatic activity which plays a key role in human cancer. EGFR-dependent signaling is involved in cancer cell proliferation, apoptosis, angiogenesis, invasion and metastasis.

Cetuximab (Erbitux(R)), a chimeric human-mouse monoclonal immunoglobin (Ig)G(1) antibody, which blocks ligand binding and functional activation of the EGFR, is currently registered in the USA, Switzerland and the European Union for the treatment of advanced, irinotecan-refractory colorectal cancer. Gefitinib, (Iressa((R))), a small molecule EGFR-selective inhibitor of tyrosine kinase activity which blocks EGF autophosphorylation and activation, has been the first EGFR-targeting drug to be registered in 28 countries worldwide, including the USA, for the third-line treatment of chemoresistant non-small cell lung cancer patients.

Ciardiello F. Future Oncol. 2005 Apr;1(2):221-234.

Antiangiogenic cancer therapies get their act together: current developments and future

prospects of growth factor- and growth factor receptor-targeted approaches

The identification of surrogate markers that can monitor the activity and efficacy of antiangiogenic drugs in patients belongs to the most critical challenges to exploit the full potential of antiangiogenic therapies. The opportunities and obstacles in further development of growth factor- and growth factor receptor-targeted antiangiogenic approaches for advanced cancer, including malignant melanoma, will be discussed herein with particular reference to selected ongoing clinical trials.

Gille J. Exp Dermatol. 2006 Mar;15(3):175-86.

Triage for Breast CancerTriage for Breast Cancer