Research

The main focus of the Tamvakopoulos lab is to unravel the complex mechanisms around cancer therapy. Inspired by the constant need for effective treatments, research has focused on the development of novel anticancer molecules based on conjugates with peptide targeting moieties. Our strategy takes advantage of aberrant target expression in cancer cells to preferentially target the cancer cells and not the surrounding healthy tissues. We are particularly interested in cell membrane receptors that become abnormal during carcinogenesis and provide a handle for the development of targeted therapeutics. Our efforts of anticancer drug discovery/development also include identification of parameters that will lead to the maximal beneficial effectiveness including drug-carrier for administration, dosing, scheduling, and route of administration.

Peptide-drug conjugate (PDC) study areas for the development of Targeted Cancer Therapeutics

To do so, the Tamvakopoulos lab is involved in the development and application of advanced bioanalytical mass spectrometry methods that demonstrate a “niche” in understanding the pharmacologic action of newly synthesized and/or established compounds. This expertise provides the necessary know-how that facilitates the process of designing future therapies, based on pharmacokinetic/drug metabolism, biodistribution and biomarker mediated responses that are central to precision therapy.

PROTACS

A major anticancer research approach of our lab aims at inhibition of oncoproteins that appear to be overexpressed in different types of cancer. One of the most widely investigated oncoproteins that is associated with up to 70% of human cancers, is c-MYC. However, its direct inhibition strategy remains ineffective and poorly elucidated. Our group is actively involved in research activities that aim to untangle this phenomenon by pharmacologically evaluating novel compounds that inhibit c-MYC mediated cancer growth, using both in vivo and in vitro experimental models. In this line, one of our projects expands on the novel concept of proteolysis-targeting chimaeras (PROTACs). The PROTAC technology introduces heterobifunctional molecules consisting of one moiety that targets a protein of interest (POI) linked by an optimally designed linker to another part that is specific to the E3 ubiquitin ligase. This chimaeric compounds hold promise in protein of interest (POI) degradation through poly-ubiquitinilation and consequent proteasomal degradation.

Ubiquitin-proteasome mechanism of the PROTAC-mediated POI degradation.

This work is expected to lead to exciting achievements in the field of targeted therapies with emphasis on “undruggable” oncogenic protein targets. Computational methods and in silico experiments support unveiling of the structural and physicochemical requirements for the development of these novel compounds.

An exciting distinction from the more conventional semi-quantitative immunoblot assays employed for PROTAC evaluation is expected via the set-up of a mass spectrometry-based assay that quantifies the degradation outcome of the POI after PROTAC administration via the detection of unique peptides for target-protein.

Published Paper:   Developing MYC Degraders Bearing the Von Hippel–Lindau Ligand to Target the “Undruggable” MYC
Christos Siokatas, Alexandra Lampropoulou, Alexandra Smina, Katerina Soupsana, Martha Kontostathi, Athina-Vasiliki Karra, Theodoros Karampelas, Anastasia S. Politou, Savvas Christoforidis, Constantin Tamvakopoulos, and Vasiliki Sarli
ACS Pharmacology & Translational Science Article ASAP
DOI: 10.1021/acsptsci.

PLATINUM-BASED DRUGS

A similar, yet distinct direction of our research lies on optimization of classic chemotherapeutic approaches via the development of novel targeted platinum (Pt) based therapeutics, with a particular focus on breast cancer. Ongoing studies with proprietary Pt-based molecules demonstrate promising pharmacological activity of Pt in biotin receptor-positive cancer cells compared to already established anti-cancer Pt drugs (e.g. carboplatin), generating opportunities for improved therapies in different types of solid tumors. It should be noted that this work has been carried out by performance of in vitro high-throughput screening assays, combined with state-of-the-art LC-MS/MS and advanced Mass Cytometry techniques. Recently a patent application describing our work with collaborators from PhenoMatriX, MA, USA on "Biotin Receptor Binding Platinum Compounds" was submitted to the European Patent Office. 

THERAPEUTIC DRUG MONITORING

As our role is heavily aligned with translational research, and as we have an established a track record in mass spectrometry-based measurements, we have placed a great deal of emphasis on Therapeutic Drug Monitoring (TDM). TDM is defined as the measurement of drug levels in biological fluids. Cancer patients can benefit significantly from TDM as there are several anticancer agents that either have a narrow therapeutic index, which could lead to severe toxicities, or have significant pharmacokinetic variability potentially resulting in suboptimal systemic drug exposure and reduced therapeutic efficacy.

Precision medicine concept; A collaborative network between clinicians and analytical scientists that corresponds to the needs of each patient.

Our aim is to contribute to individualization of cancer therapy through TDM of immune checkpoint inhibitors (ICIs) or other monoclonal antibodies for targeted therapies, tyrosine kinase inhibitors (TKIs), and Pt-based drugs. To better serve this purpose, a state-of-the-art GLP certified mass spectrometry based bioanalytical laboratory is established in our division since June 2023. Such collaborative interdisciplinary studies are ongoing with clinical colleagues from Sotiria Clinics, Evgenidion and Onassis Cardiac Surgery Centers in programs that emphasize the use of oncology and cardiology therapeutics.

LC-MS/MS method development; Determination of monoclonal antibodies levels in clinical samples via the detection and quantification of antibody-unique peptides.