Research Project Pretorian

Project Description

Τhe PRETORIAN project is dedicated to harnessing experimental discoveries concerning two novel chemical structures displaying remarkable anti-cancer properties. These discoveries are being advanced as pioneering therapeutic agents for cancer treatment.

The selection of the PRETORIAN compounds followed a rigorous evaluation process, involving the assessment of the biological activities of hundreds chemical compounds by the research teams led by Professors Aristides Eliopoulos (School of Medicine, National and Kapodistrian University of Athens-NKUA) and George Vasilikogiannakis and Manolis Stratakis (Department of Chemistry, University of Crete-UoC). The most potent chemical structures served as blueprints for the synthesis of derivative compounds, with the goal of amplifying their biological efficacy. This resulted in the development of two distinct chemical structures derived from the original compound which are further explored by the NKUA, UoC and Pharmathen teams.

The novel cyclopentanone derivative compounds confer:

• Broad spectrum cytotoxic activity against different types of malignancy, especially ovarian cancer and multiple myeloma.
• Potential for treatment of platinum-resistant tumors.
• Synergy with the proteasomal inhibitor bortezomib.
• Deceleration of tumor growth and increased numbers of intratumoral NK cells in a mouse tumor model.
• Potential for targeting tumors showing "translation addiction" via the induction of nucleolar stress.

PRETORIAN is co‐financed by the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call RESEARCH – CREATE – INNOVATE

Object and Objectives of the Project

PRETORIAN aims at the preclinical evaluation of two cyclopentenone derivatives, with the following specific objectives:

1. Comprehensive in vitro and in vivo evaluation of the new compounds as monotherapies or in combination with other chemotherapeutic or biological agents.
2. Determining the impact of the compounds on biological networks.
3. Assessing the conversion of pro-drug molecules into active final compounds.
4. Conducting toxicological analyses in experimental animals (mice).
5. Securing intellectual property rights (patents) and developing commercialization strategies for the results.

Project Implementation Methodology

PRETORIAN is a collaborative scheme of scientists from the National and Kapodistrian University of Athens, the University of Crete, and Pharmathen S.A., a leading pharmaceutical company, with a shared vision: to create new therapeutic prospects in oncology.

By combining our research expertise in chemistry and biology with our know-how in drug synthesis, testing and production, we are dedicated to continuously advancing the development of new drugs that will bolster the oncological armamentarium.

Description of work units and deliverables

The PRETORIAN project entails four workpackages (WP1-4):

WP1 focuses on establishing a pre-clinical platform necessary for the evaluation of the biological activity of the enone derivatives, with the following deliverables:

• Research Framework & Ethics
• In Vitro Study Framework
• In Vivo Study Pipeline

WP2 aims to synthesize and evaluate the cytotoxic and immunogenic effects of the new compounds, as well as their analogs. The following deliverables apply:

• Compound Synthesis on a Large Scale and Development of New Synthetic Methodologies
• Qualitative Characteristics of Compounds
• In Vitro Activity of Compounds as Monotherapies or in Combination with Other Treatments
• Mechanisms of Action (transcriptomics, proteomics)

WP3 is devoted to toxicological assessments. It aims to experimentally investigate any adverse or toxic effects of the compounds under study. The following deliverables apply:

• Synthesis of Labeled Active Compounds
• Determination of Maximum Tolerated Doses
• Comprehensive Toxicological Analysis

WP4 focuses on evaluating the in vivo activity of the cyclopentenone derivatives with the following deliverables:

• In Vivo Activity of the Compounds as Monotherapies or in Combination with Other Treatments
• Study of Commercial Viability
• Patent Protection
• Dissemination Actions

Expected results

The expected outcomes of the PRETORIAN project are as follows:

•    Identification of compounds with the potential to address platinum chemotherapy resistance in ovarian cancer while minimizing side effects for patients. By developing new chemotherapeutic drugs, the PRETORIAN project indirectly aims to achieve socially impactful results, particularly concerning the treatment of a malignancy known as the "silent killer."
•    Securing a patent, contributing to the excellence and competitiveness of the national economy.
•    Establishment of a biobank for primary ovarian cancer cell cultures, promoting greater participation of project stakeholders in European and international collaborations for the study of age-related diseases.
•    Transfer of innovative chemical synthesis methodologies developed by academic partners to the participating company. This includes innovative chemical synthesis techniques previously funded by the ERC.
•    Knowledge transfer from the participating company, Pharmathen S.A., to academic partners in the field of product research strategic utilization.
•    Enhancement of the participating company's competitiveness through the development of new products. Pharmathen S.A. is the leading research and development company in Greece (EU Industrial R&D Investments Scorecard) and is fully capable of capitalizing on the project's results. The new compounds fall within its scope of work, which encompasses the production of anti-cancer drugs.
•    Creation of new job opportunities.
•    Long-term collaboration among academic, research, and productive forces in Greece, in alignment with the strategic objective of the Operational Programme EPAnEK (National Strategic Reference Framework).