Novel 5-HT6 receptor ligands as an innovative therapy for glioblastoma treatment

Can serotonin receptors be utilized in glioblastoma treatment?

Glioblastoma is the most aggressive form of brain cancer. It is characterized by high invasiveness, meaning it rapidly spreads into adjacent brain regions. Consequently, prompt and decisive treatment is critical. Unfortunately, the efficacy of currently available therapeutic options remains unsatisfactory, prompting researchers to seek novel strategies in the fight against glioblastoma. One innovative approach involves targeting and blocking serotonin receptors. This concept will be evaluated under a Proof of Concept grant - funded by the European Funds for a Modern Economy 2021–2027 (FENG) through the Foundation for Polish Science - led by Przemysław Zaręba, PhD, Eng., from the Department of Chemical Technology and Environmental Analytics at the Tadeusz Kościuszko Cracow University of Technology.

Gliomas account for nearly 50% of all brain tumors, with multiple genetic alterations already identified as key drivers of their development. Depending on tumor grade, standard treatment typically involves surgical resection, potentially combined with chemotherapy and radiotherapy. Recent years have seen the emergence of targeted therapies for glioblastoma; however, their clinical efficacy remains limited to date.

"The therapy we are proposing relies on a rather unconventional protein target in oncology. We will focus on blocking serotonin receptors, which are typically associated with other central nervous system disorders such as depression, schizophrenia, or Alzheimer's disease. In our approach, however, we block these receptors to achieve an antitumor effect. Serotonin (5-HT) is recognized as a growth factor for several cancer cell types and has been shown to stimulate the proliferation, migration, and invasion of glioblastoma cells. In our previous research, we demonstrated that blocking 5-HT6R serotonin receptors inhibits signaling pathways linked to glioma growth and reduces serotonin levels within the tumor microenvironment. Crucially, 5-HT6R receptors are localized almost exclusively in the central nervous system, meaning this targeted intervention will not affect other tissues and organs," explains Dr. Przemysław Zaręba.

Under the Proof of Concept project, the researchers will take the next step by using molecular modeling techniques to select the most promising serotonin receptor-blocking compounds, synthesizing them, and evaluating their efficacy in cancer cells isolated directly from glioblastoma patients. These studies will be conducted in collaboration with the Medical University of Łódź, where a medical team will be responsible for obtaining patient-derived tumor cells and preparing them for assays. The primary objective is to verify whether serotonin receptor-modulating compounds exhibit true anticancer activity - specifically by inhibiting tumor cell proliferation, suppressing their migration and dissemination throughout the brain, or triggering apoptosis (programmed cell death).

"The subsequent step, which we will also initiate within this project, involves in vivo studies using animal models. After that comes the most crucial phase: clinical trials in human patients. As this phase is the most capital-intensive, successful commercialization of our product will require backing from a pharmaceutical industry investor. However, even during the Proof of Concept project, we will collaborate with two commercial partners - Farmina and AT Analytica - who will support our efforts toward future product commercialization. Under an optimistic scenario, if our molecules prove active and effective in glioblastoma treatment, they could reach the market as approved drugs in approximately 5 to 10 years," concludes Dr. Przemysław Zaręba.

Przemysław Zaręba, PhD, Eng., completed his Master's degree at the Faculty of Chemical Engineering and Technology of the Tadeusz Kościuszko Cracow University of Technology, specializing in fine chemical technology. In 2023, he earned his PhD from the same faculty, specializing in chemical engineering. His doctoral dissertation focused on central nervous system disorders, specifically depression and schizophrenia. He is a laureate of the 14th edition of the LIDER program organized by the National Centre for Research and Development (NCBR), under which he is currently leading a project aimed at developing a novel therapeutic strategy against prostate cancer.