Endoradiotherapy can be very unpleasant for cancer patients, since it does not only harm tumor cells, but also healthy ones. Sometimes, patients even need to stop therapy because of the side effects. Physicians and researchers are thus continuously searching for ways to transport radiopharmaceuticals directly and exclusively to their target.
In the interview with MEDICA-tradefair.com, Martina Benešová talks about a new agent called PSMA-617. It aims at the prostate-specific membrane antigen (PSMA) and can potentially be used both in diagnosis and treatment of prostate cancer.
Ms. Benešová, you and your colleagues recently received the "Image of the Year Award" and the "Berson-Yalow Award" at the 2015 Annual Meeting of the Society of Nuclear Medicine and Molecular Imaging (SNMMI) for the development of the agent PSMA-617. Where did the idea to develop this agent originally come from?
Martina Benešová: Our Division of Radiopharmaceutical Chemistry at the German Cancer Research Center in Heidelberg has developed the molecule PSMA-11 in 2012. This is a small molecule directed against the PSMA which is strongly expressed on the surface of prostate cancer cells and upregulated in poorly differentiated, metastatic and hormone-refractory carcinomas. It plays a significant role in prostate carcinogenesis and progression and represents a highly attractive biological target in Nuclear Medicine.
We wanted to broaden the utilization of this kind of small PSMA-targeted molecule also for its therapeutic use since PSMA-11 preferentially binds Gallium-68 which belongs to the diagnostic radionuclides for positron emission tomography (PET). We decided to replace part of the molecule, the HBED-CC chelator, for a DOTA chelator. This chelator can tightly coordinate a number of trivalent metal cations. It enables us to use the same vector molecule for both diagnostic and therapeutic purposes. Subsequent optimization of the compound properties through the systematic linker modification was performed. This strategy resulted in the identification of the theranostic agent which we call PSMA-617.
What does the utilization of this agent possibly look like?
Benešová: For use in imaging, especially in PET scans, PSMA-617 may be labeled with the positron emitters Gallium-68 or Scandium-44. For the therapeutic purposes, beta minus particle emitters like Yttrium-90 or Lutetium-177 could be complexed by the DOTA chelator.
This theranostic approach has many advantages. From an economic point of view, clinical trials with these kinds of agents can be designed to be more effective and efficient. Also, the individual costs for cancer treatment may be reduced. With the respect to personalized medicine, improved tumor targeting and pharmacokinetic properties are the most crucial findings of PSMA-617.
There was already a small trial. In what way was the agent tested?
Benešová: Prof. Uwe Haberkorn from the University Hospital Heidelberg injected patients with the Gallium-68-labeled version. He observed that the compound visualized prostate cancer with high contrast. The version labeled with Lutetium-177 was afterwards used for endoradiotherapy at the Department of Nuclear Medicine at the University Hospital Heidelberg. We obtained the "Image of the Year" award at SNMMI as this therapy induced apparently remission in a patient with metastatic prostate cancer. So, the potential of the compound was underlined by this first clinical study.
What effect was exactly observed in the patients?
Benešová: Our compound is directed against PSMA so it specifically targets the surface of prostate cancer cells. There are also other organs that express low levels of PSMA, like the kidneys and the salivary glands. During the PET imaging, we are able to directly visualize the primary cancer and even small metastases or recurrent prostate cancer.
The endoradiotherapy with Lu-177-PSMA-617 strongly affected the prostate cancer as the cancer lesions were clearly diminished. Patients with bone metastases which often lead to pain reported that the pain decreased after the first cycle. Thus it is proven that the compound has a direct influence on the cancer.
Were there any side effects observed?
Benešová: No severe side effects have been observed. Future prospective clinical trials have to confirm these observations. We further measured the distribution of radioactivity in the healthy organs and realized that the doses for the kidneys are moderate. There was no harm to the bone marrow observed, as could be the case with radioiodine isotopes, for example, which may cause hematotoxicity. No significant decrease of the different blood components was observed.
To my good knowledge, I would say that the use of PSMA-11 and PSMA-617 is in general more sensitive and specific than the use of other diagnostic PET agents, for example radiofluorinated Choline derivatives. Moreover, PSMA-617 additionally offers the possibility of highly efficient endoradiotherapy.
As aforementioned, we currently are planning a prospective multicenter trial together with academic and industrial partners to further evaluate PSMA-617 for its clinical potential.