Combination of active ingredients could improve chances of cure for ovarian cancer

Researchers test drug combination of novel chemotherapeutic agent and PARP inhibitor in laboratory trials / Effect of targeted PARP inhibitor drug can thus be increased in cell trials

Innovative targeted agents, so-called PARP inhibitors, can significantly improve the prognosis in ovarian cancer. This is especially true for patients whose tumors have certain genetic conditions. A research team led by scientists at Dresden University Medical Center and the National Center for Tumor Diseases Dresden (NCT/UCC) has now been able to show in laboratory experiments that the administration of a novel chemotherapeutic agent in combination with a PARP inhibitor significantly enhances the effect of the targeted drug, even at low doses. The scientists observed this effect in patient-derived cancer cells cultured in the laboratory, independent of any changes present in certain high-risk genes. The drug combination therefore appears to be a promising approach to expand the clinical application range of PARP inhibitors in the future and to reduce resistance. The scientists published the results of their study in the journal Gynecologic Oncology.

The National Center for Tumor Diseases Dresden (NCT/UCC) is a joint institution of the German Cancer Research Center (DKFZ), the University Hospital Carl Gustav Carus Dresden, Carl Gustav Carus Faculty of Medicine at TU Dresden and the Helmholtz-Zentrum Dresden-Rossendorf (HZDR).

Ovarian cancer has the highest death rate among gynecological cancers. This is mainly due to the fact that in 75 percent of cases, the cancer is only detected at an advanced stage due to a lack of symptoms. Even after initially successful standard therapy, there is a high probability that the tumor will return quickly. This early risk of recurrence can be significantly reduced in patients whose tumors have certain genetic conditions by additional treatment with PARP inhibitors. PARP inhibitors are active ingredients that specifically inhibit the action of enzymes from the poly-ADP-ribose polymerase (PARP) family, which enable cells to repair DNA damage. Tumors with mutations in the so-called BRCA1/2 genes already have a fundamental defect in certain DNA repair pathways. By using PARP inhibitors, the already impaired DNA repair ability of the tumor cells is specifically reduced even further. As a result, tumor cells die, while healthy cells are largely spared. In the case of recurrent disease, PARP inhibitors can also be used without this genetic modification, which is particularly beneficial for treatment. However, the majority of patients develop resistance to the innovative drugs over time.

A team of researchers led by scientists at the Dresden University Medical Center and the National Center for Tumor Diseases Dresden (NCT/UCC) has now been able to show in laboratory experiments that the combination of a novel chemotherapeutic agent from the triazene class and the PARP inhibitor olaparib significantly increases the effect of the targeted drug. This effect could be demonstrated independently of any mutation present in the BRCA1/2 genes. "The laboratory results give hope that PARP inhibitors could be used in a larger group of patients in the future and that combined drug administration can further improve the chances of curing ovarian cancer," says Prof. Pauline Wimberger, Director of the Department of Gynecology and Obstetrics at the University Hospital Carl Gustav Carus Dresden and member of the extended Board of Directors of the NCT/UCC Dresden.

Studies with an already approved chemotherapeutic agent from the triazene group indicate that this substance class is also particularly well suited for combination with PARP inhibitors due to its comparatively low toxicity. In contrast, combinations of platinum-based chemotherapies with PARP inhibitors showed too high side effects.
The chemotherapeutic agent CT913 from Wuppertal-based Creative-Therapeutics GmbH, which has now been tested in laboratory experiments and has not yet been approved, showed particularly good efficacy in the laboratory tests in combination with the PARP inhibitor olaparib, also in comparison with other triazene compounds. Gene expression analyses clarified that CT913 downregulates numerous enzymes responsible for DNA damage repair in cancer cells. "Thus, the drug has an effect similar to that of a mutation in the BRCA1/2 genes. By disrupting alternative repair mechanisms, cells rely more on repair by PARP enzymes. If these are inhibited by PARP inhibitors, this possibility of DNA repair is also blocked and many tumor cells die," explains PD Dr. Jan Kuhlmann, head of the Laboratory for Molecular Gynecological Oncology at Dresden University Hospital. Due to the mutually reinforcing effect of CT913 and the PARP inhibitor olaparib, numerous cancer cells died in the cell cultures even at low drug doses. "The low dosage of the active ingredients in combined use could help to significantly reduce resistance to PARP inhibitors in the future," said Prof. Wimberger.

The combination of the new chemotherapeutic agent with PARP inhibitors will be explored in further laboratory experiments in the future. If these studies are successful, clinical trials could follow.

Effect of PARP inhibitors

The DNA in our cells is constantly exposed to damage. Healthy cells can usually repair this damage, for example with the help of the BRCA1 and BRCA2 proteins. If the function of the BRCA proteins fails due to mutations in the corresponding genes, there is an increase in genetic changes that can cause cancer. Changes in the BRCA genes increase the risk of breast and ovarian cancer in particular. Tumors with such a defect can be combated with the help of so-called PARP inhibitors. These inhibit the enzymes PARP1 and PARP2, which are also involved in DNA repair. As a result, the DNA damage in the cancer cells can become so extensive that they die. Healthy body cells with repair proteins still functioning, on the other hand, survive.

Publication:
Catharina Wichmann, Daniel Martin Klotz, Hans-Joachim Zeiler, Ralf Axel Hilger, Konrad Grützmann, Alexander Krüger, Daniela Aust, Pauline Wimberger, Jan Dominik Kuhlmann: The effect of the triazene compound CT913 on ovarian cancer cells in vitro and its synergistic interaction with the PARP-inhibitor olaparib. In: Gynecol Oncol. 2020 Dec;159(3):850-859, https://doi.org/10.1016/j.ygyno.2020.09.018

Press contact:
Dr. Anna Kraft
Nationales Centrum für Tumorerkrankungen Dresden (NCT/UCC)
Presse- und Öffentlichkeitsarbeit
Tel.: +49 (0)351 458-5548
E-mail: anna.kraft@nct-dresden.de
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