Preclinical Imaging of Prostate Cancer - Beyond the Abstract

The article’s summary scheme below shows the general progress of new positron emission tomographic (PET) diagnostics related to prostate cancer, from its historical basis through to the development of novel modern targeting vectors, radiolabeled for specific disease identification at the molecular level.

From the earliest days through to current paradigms, the article touches on the development of multiple revolutionary technologies that focus on discovery and application of novel agents for molecular medicine diagnostics relevant to patient treatment. Central to this larger effort is the need for the establishment of reliable animal models to validate the safety and efficacy of these new agents prior to safe and successful clinical trials.

The biotechnological and computer advances of the last 30+ years completely changed our capabilities and enabled the scientific advances now bearing fruit. The latter enabled the development of PET/CT cameras, the most exquisitely sensitive radio detection modality available due its ability to simultaneously detect the two 511 keV coincident gamma rays emitted from the positron annihilation reaction. On the biological side, monoclonal antibodies and derivatives, together with advanced small molecule discovery, enabled the development of disease-specific targeting agents that could be radiolabeled with PET-emitting radionuclides. Such agents bind to specific proteins on prostate cancer membranes thereby ushering in molecular medicine targeting capability and the promise of disease-specific diagnostic agents.

Central to these technologies were advances in animal modeling sciences, most notably the ability to grow human prostate cancer cells as xenografts in immunodeficient mice. Miniaturization of PET imaging systems then allowed for generating remarkably detailed images of tumor growth in animals while the radiometric counting technique on excised tissues allowed for highly accurate quantitation of the radioactive labels in tumor and normal tissues, predicting the human biodistribution and radiation dose with sufficient accuracy. Many hundreds of PET-radiolabeled agents have now been tested in mouse xenograft models. Successful agents have been approved by the FDA and its equivalents around the world. For instance, the development [18F]-DCFPyL (see scheme below) not only allows the generation of excellent PET images that can be matched to MRI but can also serve as a platform for PSMA radioligand therapy which is also now approved.

While these advances have been undeniable, there are several deficiencies and limitations of animal testing, perhaps not readily apparent to the more general reader. For instance, the size difference between a mouse and a human is about 3000:1, so a 0.5-gram tumor in a mouse would equate mass-wise to a 1,500-gram tumor in a human and although we can readily often see 0.5-gram tumors in humans we must remain aware that the mouse model may give images within a much more forgiving system. Also, many times mice may not express the exact human protein being targeted, as mouse versions of the ‘same’ protein are often structurally different and not recognized by the injected agent, and this can also lead to better results in mice than one might expect to see in humans. Finally, the prostate cancer cells grown in mice are often chosen for the practical reason that they grow well in mice, and this tends to favor more aggressive human cell lines, often originally taken as samples from metastatic human prostate cancer. This biases current molecular targeting agents toward more aggressive disease rather than primary (often more indolent) prostatic cancer and may further suggest the combination of PET and anatomic prostate MRI for optimum results. In research laboratories new agents and imaging techniques are being tested in novel and improved preclinical animal model systems (e.g., orthotopic, metastatic, and patient derived tumors) to improve upon the tremendous advances and achievements already made, in the continuing search for the best and most reliable agents for optimized prostate cancer imaging for improved patient management. 

1. Olkowski et al. in Seminars in Nuclear Medicine, 2023; March 5, S0001-2998(23)00007-7. doi: 10.1053/j.semnuclmed.2023.02.002.