PFKFB3-Inhibition während einer Radiochemotherapie des Rektumkarzinoms – Überprüfung in einem patient-derived xenograft In-vivo-Modell

by Marcus Edelmann
Doctoral thesis
Date of Examination:2024-02-06
Date of issue:2024-01-29
Advisor:PD Dr. Dr. Lena-Christin Conradi
Referee:PD Dr. Dr. Lena-Christin Conradi
Referee:Prof. Dr. Stefan Rieken
Referee:Prof. Dr. Ralf Dressel
Persistent Address: http://dx.doi.org/10.53846/goediss-10293

 

 

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Abstract

English

Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide and the second leading cause of cancer death. Approximately 30% of colorectal carcinomas are localized in the rectum. Neoadjuvant radiotherapy (RT) or radiochemotherapy (RCT) is an integral aspect of patients’ treatment. However, Patients' response to preoperative R(C)T is heterogeneous and ranges from resistance and disease progression, despite intensive treatment up to complete tumor regression. In order to minimize the development of radiation resistance, it is important to review and optimize existing treatment approaches. Increased glucose metabolism and enhanced neoangiogenesis are considered hallmarks of cancer and are of particular interest in developing novel treatment approaches in cancer therapy. In particular, the bifunctional enzyme PFKFB3 represents a promising target. PFKFB3, as an indirect stimulator of glycolysis, affects the glycolytic activity of cancer cells and was shown to induce tumor vessel normalization (TVN) upon inhibition. Moreover, high PFKFB3 expression was shown to be associated with poor prognosis for patients with CRC. This highlights PFKFB3 as an attractive therapeutic target. An effective inhibitor of PFKFB3 is 2E-3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO). The effect of PFKFB3 inhibition by 3PO in CRC cell lines on cell viability, cell death as well as invasion and migration ability were assessed. To verify a potential radiosensitizing effect of 3PO a colony formation assay was performed. Subsequently, in vivo studies were established to evaluate the TVN effect of combined therapy of 3PO and R(C)T in patient-derived xenograft tumors. In vitro, 3PO affects cell proliferation and viability in a concentration-dependent manner and reduces CRC cell invasion and migration. Furthermore, the blockade of PFKFB3 by 3PO increases radiation-induced cell death. Moreover, the results reveal that inhibition of PFKFB3 induces TVN and alleviates tumor hypoxia culminating in increased tumor necrosis upon combined therapy of 3PO with R(C)T in vivo. Although, tumor volume indices as well as the tumor mass after explantation showed no significant differences, tumors that received 3PO and radiotherapy exhibited increased necrotic areas. The findings of this study indicate that blocking PFKFB3 by 3PO is a potential therapeutic target to induce TVN, reduce tumor hypoxia and consequently increase radiosensitivity.
Keywords: Rectal cancer; PFKFB3; Radiotherapy; Tumor vessel normalization
Schlagwörter: Rektumkarzinom; PFKFB3; Radiotherapie
 
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