Integrated multimodal imaging of dynamic bone-tumor alterations associated with metastatic prostate cancer

Abstract

Bone metastasis occurs for men with advanced prostate cancer which promotes osseous growth and destruction driven by alterations in osteoblast and osteoclast homeostasis. Patients can experience pain, spontaneous fractures and morbidity eroding overall quality of life. The complex and dynamic cellular interactions within the bone microenvironment limit current treatment options thus prostate to bone metastases remains incurable. This study uses voxel-based analysis of diffusion-weighted MRI and CT scans to simultaneously evaluate temporal changes in normal bone homeostasis along with prostate bone metatastsis to deliver an improved understanding of the spatiotemporal local microenvironment. Dynamic tumor-stromal interactions were assessed during treatment in mouse models along with a pilot prospective clinical trial with metastatic hormone sensitive and castration resistant prostate cancer patients with bone metastases. Longitudinal changes in tumor and bone imaging metrics during delivery of therapy were quantified. Studies revealed that voxel-based parametric response maps (PRM) of DW-MRI and CT scans could be used to quantify and spatially visualize dynamic changes during prostate tumor growth and in response to treatment thereby distinguishing patients with stable disease from those with progressive disease (p<0.05). These studies suggest that PRM imaging biomarkers are useful for detection of the impact of prostate tumor-stromal responses to therapies thus demonstrating the potential of multi-modal PRM image-based biomarkers as a novel means for assessing dynamic alterations associated with metastatic prostate cancer. These results establish an integrated and clinically translatable approach which can be readily implemented for improving the clinical management of patients with metastatic bone disease.

Trial registration: ClinicalTrials.gov NCT02064283.

Conflict of interest statement

Competing Interests: BDR, AR, TLC and CJG have a financial interest in the underlying technology which has been licensed to Imbio, LLC a company in which BDR and AR have a financial interest. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. A CONsolidated Standards of Reporting Trials (CONSORT) flow diagram of the overall study patient population recruitment and disposition over the course of study.

Fig 2. Intratibial PC3 tumor response to docetaxel (n = 6), radiation (IR, n = 6), or combination treatment (n = 6) shows an additive effect by anatomical and diffusion MRI compared to controls (n = 8).

(A) Tumor volumes plotted over time (p-values in legend show significance versus controls at day 7) show greater cell kill in the combination group (circles, solid line) than either docetaxel (triangles, long-dashed line) or IR (diamonds, short-dashed line) treatment alone, and all treatments resulted in significant cell kill over controls (squares, dotted line). (B) Comparison of mean ADC change to PRMADC+ at day 7 post-treatment-initialization resulted in no significant difference between measurements, but slightly elevated PRMADC+ over mean ADC in the combination treatment (significant difference from controls: * (p<0.05)). (C) ADC color over overlays are shown in the left two columns for pre-treatment and day 7, and corresponding PRMADC overlay and scatterplot are shown on the right.

Fig 3. PC3 implantations treated with zoledronic acid (ZA, n = 4) show a bone-protective effect compared to controls (n = 8).

(A) MRI tumor volume and ADC determined at day 21 post-treatment-initiation shows a retardation of tumor growth and significantly lower ADC in the zoledronic acid treated animals. (B) PRMHU+ bar plot shows significantly higher volume of bone that increased in density after treatment compared to controls. (C) PRMHU- bar plot shows minimal loss of bone in the ZA-treated group, compared to progressively increasing bone loss in the controls. (D) Representative images for a control (top) and ZA-treated (bottom) mouse showing (from top to bottom) an isosurface, CT slice, PRM overlay, and PRM scatterplot from pre-treatment to 21 days post-treatment.

Fig 4. LAPC-9 tumors show slower mixed PRMHU+/- response with docetaxel treatment compared to PC3.

(A) Time plots of tumor volume (solid line) and ADC (dashed line) show successful response to treatment (n = 3) as volume shrinkage and ADC increase. (B) PRMHU+ bar plot over time shows more bone density increase in the docetaxel-treated group compared to controls (n = 3), significant on days 14 and 21. (C) PRMHU- bar plot over time shows very little bone loss in the treated group compared to elevated bone mineral loss in the controls (though not significant in this study). (D) Representative images for a control (top) and docetaxel-treated (bottom) mouse showing (from top to bottom) an isosurface, CT slice, PRM overlay, and PRM scatterplot from pre-treatment to 21 days post-treatment.

Fig 5. PRMHU plots over time post-implantation compare un-treated bone changes in PC3 (diamonds, solid line, n = 4) to LAPC-9 (squares, dashed line, n = 6) implants as quantified by (A) PRMHU+ and (B) PRMHU-.

Fig 6. Results from clinical trial.

(A) Representative PRM overlays show stable disease (top) and progressive disease (bottom) for PRMHU (left) and PRMADC+ (right). Blue represents regions of decreased value, red increased value, and green statistically unchanged value. (B) The bar plot shows significant differences (marked with *) between stable disease (SD, gray, n = 8) and progressive disease (PD, black, n = 4) groups in volume fractions of bone PRM results (labeled PRMHU-, volume fraction of decreased attenuation at about 10 weeks post-treatment) and DW-MRI (volume fraction of increased ADC at about 2 weeks post-treatment).