A new approach for aggressive prostate cancer

Prof. Anna Dubrovska (left) and Dr. Ielizaveta Gorodetska (right) are investigating specific genes to predict the success of radiotherapy for prostate cancer. © OncoRay / Uğur Kahya

Press release Februar 15th 2024

A new approach for aggressive prostate cancer

An OncoRay research group is showing for the first time how two genes can improve diagnosis and therapy.

Prostate cancer is the most common type of cancer among men in Germany and the second most common cause of cancer-related death. Older men, in particular, are affected by the disease, when a malignant tumor formed in the prostate gland. If detected early, the prospects for successful therapy are promising. However, in later stages, the cancer can spread. It then spreads to surrounding tissues outside of the prostate or forms secondary tumors, so-called metastases. There are currently only limited treatment options for metastatic prostate cancer. Scientists at OncoRay - National Center for Radiation Research in Oncology have now found a way to predict the patient's response to radiation therapy and its success. To do this, they looked at particular genes, as they report in the journal Theranostics (DOI: 10.7150/thno.88057).

According to information from the Robert Koch Institute, a total of 65,820 people across Germany were newly diagnosed with prostate cancer in 2020. The Centre for Cancer Registry Data (ZfKD) recorded 15,403 deaths from prostate cancer that year. Most prostate cancers rely on male sex hormones called androgens to grow. Regardless of surgery and radiation therapy, androgen withdrawal is considered a standard treatment for prostate cancer patients in the advanced stages of the disease. However, with long-term androgen deprivation, prostate cancer becomes androgen-independent and continues to grow. The aggressiveness of a tumor is related to the so-called tumor stem cells. This is a small group of cells with unique properties. They can renew themselves and develop into different cell types within the tumor. Compared to other tumor cells, they are particularly mobile. “We assume that these tumor stem cells play a crucial role in the development of tumors and the formation of metastases,” says the head of the OncoRay “Biomarkers for Individualized Radiation Therapy” working group, Prof. Anna Dubrovska.

What is particularly problematic is that tumor stem cells are resistant to conventional tumor therapies. Therefore, they could be primarily responsible for the recurrence of tumors after radiation therapy. The number of tumor stem cells and their radiosensitivity vary depending on the individual tumors. “The tumors are individual as the patients are,” explains Dubrovska. Successful therapies for the future must, therefore, be tailored much more specifically to the individual patient. Hence, the scientists devote their work to unique characteristics of the so-called biomarkers of the tumor stem cells. “They give us information about the properties and number of tumor stem cells.” This allows the researchers to look deeper into the machinery of tumor growth.

Genes revealing the course of the disease

Concerning prostate cancer, they looked at two genes as biomarkers: the so-called aldehyde dehydrogenases (ALDH) ALDH1A1 and ALDH1A3. Aldehyde dehydrogenases are enzymes that play an essential role in the metabolism of humans and other living beings. Their primary purpose is to oxidize aldehydes, i.e., organic compounds. To date, 19 such ALDH genes are known in humans. They are also involved in the regulation of stem cell processes. They have long been considered in science as possible biomarkers for cancer because increased ALDH activity is associated with tumor stem cells. Does this mean that aggressive cancer cells and, thus, worse disease progression for patients can be detected early?

For their study, the research group at OncoRay, which is jointly supported by the Helmholtz Center Dresden-Rossendorf (HZDR), the Carl Gustav Carus University Hospital Dresden, and the Medical Faculty TU Dresden, used various methods to investigate the role of ALDH1A1 and ALDH1A3 in prostate cancer. They switched off the two genes in cell cultures, zebrafish and a mouse model, to see how this affected cancer growth. In addition, they analyzed various tumor tissue samples from patients with prostate cancer. The studies showed that ALDH genes regulate the survival of tumor cells in the bloodstream and metastatic spread, influence resistance to radiotherapy, and the formation of bone metastases. The researchers demonstrated that the genes can serve as potential biomarkers for the progression of the disease in patients with prostate cancer. With further molecular studies, they also clarified what role they play in the further spread of prostate cancer in the human organism.

Opportunity for new therapies

“We saw that ALDH1A1 promotes the survival of cancer cells in the bloodstream and their spread in the body,” explains Dr. Ielizaveta Gorodetska, a geneticist in the research group. In comparison, ALDH1A3 plays an opposite role and negatively influences these processes. The researchers found different levels of ALDH1A1 and ALDH1A3 in prostate cancer tissue that had already spread to other parts of the body. “If samples from cancer patients show higher amounts of ALDH1A1, the prognosis for successful therapy is worse. On the other hand, if the ALDH1A3 concentrations are high, the prognosis is better,” summarizes Dubrovska. For the first time, the Dresden scientists have proved that the ALDH genes function as biomarkers for predicting the spread of metastases and radiation resistance in patients with prostate cancer, and this role of ALDH genes is mediated by their interaction with androgens in prostate cancer cells.

This finding creates new opportunities to develop effective therapies against resistant tumor stem cells. The director of the HZDR Institute for Radiation Oncology - OncoRay and director of the Clinic for Radiation Therapy and Radiation Oncology, Prof. Mechthild Krause, explains the chances of implementation for the benefit of patients: “With this knowledge, we can carry out further investigations to significantly improve the diagnosis and treatment of patients in the future, be it with medication or individually tailored radiation therapy.” The next step will now be to check whether the results also apply to other types of cancer, such as head and neck tumors, breast cancer, or glioblastoma.​

I. Gorodetska , A. Offermann, J. Püschel, V. Lukiyanchuk , D. Gaete, A. Kurzyukova , V. Freytag , M.-T. Haider, C. S. Fjeldbo, S. Di Gaetano , F. M. Schwarz, S. Patil, A. Borkowetz, H. Erb, A. Baniahmad, J. Mircetic, H. Lyng , S. Löck , A. Linge, T. Lange, F. Knopf, B. Wielockx , M. Krause, S. Perner, A. Dubrovska: ALDH1A1 drives prostate cancer metastases and radioresistance by interplay with AR- and RAR-dependent transcription Affiliations, Theranostics, 2024 (DOI: 10.7150/thno.88057)

Additional Informationen:
Prof. Anna Dubrovska I Biomarkers for individualized radiation therapy
OncoRay – National Center for Radiation Research in Oncology
Phone: +49 351 458 7150 I E-Mail: anna.dubrovska@oncoray.de

Media contact:
Simon Schmitt | Management and press spokesman
Communication and Media Department at HZDR
Phone: +49 351 260 3400 | E-Mail: s.schmitt@hzdr.de