PSMA PET-CT ScanGETTING READY FOR TOMORROW IN PROSTATE IMAGING

Introductiono Prostate cancer (PC) is the second most frequent cancer and the sixth leading

cause of cancer death in men worldwideo When detected early, prostate cancer has more than a 90 percent cure rateo Because treatment is highly individualized, molecular imaging technologies are

dramatically improving the ways in which prostate cancer is diagnosed and treatedo 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

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)

(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.

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

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

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

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

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

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.

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

New PSMA Based PET Imaging agents

Newer Generation Antibodies

Aptamers

PSMA Inhibitors of LMW

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.

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.

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

[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 extremitiesa) coronal PET;b) sagittal PET/CTc) 18F-fluoride PET(sagittal)

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.

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

THANK YOU Tumor Board members (11th September 2015)