Page 15 - Towards personalized therapy for metastatic prostate cancer: technical validation of [18F]fluoromethylcholine

the phase III trial on the treatment of hormone-refractory metastatic PC previously 1 treated with docetaxel-containing regimen (TROPIC study), demonstrated a 30%
reduced risk of death, associated with a prolonged survival up to 2.4 months [7,
9], in favor of cabazitaxel-prednisone versus mitoxantrone-prednisone. Currently, cabazitaxel-prednisone is the only chemotherapeutic option with demonstrated
survival advantage for the treatment of patients with metastatic CRPC who have progressed under docetaxel-based chemotherapy [9, 10].
In the beginning of this decennium, molecular profiling studies have improved the knowledge about the heterogeneous biological behavior of PC. It was found that even in the presence of a castrate range <1.7 nmol/L of testosterone in the blood of CRPC patients, a proportion of these tumors remains dependent on androgen-receptor (AR) signaling for growth [11]. Five potential mechanisms of development of CRPC were described, based on ligand and AR dependence [12]. Series of progressive changes in intracellular AR signaling in CRPC in comparison to newly diagnosed (untreated) tumors were identified and validated, with AR overexpression being the most frequently identified phenotype [11]. Based on these observations, a multitude of therapeutic options against CRPC was recently proposed, including agents that interfere with androgenic stimulation of tumor growth (e.g., abiraterone, enzalutamide) [13–16] in as well as pre- or post- chemotherapy settings, immunotherapy (sipuleucel-T) [17], and bone-seeking radiopharmaceuticals (e.g., Radium-223 [18]). An example of a patient with metastatic CRPC, demonstrating AR overexpression and a good response on Enzalutamide is presented in Figure 1.
Abiraterone acetate inhibits androgen biosynthesis by irreversibly blocking CYP17, an essential enzyme in testosterone and estrogen synthesis [13]. When combined with low-dose prednisone, Abiraterone improves survival of patients with CRPC [13, 14]. Enzalutamide is an antiandrogen agent with demonstrated potential to inhibit nuclear translocation of the AR and DNA binding. Double-blind, phase III studies have demonstrated Enzalutamide to significantly prolong the survival of men with metastatic CRPC after chemotherapy [15], but also to significantly decrease the risk of disease progression and death, and to delay the initiation of chemotherapy in men with metastatic PC [16]. Sipuleucel-T is an active cellular immunotherapeutic which prolongs survival among men with asymptomatic or minimally symptomatic metastatic CRPC [17]. Radium-223 dichloride is an alpha emitter which selectively binds to areas of increased bone turnover in metastatic lesions. The emitted high-
Introduction and outline of the thesis
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