Mission: rare cancers

Out of every 100,000 people, only one person will develop a phäochromocytoma, a tumour of the adrenal gland. If such a tumour has already metastasised, a radioactive preparation can detect the malignant cells scattered throughout the body and irradiate them from the inside. However, not every tumour presents enough target molecules to which the preparation can dock with the beta emitter lutetium-177. The radiation dose is then often not sufficient to contain the cancer. By administering two approved drugs upstream of the therapy, a research group at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) succeeded in increasing the number of target molecules for radionuclide therapy in a mouse model, thereby halting tumour growth. The experiments were carried out in cooperation with the University Medical Centre and the Carl Gustav Carus University Hospital in Dresden.

Adrenal tumours such as phäochromocytoma are rare. They develop from neuroendocrine cells, which often also produce stress hormones. A typical feature of the majority of such tumours is that their cell surfaces are spiked with a unique target structure - a receptor for the hormone somatostatin. This opens up a way for specialists to combat the diseased cells. Radioactively labelled molecules, known as radionuclide therapeutics, dock onto the receptors and cause the cells to die as a result of the radiation emitted. The surrounding healthy tissue is spared.

Rare diseases are hardly attractive for the pharmaceutical industry due to small case numbers and correspondingly low profit expectations. "We believe that publicly funded research has a duty here," says Prof Jens Pietzsch, head of department at the HZDR Institute of Radiopharmaceutical Cancer Research. „In the case of phäochromocytoma, for example, we know that growth can be stopped with a suitable radionuclide therapeutic agent. And the more somatostatin type 2 receptors the tumour cells produce, the more effective this is. In our experiments, we were able to double the radiation dose in the tumour“, the biologist describes an important result of the study recently published in the scientific journal „Theranostics“. In addition, the Dresden researchers have identified genes that could be responsible for the subsequent regrowth of tumours. This is an important step towards developing further active substances for the treatment of neuroendocrine tumours in the future.

Patients with a malignant phobromocytoma could benefit from the use of the radionuclide therapeutic lutetium-177-DOTATATE. The beta emitter lutetium-177 releases electrons during decay, which lead to cell death. However, this process also produces energy in the form of gamma radiation, which can be visualised using single photon emission computed tomography (SPECT). Nuclear medicine specialists use the image data to determine the radiation dose deposited in the tumour. The more they know about the individual characteristics of the tumour, its molecular fingerprint, the greater the chance of effective treatment.

The individuality of a tumour

Before an inoperable phäochromocytoma is treated, precise diagnostics therefore clarify whether a sufficient quantity of receptors for radionuclide therapy - also known as endoradiotherapy - is present. „The formation of the somatostatin type 2 receptor varies greatly in these tumours. Some produce it more intensively, others not at all. Our aim was to use authorised drugs to increase the number of receptors prior to endoradiotherapy so that more patients can benefit from the treatment in future. Thanks to the approval, the path to the clinic is short“, explains Dr Martin Ullrich, biologist in Jens Pietzsch's team.

The researchers selected two active substances for pre-therapy: Valproic acid and decitabine. Valproic acid is primarily used to treat epilepsy and seizures, while decitabine is indicated for the treatment of certain leukaemias. However, it was known from cell experiments that both active substances can also stimulate the production of somatostatin receptors. As they do not directly change the genetic information on the DNA, but merely facilitate the reading of genes, they are categorised as epigenetic agents.

In order to find out whether the two drugs have the desired effect on phäochromocytoma, tests were first carried out with cell material (in vitro) and then, due to the promising results, also in a mouse model. „These were independent trials with multi-arm treatment regimes. All tests were repeated several times, sometimes with one active substance, sometimes with both. And of course with untreated control groups for comparison," Ullrich explains.

The result: when the epigenetic drugs valproic acid and decitabine were administered twice a few days before endoradiotherapy, the accumulation of the radionuclide therapeutic agent lutetium-177-DOTATATE - and thus also the precisely deposited radiation dose - doubled in the tumour. Ullrich measured this with the small animal SPECT camera at the HZDR, which he himself tested for mouse models. The combination therapy therefore keeps the tumour under control for significantly longer than was previously possible with the radionuclide therapeutic agent alone. However, further clinical trials are necessary before the combination can be used on patients.

Re-growth of the tumour

Tumours develop resistance to the effects of radiation by switching certain genes on or off. This means that even after endoradiotherapy, they often start to grow again after a certain point in time. In the search for strategies to further reduce this resistance to therapy in the future, the HZDR researchers sent tissue samples of the irradiated tumours to Dr Susan Richter from the Institute of Clinical Chemistry and Laboratory Medicine at Dresden University Hospital for genetic analysis, which was carried out jointly with the NCT/UCC (National Centre for Tumour Diseases Dresden). This resulted in lists of over 55,000 genes, known as transcriptomes, which Ullrich was able to reduce to a manageable list through extensive data analyses and research. His conclusion: „Among the genes that have changed significantly during endoradiotherapy, there are several candidates that could be considered as target molecules for radiosensitising combination therapies.“

„With this brand-new data, things are now getting really exciting,“ says department head Pietzsch. „We are breaking new ground. Now we need a lucky hand to fish out the right gene.“ The plan is to complete another cycle of experiments with the gene of choice in the next few years. „Then, after the combination therapy of epigenetic drugs and radionuclide therapeutics, which hopefully can soon be transferred to the clinic, there could be a further treatment step: Active substances that switch off the resistance genes responsible for the re-growth of the tumour“, Pietzsch looks cautiously to the future. The researchers also hope that it may then be possible to overcome the resistance to radiation not only in the rare phäochromocytoma, but also in other neuroendocrine tumours.

The Dresden researchers are funded by the German Research Foundation (DFG) as part of the Collaborative Research Centre Transregio 205 „The Adrenal: Central Relay in Health and Disease“ (Die Nebenniere: Central Relay in Health and Disease), which involves scientists from the University of Würzburg, Ludwig-Maximilians-Universität München, University Medicine and the University Hospital Dresden – and is already in its second funding period.

Press release of the HZDR from 09 February 2023