Translating Molecules into Imaging—The Development of New PET Tracers for Patients with Melanoma

Abstract

Melanoma is a deadly disease that often exhibits relentless progression and can have both early and late metastases. Recent advances in immunotherapy and targeted therapy have dramatically increased patient survival for patients with melanoma. Similar advances in molecular targeted PET imaging can identify molecular pathways that promote disease progression and therefore offer physiological information. Thus, they can be used to assess prognosis, tumor heterogeneity, and identify instances of treatment failure. Numerous agents tested preclinically and clinically demonstrate promising results with high tumor-to-background ratios in both primary and metastatic melanoma tumors. Here, we detail the development and testing of multiple molecular targeted PET-imaging agents, including agents for general oncological imaging and those specifically for PET imaging of melanoma. Of the numerous radiopharmaceuticals evaluated for this purpose, several have made it to clinical trials and showed promising results. Ultimately, these agents may become the standard of care for melanoma imaging if they are able to demonstrate micrometastatic disease and thus provide more accurate information for staging. Furthermore, these agents provide a more accurate way to monitor response to therapy. Patients will be able to receive treatment based on tumor uptake characteristics and may be able to be treated earlier for lesions that with traditional imaging would be subclinical, overall leading to improved outcomes for patients.

Skin Cancer Pathobiology at a Glance: A Focus on Imaging Techniques and Their Potential for Improved Diagnosis and Surveillance in Clinical Cohorts

“…As it may delay the administration of an alternative treatment, the relatively longer biological half-lives of radiolabeled antibodies pose important limitations to the clinical workflow [ 210 ]. The long-circulating half-lives also result in the need for long-lived radioisotopes and, hence, more prolonged radiation exposure to patients [ 21 ]. In addition, the size of antibodies may restrict their diffusion into solid tissues where cells expressing particular biomarkers might be found.…”

“…[ 225 ]. In a similar fashion, by relying on the accessibility of fluorodeoxyglucose ( 18 F-FDG), PET/CT rapidly entered into the clinical practice for various oncological applications [ 21 ]. Nonetheless, although PET/CT images are inherently superior to SPECT/CT images, this improvement involves a cost significantly higher.…”

“…Imaging with PET can provide real-time information on different biological processes such as glucose metabolism [ 228 ], DNA replication, hypoxia and inflammation [ 229 ], or gene expression based on interaction events between the specific PET tracer and cellular enzymes [ 230 ] or can provide details about the distribution and density of tumor receptors or other binding targets [ 231 ]. In the clinical setting, biological information obtained from PET imaging is widely used in diagnosing disease, monitoring response to therapy and minimal residual disease (MRD), and aiding in personalized medicine [ 21 ]. Therefore, it provides mechanistic insights concerning tumor heterogeneity and prognosis and identifies instances of treatment failure in various tumors, including skin cancer.…”

“…Finally, PET-CT imaging involves the administration of radiotracers for image acquisition and is inherently linked to exposure to a low dose of ionizing radiation, presenting a small but not negligible risk to the patient. Compared to other cancers, melanoma affects younger patients; therefore, the cumulative risk of radiation exposure on lifelong surveillance over treatment is high and its associated effects should be strongly considered when choosing this imaging modality for patient monitoring [ 21 ]. Because of these limitations, there is an ongoing need to develop novel imaging modalities that are highly sensitive and specific in detecting melanomas in the affected patients.…”

“…Molecular imaging techniques such as single photon emission computed tomography (SPECT/CT) and positron emission tomography (PET) introduce molecular imaging agents (probes) to determine the expression of indicative molecular markers at different stages of disease and therefore are actively employed for skin cancer detection and monitoring. The signaling pathways and molecular targets that may be harnessed for such purposes include glucose metabolism [ 18 ], integrin α v β 3 [ 19 ], melanocortin-1 receptor (MC1R) [ 20 ], PD-1/PD-L1 axis [ 21 ], and several other biochemical and molecular markers.…”