TACTIC - Disrupting Cancer's Transcriptional Addiction

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Cancer is in many respects a disease in which cellular transcription is deregulated. Transcription factors are therefore often potent oncogenes that strongly promote the growth of cancer cells. Our strategy is therefore to correct these altered transcription patterns with the help of small molecules. Many transcription factors cannot be attacked directly by small molecules. However, their activity can be indirectly modulated by targeted interventions in their regulation or the underlying transcription machinery. As part of our consortium, we deliberately cover projects at different stages of drug development, utilizing the complementary expertise and technologies at the various sites integrated into TACTIC. Our extensive target protein portfolio includes target structures such as kinases that are well established as drug targets, but also small molecule addressable transcription factors that have ligand-binding structured domains as well as highly innovative target structures such as regulators of chromatin structure and mRNA splicing.&nbsp;Conventional small molecules as well as new modalities such as bifunctional molecules like PROTACs (PROteolysis Targeting Chimeras), which specifically degrade the target structure, are used. In order to develop PROTACs efficiently, a click chemistry-based high-throughput PROTAC screening platform is currently being established, which will enable many of these molecules to be synthesized in parallel on a very small scale and tested directly in cellular systems. Synergistically, we are expanding our patient-based cell banks, which cover diverse tumor types, and developing disease-relevant in vivo models for systematic drug screening and mechanistic studies.

TACTIC (Targeting transcriptional AddiCTion In Cancer) is a national network funded by the German Cancer Aid (<a target="_blank" rel="noopener noreferrer nofollow" href="https://www.krebshilfe.de/">Krebshilfe</a>) and coordinated by the Goethe-University Frankfurt. The goal of the network is to bring together all the necessary technologies and expertise for preclinical small molecule development. The technologies developed within the TACTIC consortium are available to academic collaborators to promote small-molecule-based translational studies within the academic community. (<a target="" rel="noopener noreferrer nofollow" href="/call-for-collabration#article-1">Call for Collaboration</a>).Cell-based and protein-based therapeutic approaches are also developed as part of the overall preCDD consortium (<a target="_blank" rel="noopener noreferrer nofollow" href="https://www.precdd.de/">PreCDD)</a>.

Institute for Pharmaceutical Chemistry, Goethe University, Frankfurt

Prof. Dr. Stefan Knapp

Speaker for TACTIC

Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-University, Tübingen

Prof. Dr. Stefan Laufer

Fakultät für Chemie und Chemische Biologie, Technical University, Dortmund

Prof. Dr. Daniel Rauh

Department of Hematology and Stem Cell Transplantation, University Hospital, Essen

Prof. Dr. Christian Reinhardt

Unit for Tumor Biochemistry,  Christian-Albrechts-Universität zu Kiel

Prof. Dr. Elmar Wolf

Institut für Tumorbiologie und experimentelle Therapie, Georg-Speyer-Haus, FFM

Dr. Florian Greten

Institute for Tumor Biology and experimental Therapy, Georg-Speyer-Haus, FFM

Prof. Dr. Henner Farin

Max-Planck-Institute for&nbsp;molecular Physiology, COMAS, Dortmund

Dr. Sonja Sievers

Universitäres Centrum für Tumorerkrankungen, Frankfurt

Prof. Dr. Christian Brandts

Medizinische Klinik 2, University Medical Center, Frankfurt

 Prof. Dr. Hubert Serve

Klinik für Kinder- und Jugendmedizin, University Medical Center, Frankfurt

Prof. Dr. Jan-Henning Klusmann

Prof. Dr. Thomas Oellerich

Lehrstuhl für Biochemie und Molekularbiologie Biozentrum, University Würzburg

Prof. Dr. Martin Eilers

IfADo Leibniz-Institut, Toxicology Department, Technical University, Dortmund

Prof. Dr. Jan Hengstler

Klinik für Medizinische Onkologie &amp; Pneumologie, University Medical Center, Tübingen

Prof. Dr. Lars Zender

Medizinische Klinik Innere Medizin VIII, University Medical Center, Tübingen

Dr. rer. nat. Daniel Dauch 

Pharmaceutical and Medicinal Chemistry, Eberhard Karls University, Tübingen

Prof. Dr. Matthias Gehringer

SGC Frankfurt, Goethe University,Frankfurt

Dr. Susanne Müller-Knapp

Prof. Dr. Eugen Proschak

Institut für Pharmakologie und Klinische Pharmazie, Goethe University, Frankfurt

Prof. Dr. Sina Oppermann

p53 Drug Discovery and Transcriptional Regulation, Goethe University, Frankfurt

Dr. Andreas C. Joerger

Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University, Munich

Prof. Dr. Bernhard Küster

TUM School of Life Sciences, Technical University, Munich

Dr. Stephanie Wilhelm

Westdeutsches Tumorzentrum, DKFZ, University Medical Center, Essen

Prof. Dr. Jens Siveke

Department of Translational Genomics, University of Cologne

Prof. Dr. Roman Thomas

Team

Disrupting cancer’s transcriptional dependencies. TACTIC unites leading labs across Germany to unlock therapies targeting the ‘undruggable’ — from RNA splicing kinases to chromatin remodelers and protein-interaction domains.We build new modalities, share cutting-edge tools, and empower translational discovery across academia and industry.&nbsp;

TACTIC – Targeting Transcriptional Addiction in Cancer

Institutions

TACTIC aims to make the technologies developed by the consortium accessible to the cancer research community. We are also happy to advise members of the academic cancer drug development community in our technology areas. Our areas of coverage include all aspects of preclinical research, from screening and hit identification to hit validation, protein biochemistry, medicinal chemistry, and toxicity studies, as well as pre-clinical cancer models in 3D cell culture as well as in vivo. <a target="" rel="noopener noreferrer nofollow" href="/contact-us#contact-1">Contact</a>

Call for Collaboration

Publications

The&nbsp;German Cancer Aid is now supporting two cancer research projects with around €16 million, in which promising drug candidates undergo preclinical testing to prepare for clinical approval studies. The University Hospitals of Frankfurt and Würzburg are leading the “CAR Factory” project, which focuses on using genetically engineered immune cells to fight tumors. In the TACTIC project, coordinated by Goethe University, small molecules are being developed to help reset disrupted genetic switches in cancer cells.

pharmaceuticals in packages of different colors, antibiotics medicine tablets, colorful antibacterial tablets lie, fighting the virus.

Drug Development: German Cancer Aid Funds Two Projects at Goethe

With €11.8 million in funding until 2028, the German Cancer Aid (DKH) is supporting a promising joint project in which researchers from the Faculty of Medicine at the University of Duisburg-Essen (UDE) play a key role.TACTIC aims to more precisely target the genetic causes of cancer with innovative drugs.Led by Prof. Dr. Christian Reinhardt (UDE), Prof. Dr. Stefan Knapp (Goethe University Frankfurt), and Prof. Dr. Daniel Rauh (TU Dortmund), the project brings together experts in chemical biology, drug discovery, and oncology. A national oncology drug research center is being established to support the project’s goals

Cancer Research with TACTIC: Searching for the Right Switches

Frankfurt am Main – Our genes serve as blueprints for proteins, each performing specific functions in our cells. These processes are controlled by transcription factors. In cancer cells, this regulation is often disrupted. Many transcription factors have now been linked to cancer development.Through its new funding program for “Preclinical Drug Development”, the German Cancer Aid is supporting the large-scale TACTIC project.This nationwide research network is developing drugs that interact directly with dysregulated transcription factors in tumors, aiming to restore cancer cells to their normal state.

“TACTIC”: Developing Cancer Drugs at Universities

The German Cancer Aid is funding the TACTIC research network for five years with a total of €11.8 million.The goal: discovery and advancement of novel therapeutic compounds up to preclinical trials. Research institutions such as IfADo are also part of this nationwide effort.

Flu Hemagglutinin 3D print of hemagglutinin (HA), one of the proteins found on the surface of influenza virus that enables the virus to infect human cells. In this model, blue and purple denote areas where mutations can change the ability of the virus to attach to host cells and cause infection. For more information, visit the NIH 3D Print Exchange at 3dprint.nih.gov. Credit: NIH https://www.flickr.com/photos/niaid/14547505471/

TACTIC Against Cancer – German Cancer Aid Supports Research Netw

From the lab to the patient’s bedside – before a new cancer drug can be used in treatment, it must undergo a series of preclinical tests to ensure safety and effectiveness.Because these studies are time- and cost-intensive, research into drugs for rare or hard-to-treat cancers is often not commercially attractive for pharmaceutical companies. The German Cancer Aid aims to close this gap. At the 36th German Cancer Congress 2024, it is presenting its new focus program “Preclinical Drug Development”, through which three major projects – including TACTIC – will receive a total of €20 million over five years.

A Caucasian male technician preparing tissue to be stained and studied histologically in a laboratory. 1950

€20 Million for the Development of New Cancer Therapies

Cancer arises from&nbsp;genetic and epigenetic changes, which lead to dysregulated transcription programs. Key elements include gene expression control mechanisms, the basic transcription machinery, and mRNA processing – all offering a range of therapeutic targets. Another promising avenue: targeting tumor-specific transcription mechanisms.&nbsp; However, most oncogenic transcription factors are difficult to inhibit directly with small molecules. TACTIC aims to change that through innovative, tailored drug development strategies.

TACTIC – Oncogenic Transcription as a Target for New Cancer Ther

TACTIC Press and Publications

PROTACs are an emerging new pharmacological modality and versatile tools for target validation.&nbsp; However, developing PROTACs requires significant synthetic efforts and screening technology. To enable the rapid development of PROTACs, we developed a modular synthetic strategy based on a 384-well plate and an efficient copper-catalyzed "click chemistry" cycloaddition reaction. We optimized the reaction conditions to achieve nearly complete conversion and adapted them to low volumes (5 µL) to enable rapid "direct-to-biology" (<a target="_blank" rel="noopener noreferrer nofollow" href="https://pubmed.ncbi.nlm.nih.gov/41575171/">evaluation</a><a target="_blank" rel="noopener noreferrer nofollow" class="msocomanchor" href="#_msocom_1">)</a>&nbsp;. This platform enables the synthesis and evaluation of hundreds of PROTACs within a few days. It facilitates a comprehensive assessment of target degradability, rapid hit identification, and the selection of the most suitable E3 ligase for degrader development. TACTIC welcomes collaboration proposals using this library for drug discovery and target validation projects, contributing to the academic translational oncology community.

Rapid Development of PROTACs

<h4>The TACTIC Consortium</h4>&nbsp;Tumor cells are heavily reliant on abnormal transcriptional programs (transcriptional addiction) to sustain their growth and proliferation, making the underlying cellular machinery a prime target for cancer therapy. However, most oncogenic transcription factors cannot be directly targeted by small molecules, and the transcription machinery has been poorly explored by conventional drug discovery efforts.To address this challenge, we established a network of state-of-the-art cancer and drug development laboratories, creating a national oncology drug discovery hub for Targeting transcriptional AddiCTion In Cancer, TACTIC. This combined expertise covers all aspects of drug discovery and generates a unique, fully functional experimental drug discovery value chain.We are particularly interested in targets or targeting strategies that have not been the primary focus of industrial drug development programs, including kinases involved in RNA splicing, chromatin-modifying enzymes and more challenging targets such as protein-interaction domains. In addition to conventional small-molecule inhibitors, we are also developing new pharmaceutical modalities such as selective protein degraders.Our vision is to set up a sustainable research infrastructure and to initiate collaborative networks by providing reagents, establishing comprehensive patient-derived cell banks, and developing key technology platforms that will be available to the wider cancer research community, facilitating future drug development initiatives in both academia and industry.