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Published in final edited form as: Acad Radiol. 2022 Sep 30;30(8):1721–1726. doi: 10.1016/j.acra.2022.09.005

Tracking docetaxel-induced cellular proliferation changes in prostate tumor-bearing mice with 18F-FMAU PET

Hossein Jadvar 1,*, Ryan Park 1, Ivetta Vorobyova 1, Kai Chen 1
PMCID: PMC10050216  NIHMSID: NIHMS1835351  PMID: 36184379

Abstract

Objectives:

The aim of this exploratory preclinical study was to evaluate the efficacy of 18F-FMAU PET in quantitatively measuring cellular proliferation changes in response to a chemotherapeutic agent in experimental prostate cancer models.

Methods and Materials:

Docetaxel (DTX) – a standard therapy agent in castrate-resistant metastatic prostate cancer was used as the chemotherapy drug. Athymic male nu/nu mice were inoculated with PC-3 cells in the right flank. After the tumor diameter reached 5 mm, DTX (24 mg/kg) was injected intravenously twice a week, whereas the control group was intravenously administered with saline. The tumor size and body weight were monitored, and longitudinal PET scans were acquired with 18F-FMAU to evaluate tumor cellular proliferation. 18F-FMAU PET scans were performed at 2 h post-injection of 18F-FMAU on days 0, 11, 18, and 22. Biodistribution studies were carried out after the PET scan on day 22.

Results:

Consecutive administrations of DTX were effective in inhibiting PC-3 tumor growth compared to the control group. For PET imaging, PC-3 tumor uptake of 18F-FMAU in the DTX group was increased significantly from 3.09 ± 0.60 %ID/g (day 0) to 5.32 ± 0.37 %ID/g (day 22), whereas the 18F-FMAU tumor update in the control group remained relatively stable on day 0 (2.37 ± 0.51 %ID/g) vs. day 22 (1.83 ± 0.22 %ID/g). The tumor-to-muscle uptake ratio of 18F-FMAU was increased from 2.63 ± 0.20 (day 0) to 5.91 ± 1.1 (day 22) in the DTX group. On day 22, no statistical significance was observed on the tumor-to-muscle uptake ratio of 18F-FMAU in the DTX group vs. the control group. The tumor-to-liver uptake ratio of 18F-FMAU was also similar on day 22 in the DTX group (4.29 ± 0.09) vs. the control group (3.83 ± 0.59).

Conclusion:

18F-FMAU uptake in implanted PC-3 tumors increases with DTX despite inhibiting tumor growth. Further investigation is needed to decipher the underlying biological mechanism of this apparent flare effect and its relation to the predictability of tumor response to DTX.

Keywords: Prostate, Cancer, FMAU, Proliferation, Docetaxel

Background

Positron emission tomography (PET) with a variety of radiotracers has been investigated in preclinical and clinical studies. The most common PET radiotracer, 18F-fluorodeoxyglucose (FDG) is a glucose analog that tracks increased glucose metabolism in tumors. FDG is useful in staging/restaging, assessment of treatment response, and prognosis for many malignancies. However, its utility in the therapy response evaluation may be hindered due to the accumulation of FDG in inflammatory and healing tissues. Therefore, other radiotracers have been pursued to address the shortcomings of FDG PET in the posttreatment clinical setting. Assessment of cellular proliferation as one of the hallmarks of cancer may provide a key opportunity to differentiate posttreatment reactive changes from the residual tumor. A number of PET-based proliferation tracers have been explored, typically in conjunction with tracers for the thymidine salvage pathway of DNA synthesis, since thymidine contains the only base that is unique to the DNA (1). Therapy-induced decrease in cellular proliferation may provide an early indication of response long before the decline in viable tumor cell volume and bulk tumor size (2-4).

The most studied thymidine analog has been 18F-fluorothymidine (FLT). FLT is phosphorylated by thymidine kinase 1 (TK1), incorporated by the normal proliferating marrow and glucuronidated in the liver (5). However, FLT is an indirect reflection of DNA synthesis, as it is not incorporated into the DNA; FLT uptake in tumors is related to enhanced TK1 expression and cellular radiotracer trapping (6). The high physiologic signal in the marrow also limits its broader utility in the detection of potential sites of metastases in the bone. 2’-Deoxy-2’-[18F]fluoro-5-methyl-1-β-d-arabinofuranosyluracil (18F-FMAU) is also a thymidine analog that is phosphorylated by both cytosol TK1 and mitochondrial TK2 and incorporated into the DNA in the same pathway as thymidine and in proportion to the rate of proliferation (7, 8). Indeed, at least 10% of FMAU is incorporated into the DNA 10 min after tracer administration. In addition, highly proliferative tumors are also under “cellular stress,” which increases mitochondrial TK2 activity and hence increases FMAU trapping (9). Preliminary pharmacokinetic studies by others and by us have shown that radiolabeled FMAU behaves very similar to thymidine with respect to the rate of cellular uptake, saturability of cellular incorporation, and presence of intracellular metabolite pools. Radioisotopes carried by FMAU are resistant to degradation and are selectively retained in DNA, reflective of tumor cell division (10-12). Currently, several clinical trials (NCT02809690 and NCT02079181) are underway to investigate the utility of 18F-FMAU in diagnosing and characterizing cancers, including prostate cancer, breast cancer, and brain cancer.

While PET imaging using 18F-FMAU shows promise, what has been lacking is a framework to employ quantitative imaging to inform appropriate clinical management decisions in patients with postchemotherapy lesions. We hypothesize that a favorable response to treatment will lead to a decline in cellular proliferation, growth inhibition, or decrease in tumor size through tumor cell killing, and thereby can be noninvasively evaluated by 18F-FMAU PET. The goal of this exploratory preclinical study was to evaluate the efficacy of 18F-FMAU PET in quantitatively measuring the response to a standard chemotherapeutic agent in experimental prostate cancer models.

Materials and Methods

General

All chemicals were obtained from commercial suppliers and used without further purification. 2-O-(Trifluoromethanesulfonyl)-1,3,5-tri-O-benzoyl-α-d-ribofuranose was either synthesized in accordance with the reported procedure (13) or obtained from ABX advanced Biochemical Compounds GmbH (Germany). [18O]H2O was purchased from Huayi Isotopes Co. All other chemicals and solvents were obtained from Sigma-Aldrich unless otherwise specified. The ion exchange cartridges were obtained from ABX Advanced Biochemical Compounds GmbH (Germany). Analytical and semipreparative reversed-phase high-performance liquid chromatographies (HPLC) were carried out using two Thermo Scientific UltiMate 3000 HPLC systems. Semipreparative HPLC was performed using a Phenomenex Luna C18(2) reversed-phase column (5 μm, 250 mm × 10 mm). The flow rate was 3.5 mL/min with the isocratic mobile phase of 4% acetonitrile in water. The UV absorbance was recorded at 254 nm. Analytical HPLC was performed using a Phenomenex Luna C18(2) reversed-phase column (5 μm, 250 mm × 4.6 mm). The flow rate was 1 mL/min with the isocratic mobile phase of 8% acetonitrile in water with 0.1% trifluoroacetic acid (TFA). The UV absorbance was recorded at 254 nm. Model 101 and model 105 radiodetectors (Carroll & Ramsey Associates, Berkeley, CA) were used for the semipreparative and analytical HPLC system, respectively. 18F-FMAU was radiosynthesized in a semiautomatic synthesis module as previously reported (14).

Cell culture

The human prostate cancer PC-3 cell line (ATCC CRL-1435) was obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA). PC-3 cells were maintained at 37 °C in a humidified atmosphere containing 5% CO2 in RPMI-1640 media supplemented with 10% fetal bovine serum (Thermo Fisher Scientific, NY, USA) and 1% penicillin-streptomycin.

Animal models and docetaxel (DTX) treatment

All animal studies were approved by the Institutional Animal Care and Use Committee of the University of Southern California. Male athymic nude mice (about 4–6 weeks old) were obtained from Envigo (Livermore, CA, USA). The PC-3 human prostate cancer xenograft model was generated by subcutaneous injection of 5 × 106 PC-3 cells suspended in 50% PBS and 50% Matrigel Matrix (Corning, NY, USA) in the front flank of mice (n = 3 for the treatment group and n = 4 for the control group). Tumor growth was monitored by caliper measurements of the perpendicular dimensions. The PC-3 tumors were allowed to grow to a size of 500 mm3 in volume and then the treatment started. DTX, a standard therapy in castrate-resistant metastatic prostate cancer, was used as a chemotherapy drug. DTX (24 mg/kg) was injected intravenously twice/week, whereas the control group was intravenously administered with saline. During the therapeutic period, the tumor size was monitored, and longitudinal PET scans were acquired using 18F-FMAU to evaluate tumor cell proliferation. 18F-FMAU PET scans were performed on days 0, 11, 18, and 22 (Fig. 1). Biodistribution studies were carried out at the endpoint of PET scans on day 22.

Fig. 1.

Fig. 1.

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Timeline of PET imaging with 18F-FMAU and chemotherapy (tail vein intravenous injection of Docetaxel (DTX): 24 mg/kg twice per week).

MicroPET imaging

MicroPET scans were carried out using a rodent scanner (Siemens Inveon microPET scanner, Siemens Medical Solutions). About 7.4 MBq (200 μCi) of [18F]FMAU was injected through the tail vein under isoflurane anesthesia conditions. Five-minute static scans were obtained at 2 h post-injection (pi). The three-dimensional ordered subset expectation maximization (3D-OSEM) algorithm was applied for image reconstruction. For each microPET scan, the regions of interest (ROIs) were drawn over the tumor, muscle, liver, and kidneys on the decay-corrected whole-body coronal images. The tissue tracer uptake was then calculated.

Biodistribution

On day 22 of the DTX treatment, mice were euthanized and dissected after microPET imaging. Blood, tumor, major organs, and tissues were collected and weighed wet. The radioactivity in the tissues was measured using a gamma counter (PerkinElmer 2480 WIZARD2). The results were presented as the percentage injected dose per gram of tissue (%ID/g). For each mouse, the radioactivity of the tissue samples was calibrated with a known aliquot of the injected activity. Mean uptake (%ID/g) for a group of animals was calculated with standard deviations.

Immunohistochemical assays

Xenograft tumor tissue samples were fixed in 4% freshly prepared buffered paraformaldehyde, embedded in paraffin according to standard histologic protocols, and sectioned at a thickness of 5 μm. Routine histologic staining with hematoxylin and eosin (H&E) and immunohistochemical assays for Ki67 cellular proliferation index were performed to obtain a qualitative appraisal of the magnitude of cell proliferation in the implanted PC-3 prostate tumors.

Statistical analysis

Two-group comparisons of data were performed using an unequal variance two-tailed Student t-test with a significance probability level of less than 0.05.

Results

Treatment Studies

As shown in Fig. 2, the inhibition of tumor growth was observed in the treatment group. In general, the PC-3 tumor sizes in the control group were larger than those in the treatment group from day 7 of the treatment initiation. On day 22, compared to the study baseline, the average tumor size changes were −48.7% and 651.3% for the treatment group and the control group, respectively.

Fig. 2.

Fig. 2.

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PC-3 tumor size change (%) from the study baseline for the treatment group vs. the control group.

MicroPET Studies

The tumor-targeting efficacy and biodistribution of 18F-FMAU were examined in nude mice-bearing PC-3 tumor xenografts at 2 h pi with static PET scans in the treatment and control groups. All PC-3 tumors were visible after the injection of 18F-FMAU. Representative PET whole-body coronal slices containing PC-3 tumors at 2 h pi in the treatment and control groups are shown in Fig. 3. On days 11, 18, and 22, the PC-3 tumor uptake of 18F-FMAU in the treatment group is visually higher than that in the control group.

Fig. 3.

Fig. 3.

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PET images at 2 h post-injection of 18F-FMAU in representative mice of the treatment group vs. the control group.

The radioactivities accumulated in the PC-3 tumors and major organs were evaluated by measuring the ROIs of the entire organ for each PET scan. The quantitative data of 18F-FMAU uptake in PC-3 tumors at 2 h pi are presented in Fig. 4a. The %ID/g values of 18F-FMAU in the treatment group were higher than those in the control group on day 11: 4.28 ± 0.34 vs. 2.26 ± 0.46, P = 0.002; day 18: 4.95 ± 0.77 vs. 2.13 ± 0.37, P = 001; and day 22: 5.32 ± 0.37 vs. 1.83 ± 0.22, P = 0.0001. The PC-3 tumor uptake of [18F]FMAU (5.32 ± 0.37 %ID/g) in the treatment group on day 22 were significantly higher than that on day 0 (3.09 ± 0.60 %ID/g, P = 0.02). In the control group, however, the PC-3 tumor uptake of 18F-FMAU (1.83 ± 0.22 %ID/g) on day 22 remained similar to that on day 0 (2.37 ± 0.51 %ID/g, P = 0.1).

Fig. 4.

Fig. 4.

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Quantitative data analysis of PET at 2h post-injection of 18F-FMAU. Blue: treatment group; Orange: control group. a) 18F-FMAU uptake in PC-3 tumor (%ID/g). b) Tumor-to-muscle (T/M) ratio. c) Tumor-to-liver (T/L) ratio. Statistical significance between two groups is shown (*P < 0.05; **P < 0.01; ***P < 0.001; n.s., non-significant).

Based on the quantitative data from the PET scans, the tumor-to-non-target (T/M and T/L) ratios were calculated (Figs. 4b and 4c). The values of T/M for 18F-FMAU in the treatment group were significantly greater than those in the control group (T/M: 3.65 ± 0.43 vs. 2.88 ± 0.26 (P = 0.03) on day 11, and 6.56 ± 1.25 vs. 2.94 ± 0.33 (P = 0.002) on day 18. On day 22, no significant difference in T/M values were observed for the treatment group (5.91 ± 1.11) vs. the control group (4.14 ± 0.99, P = 0.03). Compared to day 0, a significantly higher T/M values on day 22 were observed for the treatment group (5.91 ± 1.11 vs. 2.63 ± 0.20, P = 0.01) and the control group (4.14 ± 0.99 vs. 2.41 ± 0.46, P = 0.02). On day 18, the values of T/L for 18F-FMAU in the treatment group were significantly higher than that in the control group (T/L: 5.19 ± 0.96 vs. 2.68 ± 0.22, P = 0.004). Compared to day 0, a significantly higher T/L values on day 22 were observed for the treatment group (4.29 ± 0.09 vs. 2.16 ± 0.23, P = 0.001) and the control group (3.83 ± 0.59 vs. 2.04 ± 0.44, P = 0.003).

Biodistribution

The data from the ex vivo biodistribution at 2 h pi on day 22 are shown in Fig. 5. The mean PC-3 tumor uptake and liver uptake of 18F-FMAU in the treatment group were measured to be 4.33 %ID/g and 7.05 %ID/g, respectively, which are lower than those in the control group (9.40 %ID/g and 10.62 %ID/g). For the 18F-FMAU uptake in muscle and kidneys, the mean values in the treatment group were measured to be 7.05 %ID/g and 9.36 %ID/g, respectively, which are higher than those in the control group (4.34 %ID/g and 5.49 %ID/g).

Fig. 5.

Fig. 5.

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Biodistribution of 18F-FMAU in major organs of PC-3 tumor-bearing athymic male nude mice at 2 h post-injection on day 22. Blue: treatment group; Orange: control group.

Tumor Histopathology

A qualitative visual assessment of the immunohistochemical assay showed higher expression of Ki67 in the PC-3 tumors of the control group when compared to those in the treatment group (Fig. 6). Hematoxylin and Eosin (H&E) staining demonstrated patchy areas of tumor necrosis in the PC-3 tumors of the treatment group.

Fig. 6.

Fig. 6.

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Hematoxylin and Eosin (H&E) staining of PC-3 tumors (left panel) and immunohistochemical staining of PC-3 tumors for Ki67 cellular proliferation index (right panel). Note the relatively strong expression of Ki67 in the PC-3 tumor tissue in the control group vs. the treatment group. The H&E stain of the treated tumor shows patchy areas of hypocellularity due to necrosis.

Discussion

Despite the fact that an increasing number of new drugs are being developed targeting different tumor biology, anticancer treatment responses are still being assessed based on the measurement of tumor size before and after treatment. As targeted chemotherapies, especially early on, may not cause significant changes in the size of lesions, early assessment of response to such treatments may not be accurate using conventional size measurement. Thus, a clinically applicable technique that provides a more direct measure of tumor cell division is in high demand.

The therapeutic landscape for metastatic prostate cancer has been evolving rapidly. The therapeutic armamentarium includes androgen deprivation therapy with or without second generation anti-hormonal therapy, chemotherapy including docetaxel and the next generation microtubule inhibitor, cabazitaxel, sipuleucel-T immunotherapy (cancer vaccine), and alpha-particle therapy of bone lesions with 223RaCl2, each prolonging the median overall survival by only about 3-5 months (15). Unfortunately, patients develop resistance to these therapies and their disease continues to progress unpredictably. The currently approved or investigational prostate-specific membrane antigen (PSMA) radioligand therapy (with beta emitter 177Lu or alpha-emitter 225Ac) and recent investigations with checkpoint inhibitors (e.g., pembrolizumab) are also associated with an unpredictable wide spectrum of response that can range from none to short-term favorable biochemical and radiological responses, and there are yet no comprehensive data on long-term outcome. Clinicians would like to know whether patients with metastatic prostate cancer are benefiting from therapy within 1 mo. of starting it (16). Such knowledge allows for the discontinuation of non-efficacious treatments (with their associated biological and financial toxicities) and provides the opportunity for administering other potentially beneficial therapies.

Imaging can have a major role in defining intermediate endpoints that help to inform clinical decision-making by customizing the management of individual patients to optimize outcomes. Accurate assessment of treatment response in metastatic prostate cancer is challenging in view of the remarkable tumor heterogeneity and the available choice among many established and novel therapeutic approaches. Anatomic imaging with the use of radiographic criteria (e.g., RECIST 1.1) can be helpful only in patients with measurable lymphadenopathy and soft tissue disease. However, in the majority of patients who harbor bone lesions, the disease is not measurable and there are no validated criteria for response based on bone scans. While FDG PET may be useful for treatment response evaluation in this clinical setting, however, FDG uptake is nonspecific and treatment-induced reactive changes may limit assessment. In addition, although PSMA PET/CT can be useful before and after local and systemic treatment in patients with metastatic disease, it should not be performed within 3 months after initiation of systemic therapy in hormone-sensitive prostate cancer (17). Therefore, there is clearly a need for an imaging method that can assess response and predict resistance to treatment early (preferably within 1 mo.) after therapy initiation that is independent of metabolic pathways, biomarker expression, and treatment. We hypothesized that imaging assessment of downstream cellular proliferation and DNA synthesis with 18F-FMAU PET in metastatic prostate cancer may offer a more specific approach to therapy response assessment. We tested our hypothesis in a preclinical model of implanted human prostate cancer xenografts treated with docetaxel (a standard chemotherapy agent) in comparison to a control untreated group.

18F-FMAU PET provides an imaging record of the proliferating cells in the S-phase during the radiotracer uptake and imaging data acquisition period. It is reasonable to anticipate that a favorable response to treatment (e.g., docetaxel) will lead to a decline in cellular proliferation, growth inhibition, or decrease in tumor size through tumor cell killing. This phenomenon was clearly observed in our experiments. However, interestingly, we noted that despite treatment-induced tumor growth retardation and patchy histological necrosis, the 18F-FMAU uptake in the implanted tumors increased initially before a declining trend by day 22. This observation may appear surprising at first glance, however, there are potential mechanisms that may be involved. It is interesting to note that a similar preliminary observation was made in patients with a variety of cancers undergoing treatment with capecitabine treatment in whom there was a wide range (−24.4% to +23.3%) change in tumor 18F-FMAU uptake (18). While our preclinical study may not be directly comparable to the aforementioned pilot clinical investigation in tumors other than prostate cancer which were treated with a different chemotherapy agent, it is noteworthy that a number of patients demonstrated an increase in tumor 18F-FMAU uptake with chemotherapy. This observation is reminiscent of the “flare” phenomenon that has been described in some patients undergoing treatment for metastatic disease, which is generally predictive of a favorable response to therapy (19).

Deciphering the underlying mechanistic details of the observed flare was beyond the scope of our study. However, a treatment-induced increase in tumoral 18F-FMAU uptake may be related to the upregulation of mitochondrial mass and TK2 expression, reflecting the tumor response to a variety of stress factors (20). Another source for higher tumor 18F-FMAU uptake during chemotherapy may be due to inflammatory cells that infiltrate tumors and undergo proliferation and cellular stress (21). Further studies are warranted to test these hypotheses.

Conclusions

18F-FMAU uptake in implanted PC-3 tumors increases with DTX treatment despite the decline in tumor size. This may reflect a flare phenomenon due to increased cellular stress of the tumor and its microenvironment.

Funding:

Supported in part by grants R21-CA142426 and P30-CA014089 from the U.S. National Institutes of Health.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Availability of data and materials: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval

All studies were done on protocols approved by the USC Animal Care and Use Committee.

Competing interests

None

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