New substance could improve efficacy of established breast cancer treatments

Physicians from Karl Landsteiner University of Health Sciences in Krems (Austria) demonstrate potential for clinical application, collaborating with research groups from Germany, the USA and China.

A new active ingredient against breast cancer shows better tolerability than comparable substances in laboratory tests – and could also improve the efficacy of established cancer treatments. The targeting agent is therefore a good candidate for clinical development and works by influencing the activation of naturally occurring cell death, or apoptosis – a cellular mechanism which is switched off in many tumor cells, allowing cancer cells to multiply unimpededly. The results of the investigations into the new substance have now been published. Researchers at Karl Landsteiner University of Health Sciences in Krems played a leading role in the study, working with colleagues from Heidelberg University, Harvard Medical School and highly regarded groups in the USA and China.

Weighing up the benefits of eliminating malignant cells against causing irreparable damage to healthy ones plays a greater role in the treatment of cancer than in any other disease. Findings now published by a research group led by Dr. Klaus Podar at Karl Landsteiner University of Health Sciences are therefore sure to attract a lot of attention within the cancer research community. The group was able to demonstrate the therapeutic suitability of a novel targeting agent when used in combination with established cancer drugs, with results showing good tolerability and high efficacy. These findings build on previous work undertaken by Dr. Podar in collaboration with other groups that identified a new structure which is often present in tumor cells. This structure is the target of the recently developed agent, which shows potential for use in the treatment of breast cancer. The data being published now paves the way for developing the substance for clinical application.

THERAPY TO INDUCE CANCER CELL DEATH

The active substance, called EU-5346, inhibits the binding of two proteins in cancer cells, Mcl-1 and Bim. The binding of Mcl-1 and Bim suspends Bim-induced programmed cell death, or apoptosis. Apoptosis is generally a necessary mechanism for the body to dispose of unwanted cells.

The substance that we have tested makes tumor cells ‘mortal’ again. It therefore shortens the life of breast cancer cells and can also prevent the development of resistance to certain cancer drugs. And it goes without saying that both of these are positive effects when it comes to treatment.”

Dr. Sonia Vallet, the study’s lead author from the Clinical Department of Internal Medicine II at Krems University Hospital

Many research groups and pharmaceutical companies are currently focusing on the development of targeting agents which, like EU-5346, produce these effects by inhibiting the anti-apoptotic protein Mcl-1. However, clinical application has been ruled out for many of these substances due to strong side effects. Dr. Vallet and her colleagues from Heidelberg University, Harvard Medical School and highly regarded groups in the USA and China therefore decided to incorporate laboratory investigations into the side effects of EU-5346 into their study. Dr. Podar was pleased with the outcome: “We were all delighted when the results showed that EU-5346 was comparatively less toxic to the heart, blood and nerves.”

TACKLING RESISTANCE

The group also tested the breast cancer cell targeting effects of EU-5346 in combination with established breast cancer medications. Tumor cells often develop resistance to these drugs, especially tamoxifen, trastuzumab and paclitaxel. The researchers demonstrated that in all cases, combining these medications with EU-5346 improved or reactivated their anti-tumor effects. “We think the findings show that EU-5346 is a promising candidate for further drug development in a clinical setting,” said Dr. Vallet, summarizing the encouraging results of the international collaboration. “I’m convinced that Mcl-1 inhibitors have the potential to play a major role in the treatment of other cancers too, and not just breast cancer,” Dr. Podar added. Further research is required into the prevalence of Mcl-1 and other specific anti-apoptotic proteins in individual tumor cells for the development of a clinical application. This data would provide insights into the potential efficacy of EU-5346 and of rationally derived combination therapies including EU-5346, which could be used for personalized treatment.

Karl Landsteiner University’s collaboration with internationally respected cancer research institutions speaks to the high level of research which is taking place at Lower Austria’s university hospitals. Strong links with the hospital’s patient care operations are important in ensuring that the university’s research tackles real-world challenges faced in the course of routine medical care.

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