Role of PSMA scan in Ca Prostate as a diagnostic tool in PET CT imaging

1. PSMA PET-CT Scan
GETTING READY FOR TOMORROW IN PROSTATE IMAGING

2. Introduction
o Prostate cancer (PC) is the second most frequent cancer and the sixth leading cause of cancer
death in men worldwide
o When detected early, prostate cancer has more than a 90 percent cure rate
o Because treatment is highly individualized, molecular imaging technologies are dramatically
improving the ways in which prostate cancer is diagnosed and treated
o Broadly defined, molecular imaging is the non-invasive detection and measurement of cellular
and molecular processes in whole living beings using a variety of modalities including positron
emission tomography (PET), single photon emission computed tomography (SPECT), magnetic
resonance (MR), computed tomography (CT), ultrasound, fluorescence, or bioluminescence

3.  Conventional imaging modalities, including bone scintigraphy (bone scan), CT, ultrasound,
and MR imaging, are currently used to detect primary PCa and metastatic disease for staging
and risk stratification
 Current and new agents undergoing clinical study for radionuclide imaging of PCa include:
 2-18F-fluoro-2-deoxy-D-glucose (FDG)
 111In-7E11 antibody (ProstaScint™)
 18F-fluorodihydrotestosterone (18F-FDHT)
 radioacetate analogs
 radiocholine analogs
 anti-1-amino-3-18Ffluorocyclobutane-1-carboxylic acid (anti-[18F]FACBC)

4.  (A) After travelling in tissue
(positron range) positron looses
energy and annihilates with
electron resulting in two 511 keV
annihilation photons travelling in
opposite directions
 (B) Annihilation photons are
registered externally by
radiodetectors consisting of
scintillation crystals and
photomultiplier tubes and
assembled in a ring. Only photons
that are registered in coincidence
are used for image reconstruction.

6.  18F-FDG PET which is useful in other solid cancers is not used routinely to
diagnose early stages of prostate cancer due to low-level metabolism of
most prostate cancers
 Ga-68 PSMA Imaging is a recent advancement in nuclear medicine which is
generating a lot of interest worldwide for the management of metastatic
prostate cancer

7.  FDG is an analog of glucose and is the most widely used metabolic radiotracer for PET imaging
of tumors
 Like glucose, FDG is transported into cells and phosphorylated but unlike glucose the
phosphorylation product of FDG is trapped within the cell and accumulates
 Higher glucose utilization is characteristic of most tumors, however, PCa can vary greatly in
growth rate, ranging from slow-growing and less aggressive to rapidly disseminating and
aggressive
 As a result FDG imaging of PCa has produced mixed
Results

9.  FDG was not useful in:
 Detecting primary organ-confined prostate cancer detecting local recurrence after radical
prostatectomy
 in differentiating between post-operative scar and local recurrence
However, FDG is useful in:
 detecting bone and soft-tissue PCa metastases, although it is less sensitive than bone scan
 It has also been shown that FDG uptake correlates with elevated prostate-specific antigen (PSA)
levels and the rate of increase in PSA as a measure of metastatic disease progression
 From these results it has been suggested that FDG is useful for imaging PCa in selected populations
of patients with aggressive disease

10. What is PMSA
 PSMA (Prostate Specific Membrane Antigen) is a membrane glycoprotein which is
overexpressed manifold on prostate cancers, and the expression increases with tumor
aggressiveness, androgen-independence, metastatic disease, and disease recurrence.
 PSMA is an excellent target for radionuclide imaging and therapy of prostate cancer for
several reasons. It is mainly expressed in prostate cancer in all stages of the disease,
upregulated in androgen refractory or metastatic disease, expressed on the cell surface as
an integral membrane protein, not released into the circulation, and internalized after
antibody binding (receptor-mediated endocytosis)
 Ga-68 PSMA PET/CT Imaging identifies tumor cells expressing PSMA antigen with
excellent sensitivity & specificity, thereby detecting lesions remaining unidentified by
conventional methods

11.  Advantages/ Indications:
 PET Imaging with 68Ga-PSMA ligand can present lesions suspicious for prostate
cancer with excellent contrast and a high detection rate even when the level of
prostate specific antigen is low
 PSMA expression allows the identification of benign and malignant prostatic
epithelium and may be a potentially valuable marker in the treatment of patients
with prostate cancer
 68Ga-PSMA PET has promising potential for restaging in recurrence/ biochemical
failure after definitive treatment of prostate cancer
 PSMA PET could be used as a marker of patient response to anti-androgen drugs

12.  PSMA is a type II transmembrane protein that is over-expressed in PCa, including
androgen-independent, advanced and metastatic disease as well as in a few subtypes of
bladder carcinoma, schwannoma, and in the tumor neovasculature of many solid tumors.
 PSMA is also expressed on astrocytes where it is known as glutamate carboxypeptidase II
(GCPII) and cleaves N-acetylaspartylglutamate (NAAG) into Nacetylaspartate (NAA) and
glutamate
 It is also located on the luminal side of the brush border cells in the jejunum, where it is
known as folate hydrolase I, and cleaves γ- linked glutamates from folates
 PSMA expression and localization in the normal human prostate is associated with the
cytoplasm and apical side of the epithelium surrounding prostatic ducts but not basal
epithelium, neuroendocrine or stromal cells
 Cytoplasmic PSMA is an N-terminally truncated form of PSMA called PSM’, which has no
folate hydrolase activity or capacity to hydrolyze NAAG
 It appears to be the product of post-translational modification rather than of mRNA
splicing.

13.  The function of PSM’ is unknown.
 Dysplastic and neoplastic transformation of prostate tissue results in the transfer of
PSMA from the apical membrane to the luminal surface of the ducts
 Further transformation eventually leads to expression on the plasma membrane of less
differentiated epithelial cells, which is associated with the transition into and
achievement of androgen growth independence
 As tumor cells advance in Gleason grade, the ratio of PSMA/PSM’ reliably increases
 Because the expression of PSMA generally increases with increasing Gleason score,
PSMA function may be concomitant with or help facilitate malignant transformation
and/or metastasis.
 Biological mechanisms for aiding malignant transformation or metastasis have not yet
been elucidated, although PSMA-driven provision of additional folate intake as a
growth advantage has been postulated

14. New PSMA Based PET Imaging agents

15.  PMSA studies are able to determine the extent of prostate cancer and whether it has spread
to the lymph nodes or other parts of the body, unlike traditional imaging technologies such
as magnetic resonance imaging (MRI) and computed tomography (CT), which are often
unable to detect the spread of prostate cancer cells.
 Molecular imaging technologies help select the most effective therapy for prostate cancer,
taking into account a tumor’s unique molecular properties and whether the cancer is localized
or diffuse, or spread out.

17. Benefits of Ga 68 in PMSA Scan
 It is produced from a long shelf-life and cost-effective generator.
 The half-life of 68Ga permits production and application of resultant agents, and the labelling
synthesis is amenable to automation and kit type preparation.
 It provides sufficient levels of radioactivity for high quality images, short scanning time (fast
patient examination) while minimizing the radiation dose to the patient and personnel, and
allows fast dischargement of the patient.
 It also allows repetitive examinations within the same day
 The majority of the therapeutic radionuclides is also metals and might allow for the theranostic
development.

22.  68Ga-PSMA PET/CT with Red arrows
point to several small lymph nodes
with clearly visible pathological tracer
uptake
 A1 CT
 A2 PET
 B1 fusion of PET and CT,
 B2 MIP. Reproduced from

25. [68Ga]BPAMD was injected
i.v. into a patient with
known extensive bone
metastases of prostate
cancer, and revealed intense
accumulation in multiple
osteoblastic lesions in the
central skeleton, ribs and
proximal extremities
a) coronal PET;
b) sagittal PET/CT
c) 18F-fluoride PET(sagittal)

26.  The study involves a special molecule called a monoclonal antibody developed in a
laboratory and designed to bind to the prostate-specific membrane antigen on cancer
cells. This antibody is paired with a radioactive material called Gadolinium 68 that can be
detected by a gamma camera. When injected into the patient’s bloodstream, the
radioactive antibody travels and attaches to cancer cells. The gamma camera then
produces three-dimensional images of the tumor and its location inside the body.
 This study is performed over as many as three days. On the first day, the patient first
receives an intravenous (IV) injection of the radioactive antibody.
 Imaging is performed in two sessions, separated by 24 or more hours. Each imaging
session will last between two and four hours.
 The camera rotates around the patient, who remains still.

27. Conclusion
 A major unmet medical need is a highly specific and sensitive molecular imaging agent or
method for staging and monitoring patients with PCa.
 The ultimate goal of such an agent would actually be predictive, i.e., determining whether a
patient’s tumor is indolent vs. aggressive due to the vastly different therapeutic approaches of
managing patients with tumor biology at opposite ends of the spectrum of malignancy.
 Because PSMA is elevated in aggressive, androgen-insensitive disease, it may serve as an
imaging biomarker that reports on tumor biology.
 For instance, PSMA-targeted imaging agents have been shown in preclinical models to report
on the activity of androgen signaling and response to taxane therapy
 The low molecular weight PSMA inhibitors are particularly promising, with 18F-DCFBC 8,
68Ga-HBED-CC 15, and BAY1075553 having proved their mettle in initial clinical studies

29. THANK YOU
Tumor Board members (11th September 2015)