1. In a mouse model of prostate cancer (PCa), a radiolabeled antibody (89Zr-11B6) targeting the androgen receptor (AR) pathway noninvasively detected AR-active primary and metastatic PCa lesions.
2. Using 89Zr-11B6, tumor response to treatment was monitored and demonstrated the utility of this imaging technique to assess disease activity as a function of therapeutic treatment.
Evidence Rating Level: 2 (Good)
Study Rundown: AR signaling activity is a hallmark of PCa progression and has been therapeutically targeted with androgen deprivation treatments, but reactivation of the AR pathway typically occurs and indicates a refractory disease state. Techniques to monitor disease progression and treatment efficacy are lacking since levels of prostate-specific antigen (PSA), which also denotes AR activity, are susceptible to changes based on various other factors. In this work, an antibody-based imaging technique was developed to enable noninvasive detection and monitoring of PCa tumors based on AR activity.
Initially, the radiolabeled 89Zr-11B6 antibody, which detects AR-regulated human kallikrein-related peptidase 2 (hK2), was tested in mice genetically engineered to express hK2 in the prostate. Positron emission tomography (PET) was used to determine that 89Zr-11B6 did not radiolabel tissues in control mice whereas injection with 89Zr-11B6 led to specific labeling of prostate tissue in the genetically engineered hK2-expressing mice. Moreover, metastatic lesions were also detected by PET with 89Zr-11B6 in mice with bone xenografts of various AR-active PCa. In the bone metastasis model of PCa, PET with 89Zr-11B6 was also able to detect changes in tumor AR activity after therapeutic intervention. Specifically, after surgical castration, 89Zr-11B6 uptake decreased by over 50%. Incidentally, conventional metrics for evaluating treatment efficacy, like PSA and 18F-sodium fluoride (18F-NaF) readings, remained unchanged.
This study demonstrated the utility of an antibody-based imaging method to detect PCa and monitor treatment efficacy based on AR activity changes over time. Currently, a humanized version of 89Zr-11B6 is being evaluated for safety before entering into human clinical trials. Success of this new method may not only improve diagnosis of PCa but also help adjust treatment plans based on real-time evaluations of effectiveness.
In-Depth [animal study]: Transgenic C57BL/6 KLK2 mice were generated to express prostate-specific hK2 under the probasin promotor. 89Zr-11B6 (50 µg) was administered through tail-vein injection and PET imaging was completed 96 hours later using a microPET Focus 120 scanner. While no uptake of 89Zr-11B6 was seen in wild-type C57BL/6 mice, 89Zr-11B6 was able to accumulate within and identify the prostate tissue in hK2-expressing transgenic mice.
To generate the bone metastasis models, male CB-17 severe combined immunodeficient mice were injected with 1×105 cells (VCaP, LNCaP-AR, and PC3 control) in the tibia. The VCaP and LNCaP-AR cell lines were chosen to represent two different forms (osteoblastic and osteolytic, respectively) of bone metastases. In both cases, 89Zr-11B6 was able to detect lesions in the tibia, with the intensity of signal directly correlating with differences in relative hK2 expression levels. The PC3 line was chosen as an AR-negative control, which demonstrated little accumulation of 89Zr-11B6 in the PET results.
In the LNCaP-AR intraosseous model, 89Zr-11B6 was also evaluated for its ability to track changes to the tumor’s AR activity in response to therapeutic treatment. After surgical castration, 89Zr-11B6 uptake decreased from nearly 20% injected activity/gram (IA/g) to less than 10% IA/g (p<0.005, n=5 per group). However, standard blood PSA levels (n=4 per group) before and after castration did not change, and conventional methods to detect metastatic bone disease using 18F-NaF imaging did not reveal changes to lesion AR activity (n=5 per group).
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