Perspectives of Targeted Radionuclide Imaging and Therapy of Fibroblast Activation Protein (FAP) in Cancer
Group Gourni Tumors develop within a complex microenvironment consisted of diverse cell types surrounded by a matrix rich of proteins, termed tumor stroma. Stroma includes immune cells, fibroblasts and vascular enothelial cells. Cancer cells rely on extensive support from the stroma to survive, proliferate and invade, thus making stroma an important potential target for anti-cancer therapy. Targeting elements of stroma, may be a useful therapeutic strategy to prevent tumor growth and progression. One of those elements is the fibroblast activation protein (FAP) which is overexpressed on activated fibroblasts on several tumors types.
The current project aims at designing and evaluating novel FAP-specific inhibitors for the generation of radiotracers with the potential to be used for the diagnosis and treatment of FAP-positive tumors. The novel radiotracers are thoroughly investigated in vitro and in vivo using cell lines and xenografted tumor models to understand their binding properties and their in vivo performance.
Design, synthesis, analysis, and optimization of novel small molecule inhibitors against prostate cancer
Group Pandey Androgens are linked to pathology of prostate cancer. Cytochrome P450 CYP17A1 and Aldo-keto reductase AKR1C3 involved in steroid metabolism are drug targets. The current anti-prostate cancer drug, abiraterone, targeting CYP17A1, is not very effective, and has side effects. We found that Abiraterone inhibits CYP21A2 and cortisol production; and a metabolite of abiraterone is a potent androgen, which ultimately defeats the treatment. With computational and medicinal chemistry groups from Denmark, Poland, Italy and Spain, we produce novel inhibitors of CYP17A1 and AKR1C3. We design and improve the compounds and test them in the laboratory. After the virtual screening, we apply machine learning and automated workflows to identify pharmacophores for structural modifications and synthesis of novel chemicals. Nanoparticle based delivery is used to enhance the efficacy. Using several cell and recombinant protein models novel inhibitors are being tested which are now working at nano molar levels.
Towards understanding the role of the minor spliceosome in cancer
Group Rubin Genes are composed of coding units (exons), interspersed with non-coding regions called introns. The process of protein production involves splicing together exons while removing introns from the mRNA molecule. Evolution has given rise to a cellular apparatus called the spliceosome, responsible for carrying out this splicing process. Alternative splicing enables the generation of diverse protein isoforms from a single gene. Splicing is tightly regulated under normal physiological conditions. Our recent findings indicate that cancer cells use a specialized spliceosome, the so-called minor spliceosome, to increase cancer relevant mRNAs. As such cancer hijacks the minor intron-splicing machinery to enhance the expression of transcripts containing minor introns. Proteins encoded by those genes have been shown to activate critical cell survival pathways such as cell cycle regulation and DNA repair. Exploiting the reliance of cancer cells on minor intron-containing genes presents a novel therapeutic opportunity for targeting cancer. By inhibiting the minor spliceosome, we can selectively induce cell death in cancer cells while sparing healthy neighboring cells.