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Multimodal imaging provides insight into targeted therapy response in metastatic prostate cancer to the bone.

ABSTRACT: Metastatic prostate cancer to bone remains incurable, driving efforts to develop individualized, targeted therapies to improve clinical outcomes while limiting adverse side-effects. Due to the complexity in cellular signaling pathways and the interaction between cancer and its microenvironment, multiparametric imaging approaches for treatment response may improve understanding of the biological effects of therapy. An orthotopic model of castration resistant prostate cancer (CRPC) bone metastasis was treated with the tyrosine kinase inhibitor Cabozantinib (CABO). Response was assessed using CT to monitor bone volumes, 99mTc-MDP SPECT for bone metabolism, and anatomical and diffusion MRI for tumor volume and cell death. A concurrent clinical trial of CABO for CRPC patients also evaluated multimodality imaging in correlation with standard response criteria. Response in the preclinical study found significant slowing in tumor growth rate (P<0.01), rise in tumor apparent diffusion coefficient (ADC, P<0.001), and drop in 99mTc-MDP adsorption (P<0.05). Loss of bone volume did not slow with treatment, attributed to the highly aggressive and osteolytic nature of the PC3 cell line. Clinical trial analysis found only a single subject who progressed after 12 weeks of therapy. Imaging at 6 weeks corroborated the 12-week radiological assessment with positive response visible as increased ADC and decreased vascular metrics. Conversely, the subject who progressed at 12 weeks had no change in ADC, and substantial drops in vascular metrics. These results showcase a multifaceted translational imaging approach for detecting targeted treatment response with effective blockade of tumor vascularization, tumor cell kill, and reduced proliferation.

SUBMITTER: Hoff BA

PROVIDER: S-EPMC6056245 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Multimodal imaging provides insight into targeted therapy response in metastatic prostate cancer to the bone.

Hoff Benjamin A BA Brisset Jean-Christophe JC Galbán Stefanie S Van Dort Marcian M Smith David C DC Reichert Zachery R ZR Jacobson Jon A JA Luker Gary D GD Chenevert Thomas L TL Ross Brian D BD

American journal of nuclear medicine and molecular imaging 20180605 3

Metastatic prostate cancer to bone remains incurable, driving efforts to develop individualized, targeted therapies to improve clinical outcomes while limiting adverse side-effects. Due to the complexity in cellular signaling pathways and the interaction between cancer and its microenvironment, multiparametric imaging approaches for treatment response may improve understanding of the biological effects of therapy. An orthotopic model of castration resistant prostate cancer (CRPC) bone metastasis ...[more]

PMID: 30042870

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Project description:BackgroundProstate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT) has demonstrated efficacy and tolerability with a dose-response effect in phase I/II trials in men with metastatic castration-resistant prostate cancer (mCRPC). The need for positive PSMA imaging before PSMA-TRT to select patients is largely practiced, but its utility is not proven. Given target heterogeneity, developing a biomarker to identify the optimal patient population remains an unmet need. The aim of this study was to assess PSMA uptake by imaging and response to PSMA-TRT.MethodsWe performed an analysis of men with mCRPC enrolled in sequential prospective phase I/II trials of PSMA-TRT. Each patient had baseline PSMA imaging by planar 111 In and/or 177 Lu SPECT (N = 171) or 68 Ga-PSMA-11 PET/CT (N = 44), but the results were not used to include/exclude treatment. Semiquantitative imaging scores (IS) on a 0-4 scale were assigned based on PSMA uptake in tumors compared to liver uptake. We compared the ≥50% PSA decline response proportions between low (0-1) and high (2-4) PSMA IS using the χ2 -test. We used multivariable logistic regression analysis to understand the relationship between independent and dependent variables, including IS, radionuclide activity (dose) administered, CALGB (Halabi) prognostic risk score, prior taxane use.Results215 men with progressive mCRPC received PSMA-TRT as follows: 177 Lu-J591 (n = 137), 177 Lu-PSMA-617 (n = 44), 90 Y-J591 (n = 28), 177 Lu-J591 + 177 Lu-PSMA-617 (n = 6). High PSMA expression (IS 2-4) was found in 160 (74.4%) patients and was significantly associated with more frequent ≥ 50% PSA reduction (26.2 vs. 7.3%, p = .006). On multivariate logistic regression analysis, higher IS was associated with a ≥50% decrease in PSA, even after accounting for CALGB (Halabi) prognostic score, the dose administered, and previous taxane use (OR, 4.72; 95% CI, 1.71-16.85; p = .006). Patients with low PSMA expression (N = 55, 24.7%) were less likely to respond. Thirteen of 26 (50%) with no PSMA uptake (IS = 0) had post-PSMA-TRT PSA decline with 2 (7.7%) having ≥ 50% PSA declines.ConclusionCollectively, the data provide evidence in favor of the hypothesis that patients with high PSMA uptake and high administered radionuclide dose correlate with a higher chance of response.

Dataset Information

Multimodal imaging provides insight into targeted therapy response in metastatic prostate cancer to the bone.

Publications

Multimodal imaging provides insight into targeted therapy response in metastatic prostate cancer to the bone.

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