New PET radiopharmaceuticals: targeting the L-amino acid transport

system in prostate cancer

Jørgen FrøkiærDepartment of Clinical Physiology and Nuclear Medicine

Aarhus University Hospital - SkejbyAarhus University, Denmark

JF@KI.AU.DK

ISCORN, Mikulov, May 11-14, 2010 Czech Republic

Prostate cancer epidemiology in briefHow is prostate cancer diagnosed – biomarkers?Which diagnostic modalities does nuclear medicine provide?Why target the L-amino-acid transport system?Development of and experience with novel tracersNext steps

Agenda

Prostate cancer epidemiology in briefHow is prostate cancer diagnosed – biomarkers?Staging of prostate cancerWhich diagnostic modalities does nuclear medicine provide?Why target the L-amino-transport system?Development of novel tracersNext steps

Cancer incidents in Danish males (2006)

Prostate cancer epidemiology in briefHow is prostate cancer diagnosed – biomarkers?Staging of prostate cancerWhich diagnostic modalities does nuclear medicine provide?Why target the L-amino-transport system?Development of novel tracersNext steps

Prostate cancer in Danish males (2006)

PSA and other biochemical biomarkers (screening)Symptoms (LUTS, back pain etc…)Rectal examinationBiopsi proven verification Molecular imaging ??

How is prostate cancer diagnosed?

Jani B. et al. Am J Clin Oncol 2010

Prostate cancer modality time trend analysis from 1973-2004 (USA)

Andriole GL et al. NEJM, March 26 2009

No early mortality benefit from annualprostate cancer screening (USA)

Prostate cancer is the most common malignancy in men comprising 33% of newly diagnosed cancers in the United States.Accurately detecting the presence of disease CONFINED to the prostatic bed versus that of that of extraprostatic spread to lymph nodes or the skeletal system has profound treatment implications.Ultrasound, MRI and CT may only be useful for local T stagingTHUS - there is currently no definitive imaging technique in the initial staging and restaging of prostate carcinoma.

..Some additional facts about prostate cancer

Molecular imaging with 111-In-Capromab pendetide does not demonstrate sufficient sensitivity.Prostate cancer cells has a low ability to take up 18-F-FDG and is not appropriate for clinical use. Urine excretion!PET tracers including 11-C-acetate, 11-C-choline, 11-C-methionine and 18-F-fluorocholine may characterize different metabolic aspects of prostate carcinoma.

Nuclear Medicine Imaging in Prostate Cancer

Molecular imaging with 111-In-Capromab pendetide does not demonstrate sufficient sensitivity.Prostate cancer cells has a low ability to take up 18-F-FDG and is not appropriate for clinical use. Urine excretion!PET tracers including 11-C-acetate, 11-C-choline, 11-C-methionine and 18-F-fluorocholine may characterize different metabolic aspects of prostate carcinoma.

Nuclear Medicine Imaging in Prostate Cancer

Thus there is a need for a better radiotracerwith little of no urinary excretion for the evaluationand staging of patients with prostate carcinoma

Development of L-Amino Acids analogs for PET

In the 90´ies the metabolically active amino acid L-methyl-11C-methionine was used clinically to distinguish malignant tissue from normal tissue or benign growths in the brain with PET.L-Amino Acid Transporter-1 (LAT-1) is mainly expressed in fetal tissue and cancer cells corresponding to a so-called oncofetal antigen.The movement of the naturally occuring amino acids such as L-leucine and L-methionine across tumor cell membranes occurs predominantly through carrier mediated transport by the sodium-independent LAT-1

Background

PALACIN, M. et al. Physiol. Rev. 78: 969-1054 1998

General molecular structure of ATs

Martarello L et al. J Med Chem 45:2250-59, 2002

Synthesis of the first synthetic L-amino acid analogsSynthesis of 18F-FMACBC and 18F-FACBC

Superior uptake of the anti-analogueat late time points in rat brain tumor

Shoup TM et al. JNM 40:331-338, 1999

Martarello L et al. J Med Chem 45:2250-59, 2002

Synthesis of the first synthetic L-amino acid analogsSynthesis of 18F-FMACBC and 18F-FACBC

Superior uptake of the anti-analogueat late time points in rat brain tumor

Shoup TM et al. JNM 40:331-338, 1999

SELECTION OF ANTI-18F-FACBCAS LEAD COMPOUND

Shoup TM et al. JNM 40:331-338, 1999

Biodistribution shows superior activity ratio of FACBC compared with FDG in tumor-bearing rats

18F-FACBC 18F-FDG

Biodistribution shows superior activity ratio of FACBC compared with FDG in tumor-bearing rats

18F-FACBC 18F-FDG

Shoup TM et al. JNM 40:331-338, 1999

Intense tumor uptake of 18F-FACBC in the brain

Shoup TM et al. JNM 40:331-338, 1999

MRI GdDTPA(pre-surgery)

FDG(8 wk post)

FACBC(1 wk post)

Experience with 18F-FACBC based on initial studies in tumor-bearing rats and human

There is a marked uptake of 11F-FACBC in the brain of rats with 9L gliosarcoma.High tumor accumulation of 11F-FACBC in a patient with glioblastom multiforme.High tumor to brain ratio suggest that 11F-FACBC is a potentially valuable agent for the diagnosis of metastatic disease in humans by PET.

Anti-18F-FACBC for prostate cancer detection

Prostate cancer cells are slow growingNeed a tracer with no or low urinary excretionProper cell lines available for testingGood animal models available for testing uptake in tumor cells

Basic conditions for preclinical experiments:

Anti-18F-FACBC has a higher affinity for DU145* than for 18F-FDG

Presence Absenceof natural amino acids and D-glucose in medium

*DU 145 PCa is an androgen independent human prostate cancer cell line

Oka S et al. JNM 48:46-55, 2007

Oka S et al. JNM 48:46-55, 2007

Biodistribution of anti-18F-FACBC compared with 18F-FDG in the OPCT* rat model

*OPCT is a rat model with orthotopic prostate cancer transplanatation

Oka S et al. JNM 48:46-55, 2007

Biodistribution of anti-18F-FACBC compared with 18F-FDG in the OPCT* rat model

*OPCT is a rat model with orthotopic prostate cancer transplanatation

Oka S et al. JNM 48:46-55, 2007

Higher contrast of anti-18F-FACBC than 18F-FDG in the OPCT rat model by autoradiography

A + B) FACBC

C + D) FDG

Oka S et al. JNM 48:46-55, 2007

Dynamic micro-PET study of anti-18F-FACBC and 18F-FDG in the OPCT rat model

FACBC

FDG

Oka S et al. JNM 48:46-55, 2007

Superior discrimination of tissue inflammation with anti-18F-FACBC than with 18F-FDG in the DPCI rat

*DPCI is a rat model with benign prostate hypertrophy

First clinical proof of concept study with anti-18F-FACBC for prostate cancer detection

Eight patients underwent dynamic prostate PET-CT imagingGood correlation of local FACBC uptake with either sextant biopsy or histology of the surgically removed prostateTwo patients with malignant lymph nodes had intense uptake correspondinglyIn correlation of lymph node status, 7 of 9 patients had excellent concordance of anti-18F-FACBC pelvic nodal findings with clinical follow-up.

Schuster DM et al. JNM 48:56-63, 2007

Coronal PET and CT fused anti-18F-FACBC images from 63 y-old male with bilateral prostate carcinoma

Schuster DM et al. JNM 48:56-63, 2007

Representative time-activity curve showing rapid uptake of anti-18F-FACBC in prostate carcinoma

Schuster DM et al. JNM 48:56-63, 2007

Extensive invasive prostate carcinoma with uptake of anti-18F-FACBC in left iliac lymph nodes

Schuster DM et al. JNM 48:56-63, 2007

Restaging of biopsy proven prostate carcinoma with uptake of anti-18F-FACBC in prostate bed

PET CT fused Uptake in prostate bed

Schuster DM et al. JNM 48:56-63, 2007

Schuster DM et al. JNM 48:56-63, 2007

Is LAT-1 a novel biomarker in PC?

1) Identify whether LAT-1 is a true specific biomarker for prostate cancer byComparing LAT-1 with Ki-67 labellingComparing with the Gleason score

Sakata T. et al. Pathol Int. 2009 Jan;59(1):7-18.

Molecular structure of L-Amino Acid Transporter-1(LAAT1 = SLC7A5)

Extracellular

Plasmamem

Intracellular

Sakata T. et al. Pathol Int. 2009 Jan;59(1):7-18.

Characterization of LAT-1 in prostate cancer

Extracellular

Plasmamem

Intracellular

A) Generation of higly specific monoclonal ab´s

B) Immunohistochemistry of prostate biopsies

Since anti-18F-FACBC has shown this excellent uptake within primary and metastatic prostatic carcinoma with very limited renal excretion compared with FDG Anti-18F-FACBC may therefore be helpful in detecting and in the preoperative differentiation of the more aggressive clear cell renal cell carcinoma from that of the less agressive papillary carcinoma.

Experience with anti-18F-FACBC in renal cancer

Hyper-cortical uptake of anti-18F-FACBC

Axial CT PET Fused image

Iso-cortical uptake of anti-18F-FACBC

Axial CT PET Fused image

Role of anti-18F-FACBC in renal cancer?

Anti-18F-FACBC did not prove useful in visualizing clear cell renal cell carcinoma but in the few cases demonstrated better conspicuity for papillary cell tumors. In order to determine if anti-18F-FACBC may have some utility in determining preoperatively if a lesion is a papillary cell subtype, a larger series would be necessary.

Imaging with anti-18F-FACBC demonstrates uptake in both primary and metastatic prostate carcinoma on initial staging as well as uptake in recurrent prostate carcinoma within the prostate bed, lymph nodes, and bone. Anti-18F-FACBC PET/CT has succeeded in identifying neoplastic foci, even when other tracers were negative, Anti-18F-FACBC was instrumental in directing biopsy to prove neoplastic recurrence in one patient in whom lymph nodes were not obviously enlarged.

Initial experience with anti-18F-FACBC

The IPR for the compound has been acquired by GELarger POC trials are needed for establishing a definite role ofanti-18F-FACBC in prostate cancer

Next step with anti-18F-FACBC

Thank you for your attention