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Novel RNA therapy effective against aggressive brain tumors

Glioblastomas are particularly aggressive brain tumors that quickly invade healthy brain tissue. Since these tumors cannot usually be completely removed surgically, the prognosis for glioblastoma patients is very poor. The standard therapy, which consists of a combination of surgery, radiation, and chemotherapy, does not offer a cure. Therefore, there is an urgent need for effective treatment options. Researchers at the University Medical Center Mannheim (UMM), the DKFZ-Hector Cancer Institute at UMM, and the University Hospital Bonn (UKB) are investigating a new therapy involving a novel class of drugs made from RNA polymers, known as Spiegelmers, which aim to block the regeneration of glioblastomas.

In 2019, the GLORIA study was launched including six university hospitals in Germany under Mannheim leadership. This study is the first to investigate how the drug Olaptesed Pegol (NOX-A12, TME Pharma) works in combination with radiation therapy in glioblastoma patients.

"The unique aspect of our therapeutic approach is that we are no longer focusing solely on the radiation effects in tumor cells but also on their environment, the so-called tumor microenvironment. The Spiegelmer NOX-A12 prevents the formation of new blood vessels through a mechanism that is specifically triggered by remaining tumor cells after radiation therapy to regenerate," explains Professor Dr. Frank Giordano, Director of the Department of Radiation Therapy at UMM, who also conducts research for the DKFZ-Hector Cancer Institute.

Tumor cells depend on the supply of nutrients and oxygen in the blood. They emit signaling molecules that promote the formation of new blood vessels and encourage them to grow towards and nourish the tumor. Even deadly brain tumors attempt to regenerate in this way after therapy. CXCL12 is one such endogenous signaling molecule that stimulates blood vessel formation. The Spiegelmer NOX-A12 inhibits CXCL12 and thus hinders the tumor's regeneration. "Interestingly, the principle seems to work only in combination with radiation therapy because glioblastomas use this repair mechanism via CXCL12 particularly after irradiation," emphasizes Professor Giordano.

In a preliminary Phase I/II study, the new therapy was first tested on a small group of patients with newly diagnosed glioblastomas resistant to standard therapy. The primary aim was to gather information about the safety and preliminary efficacy of NOX-A12 in combination with radiation therapy.

Additionally, the study provided new insights crucial for the further development of the NOX-A12 therapy. Under the leadership of research groups at the University Hospital Bonn, tumor tissue samples were examined using state-of-the-art methods. "When the tumor cells and, interestingly, the vascular cells themselves produce a lot of CXCL12, it seems to correlate with a better response to NOX-A12 therapy," explains Professor Dr. Michael Hölzel, Director of the Institute for Experimental Oncology at UKB, who also conducts research at the University of Bonn. "However, further studies and a larger number of samples are needed to substantiate this observation," Professor Hölzel notes.

The initial data are promising enough that the US Food and Drug Administration (FDA) has not only accepted the application for NOX-A12 as a new investigational drug (IND) but has also endorsed the application for Fast-Track Designation, thereby shortening a process that usually takes several years.

The study involves the university hospitals in Mannheim, Bonn, Essen, Münster, Tübingen, and Leipzig. The results of the study have been published in the renowned journal Nature Communications.

20240523 PM  Hoelzel Herrlinger Layer 1212 wp header
From left: Dr. med. Julian Layer, Prof. Dr. med. Michael Hölzel, Prof. Dr. med. Ulrich Herrlinger
© University Hospital Bonn

Publication:

Frank A. Giordano, Julian P. Layer, Sonia Leonardelli, et al.

L-RNA aptamer-based CXCL12 inhibition combined 1 with radiotherapy in newly-diagnosed glioblastoma: dose escalation of the phase I/II GLORIA trial

Nature Communications, DOI: 10.1038/s41467-024-48416-9

Contact:

Prof. Dr. med. Michael Hölzel

Director of the institute of Experimental Oncology

University Hospital Bonn

E-Mail: Michael.Hoelzel@ukbonn.de

Press contact:

Jana Schäfer

Deputy Press Officer

University Hospital Bonn, Communication and Media

E-Mail: jana.schaefer2@ukbonn.de

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