PSMA SPECT imaging with 99m. Tc-MIP-1404 in patients with prostate cancer (PCa): Comparison with Bone scan, CT or MRI.

Transcription

1 PSMA SPECT imaging with 99m Tc-MIP-1404 in patients with prostate cancer (PCa): Comparison with Bone scan, CT or MRI. Shankar Vallabhajosula, Ph.D., Berna Polack, M.D., Yulia S. Jhanwar, M.D. Anastasia ikolopoulou, Ph.D. Thomas W. Armor, M.S., Scott T. Tagawa, M.D., Douglas Scherr, M.D., Brian Robinson, M.D., Stanley J. Goldsmith, M.D., John W. Babich, Ph.D. Departments of Radiology, Medicine, Urologic ncology Weill Cornell Medical College, ew York, Y., and Molecular Insight Pharmaceuticals (Progenics Pharmaceuticals Inc), Tarrytown, Y. EAM 14 Abstract P345, ctober 20, 2014

2 Prostate Specific Membrane Antigen (PSMA) PSMA is a surface antigen expressed virtually on all prostate cancer cells PSMA expression increases progressively in: Higher grade tumors Metastatic disease Hormone-refractory Prostate cancer PSMA is internalized following binding PSMA is expressed also on the neo-vasculature of solid tumors but minimally on normal tissue PSMA { 7E11 Intracellular portion J591 Extracellular portion Cell membrane

3 Enzymatic Site of PSMA is known (AALADASE and PSMA are Homologous) AAG Binding to PSMA Substrate binding domain contains two basic sub-pockets Catalytic domain contains a bi-nuclear zinc binding site coordinating a water molecule where hydrolysis of peptide bond occurs The major basic patch binds glutamate via electrostatic interactions Davis et al. (2005) Proc. atl. Acad. Sci. USA 102,

4 H H H H H H H C 2 H H H H MIP-1404 (104 nm) Re-MIP-1382 (2.0 nm) H H 99m Tc-MIP-1404 H H 99m Tc(C) 3 Re-MIP-1382 (2.0 nm) H H H C 2 H H H H

5 Preparation of 99m Tc-MIP-1404 Multi-step preparation (A) Add 99m Tc 4 - to tri- carbonyl vial Add MIP precursor (100 μg) Heat the vial for 100 o C for 1 h Add 0.2 ml of HCl, 2 trap 99m Tc complex on sep- Pak wash the Sep Pak with water Elute 99m Tc- MIP with 1 ml ethanol Dilute with 9 ml saline Sterilize by membrane filtrason Kit preparation (B) Add 99m Tc 4 - to MIP-1404 kit Heat the vial for 100 o C for 1 h Add 0.2 ml of HCl, 1 Dilute with saline (3-6 ml) Sterilize by membrane filtration Radiochemical purity (RCP) Prep A = 94.2 ± 1.2 % Prep B = 93.4 ± 1.4 %

6 Vallabhajosula et al A 99m Tc-MIP-1404 A = Kit preparason B = MulS- step preparason P 679 B A simple kit preparation used for phase II studies

7 99m Tc-MIP-1404: Phase I Studies 1. MIP Protocol: (MIP-TcTx-P101) A Phase I Study of the Pharmacokinetics, Tissue Distribution and Metabolism of Small Molecule Inhibitors of PSMA, 99m Tc-MIP-1404 and 99m Tc- MIP-1405 in Patients with Metastatic Prostate Adenocarcinoma and Healthy Volunteers. 2. MIP Protocol: (MIP-TCTX-P104) A Phase 1 Pilot Study of 99m Tc-MIP-1404 SPECT)/ CT Imaging in Men with Prostate Cancer Undergoing Prostatectomy and/or Pelvic Lymph ode Dissection (PLD).

8 99m Tc-MIP-1404 Planar and SPECT in Patients with PCa : Comparison with Bone scan and CT Patient no age Gleason Score (3/4) 4.3 PSA CT Bone Scan 99m Tc- MIP L and distant organ (4/5) 8.9 Suspicious for metastatic bone Suspicious for metastatic bone (3/4) lung mets +lung mets Lung demonstrated by CT and MIP (3/3) L L demonstrated by MIP (4/4) (3/4) (4/4) 48.4 L demonstrated by CT and MIP (4/4) (3/4) 0.02 o evidence for in Chest CT Suspicious for metastatic bone o bone L demonstrated by MIP1404

9 99m Tc-MIP-1404 Bone scan Case 2 : 76 yr-old PCa patient with multiple bone and lymph node. Gleason score: 8, PSA:48.4

10 Case 2 SPECT- CT images 99m Tc-MIP-1404 SPECT

11 99m Tc-MIP-1404 Bone scan Case 3 :74 yr- old Pca pa:ent with lymph node, Gleason score 7.

12 Diagnos:c CT 99mTc-MIP-1404 SPECT 8 mm May 2012 Case 3 Sept 2012

13 99m Tc-MIP-1404 Bone scan Case 4: 80 yr- old pa:ent with Pca with Gleason score 6, PSA 2.0

14 Case 4 99m Tc-MIP-1404 SPECT

15 In a 71 year old male with rapidly rising PSA (1.37 to 8.8 ng/ml), PSMA planar scan demonstrated numerous osseous lesions and multiple spine lesions compared to bone scan and negative CT scan. However, both bone scan and CT scan identified several lesions 3-6 months after the PSMA scan. CT Bone scan Tc-MIP-1404 Bone scan Follow - up CT Jan 11 Jan 11 March 11 June 11 ct 11

16 Primary prostate cancer patients PaSent no Age PSA Gleason score MRI 99m Tc- MIP L involvement (4/4) Suspicious (3/4) Suspicious +++ suspici ous (3/5) (4/4) (3/4) (4/5) (3/3) o tumor (3/4) Suspiciuos +/ (4/5) + Suspicious - - MRI MIP

17 MRI and of 99m Tc-MIP-1404 in primary prostate cancer

18 TcTX-P m Tc-MIP-1404 SPECT Prior to Prostatectomy

19 R 99m Tc-MIP-1404 SPECT/CT at 3 hrs post injection L Pathology vs. SPECT/CT

20 99m Tc-MIP-1404 SPECT/CT at 3 hrs post injection R L Rt lesion

21 A. In a high risk patient (GS=9) scheduled for prostatectomy, PSMA was positive while MRI was suspicious. Case 1: 71 yr- old pa:ent with Gleason score 9 A 99m Tc-MIP-1404 SPECT MRI

22 99m Tc-MIP-1404 SPECT Case 5: 75 yr- old pa:ent with Pca with Gleason score 8. MRI: multifocal nodular signal abnormality suspicious for tumor

23 99m Tc-MIP-1404 SPECT Case 6: 60 yr- old pa:ent with Pca with Gleason score 7. MRI: nodular abnormality suspicious for tumor

24 99m Tc-MIP-1404 SPECT Case 7: 64 yr- old pa:ent with Pca with Gleason score 6. MRI: minor nonspecific signal abnormalities

25 Histopathology of Prostate Cancer Lesions: PSMA Expression vs. Gleason Score (GS) PG DL DL PSMA Expression PG GS - 6 GS - 7 GS - 9

26 99m Tc-MIP-1404: SUMMARY In pts. with metastatic PCa, PSMA planar/spect scans were positive in all patients. In 2/9 patients, PSMA scan shows more lesions compared to bone scan and CT. Also 3/9 PSMA SPECT identified soft tissue lesions in axillary & para-aortic lymph nodes. In pts. with primary PCa, PSMA SPECT clearly identified the PCa foci (with GS >7), confirmed by histopathology and PSMA staining. With MRI, 5/9 lesions were +ve, 3/9 were suspicious. These pilot studies clearly document that PSMA scan with 99m Tc- MIP may be an appropriate imaging biomarker for early detecson of PCa and to select pasents for appropriate therapy. EAM 14 Abstract P345, ctober 20, 2014

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