We had the privilege of interviewing Dr. Filipe Elvas, an assistant research professor from the Center for Radiopharmaceuticals Antwerp (CREANT) at the University of Antwerp. His work revolves around the development and validation of radiopharmaceuticals to visualize tumor biomarkers and monitor response to therapy. In this interview, we delve into the intriguing intersection between the theranostic approach (here is the link to the previous article on theranostic) and the multifaceted tumor microenvironment.
Tumor microenvironment, cancer associated fibroblasts and fibroblast activation protein (FAP).
Filipe explained that the tumor microenvironment is a dynamic and complex ecosystem surrounding tumor cells. It includes components like the extracellular matrix, blood vessels, immune cells, and other stromal (assisting) cells, such as cancer associated fibroblasts (CAFs). This microenvironment plays a crucial role in promoting cancer progression by supporting tumor cell survival, proliferation, invasion, and metastasis.
FAP is expressed in approximately 90% of epithelial cancers, particularly in the cancer associated fibroblasts within the tumor microenvironment. When asked about the percentage of fibroblast activation protein (FAP) expressed in tumors, Filipe noted that the expression level varies depending on the tumor type. In some cases, like pancreatic cancer, FAP can comprise a significant portion of the tumor, up to 80%. Besides localization in the Tumor microenvironment, FAP expression is also observed on the surface of certain tumor cells, especially in tumors of mesenchymal origin, such as mesotheliomas (cancer of the thin layer covering many internal organs) and sarcomas (cancers that start in bone and connective tissues).
Figure 1. Illustrative representation of the tumor and its microenvironment.
We inquired whether CAFs act as a physical barrier or promote tumor growth. Filipe explained that fibroblasts have multiple roles beyond acting as a physical barrier. They communicate with tumor cells by releasing various factors, some of which promote tumor growth. CAFs also interact with immune cells and can create an immunosuppressive environment. Researchers are interested in targeting CAFs, particularly those expressing FAP, to enhance cancer therapies.
Regarding the current strategy of using radiolabeled compounds (radiopharmaceuticals) to target FAP, we asked why he chose this protein over others. The high FAP expression in most cancers together with its association with poor patient prognosis make this protein an attractive cancer diagnostic marker and therapeutic target. Filipe explained that the team at the UA has developed radioligands to visualize and monitor FAP expression in the course of therapies targeting the tumor microenvironment cells, including fibroblasts. By imaging FAP, they aim to select eligible patients for targeted therapies, improve treatment response rates and maximize the therapeutic effect.
Theranostic approach and the tumor microenvironment: current challenges and opportunities
In discussing the theranostic approach, Filipe emphasized its significance in understanding what's being treated and treating what's observed. Filipe explained that radiopharmaceuticals targeting the tumor microenvironment can be labelled with diagnostic or therapeutic radionuclides, each with distinct properties.
He highlighted the differences between alpha particle-emitting radioisotopes, known for their high energy but short range, and beta minus particle-emitting radionuclides, which have lower energy when compared with alpha particles, but a slightly longer range. Most clinical therapies currently rely on beta minus emitters due to their wider availability and extensive clinical evidence.
He also mentioned the "cross-fire effect," where neighbouring non-cancerous cells also receive radiation when targeted radioisotopes accumulate nearby. While beta minus emitters are suitable for primary and bulk tumor treatments, he acknowledged concerns about potential toxicity to non-targeted or healthy tissues.
Filipe discussed the emerging use of alpha emitters for radionuclide therapy, emphasizing their smaller range, which spares healthy tissue, and their ability to cause non-repairable double-strand DNA breaks, as opposed to the reversible single-strand breaks caused by beta minus emitters. He noted that the internalization of the ligand-receptor complex after binding to FAP plays a role in maximizing therapeutic effects, concentrating radioactivity closer to the cell nucleus.
In a broader context, we discussed the future of theranostics with regards to the tumor microenvironment. He mentioned the growing interest in targeting various components of the tumor microenvironment and the need to expand the production and availability of radionuclides for therapy.
Filipe pointed out the challenges associated with establishing production at every clinical treatment site, characterizing it as unmanageable. He emphasized the necessity for a centralized approach to create a dependable supply network. Longer-lived isotopes like Lutetium-177 pose no shipping concerns due to their extended half-life, making them suitable for transportation to various destinations.
On the other hand, for shorter-lived isotopes like Astatine-211, Filipe suggested that a way forward to provide improved access would be having a cyclotron network that can cover a wide geographical area. Some centers might also require on-site generators for even shorter-lived isotopes like bismuth-213, with a half-life of 45 minutes. The decision on which isotopes to utilize remains uncertain, but he anticipates that the most widely available ones will prevail.
We asked Filipe about his favourite radioactive element for theranostic applications.
Filipe's preferred approach in theranostics involves using two radionuclides of the same element: one for diagnostics and one for therapy. He especially favours copper-64 for imaging and copper-67 for therapeutic purposes.
Copper-64 is readily available in cyclotrons, with a half-life of approximately 13 hours. This is sufficient for imaging and convenient shipping to nearby locations. In contrast, copper-67 production typically requires larger linear accelerators (linacs), but it provides the high specific activity and purity needed. Copper-67 has a longer half-life of 62 hours, making it logistically easier to ship from production sites. This extended half-life is important for ensuring the accumulation of the radiopharmaceutical within tumors to induce effective damage.
Filipe believes that the copper-64/copper-67 combination offers a compelling solution for diagnosing diseases and subsequently treating them with a matching radioligand, creating a well-rounded theranostic approach.
The future of theranostic education…
In closing, we asked Filipe if current undergraduates and graduates were adequately prepared to handle the multidisciplinary challenges of theranostics, encompassing diverse fields such as physics, chemistry, pharmacology, medicinal chemistry, and physiology. The question also touched upon whether more specialized courses should be offered to address this need.
Filipe responded by emphasizing the importance of providing specific training for graduates, noting that theranostics is not extensively covered in most pharmacy courses. While some introductory courses, like the one Filipe mentioned, introduce the topic and provide examples of diagnostics, he expressed that it falls short of meeting the demand for specialized training.
Filipe further discussed the involvement of various professional societies in the field, including the European Nuclear Medicine Society (EANM), the Society for Nuclear Medicine and Molecular Imaging (SNMMI), and the International Atomic Energy Agency (IAEA). These societies, but also multiple industry-driven initiatives, actively promote theranostics and the expansion of facilities offering radionuclide therapy. They serve as valuable sources of information and provide procedural guidelines to encourage the use of radionuclide therapy. Their efforts aim to provide early guidance to centers in need, promote theranostics, and strengthen nuclear medicine at the local level.
Collaborative initiatives are prevalent, particularly within the oncology community. Clinicians and nuclear medicine experts work together to advance the field. Filipe cited the example of the European School of Multi-Modality Imaging and Therapy (ESMIT), which operates under the EANM. This pioneering initiative offers advances courses on diagnostics and therapeutic applications of nuclear medicine in oncology, enabling participants to benefit from the experiences of those who have previously worked with radiopharmaceuticals. The goal of such courses is to make this knowledge accessible on a broader scale, with specific training offered at various sites.
Article written by Lorenzo Cianni and edited by Christien Bowman
Disclaimer:
The views and opinions expressed in this article are solely the ones of the interviewed and do not necessarily reflect the views or opinions of the University of Antwerp or any other organization. These statements were provided based on my own personal experiences, knowledge, and beliefs as an individual. Any reference to the University of Antwerp or other organizations is purely for context and should not be construed as the official position of the organization.
The interviewed is solely responsible for the accuracy and completeness of the information provided during the interview. The University of Antwerp or any other organization holds no responsibility for any statements or claims made herein. This disclaimer applies to all forms of media and communication where this interview is presented or referenced.
Filipe Elvas, PharmD, PhD