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Targeted Anti-Cancer Therapies

Periodic Reporting for period 2 - TACT (Targeted Anti-Cancer Therapies)

Berichtszeitraum: 2022-04-01 bis 2024-03-31

Around 10 million people died from cancer in the year 2022, according to a recent estimate by the International Agency for Research on Cancer (IARC). Despite marked improvements in therapy, approximately 1 in 5 men or women will develop cancer in a lifetime, whereas around 1 in 9 men and 1 in 12 women die from it, making cancer one of the leading causes of death worldwide. For the past decades, chemotherapy has been the preferred therapeutic option against several cancers, but at the expense of enduring and trying side effects. Antibody-Drug Conjugates (ADC) is a fast growing class of oncology therapeutics. They consist in a highly potent toxic drug connected to an antibody that is selectively targeting certain tumor cells. By combining the cytotoxicity of the drug and the targeting properties of the antibody, ADC kill cancer cells selectively, representing thus a marked improvement compared to conventional chemotherapies. After more than 50 years of research, the marketing of a dozens of ADC has now provided clinicians with innovative therapeutics to fight breast cancer, lymphomas, as well as a variety of leukemia. However, ADC are still riddled with limitations: they can only be used in a limited number of cancers, they are expensive, and still lead to profound side effects.
Targeted Anti-Cancer Therapies (TACT) was an international, multidisciplinary training and research programme aiming to train 11 Early-Stage Researchers (ESR) on the development of state-of-the-art targeted anti-cancer therapeutics and equip them with transferable, future career-enhancing skills to create the next generation of experts in Europe. More specifically, this programme was focused on key interconnected priority themes for the conception of more effective generations of Protein-Drug Conjugates (PDC): site-selective bioconjugation methods; novel and safer payloads; environment-specific cleavable linkers; more efficient protein-based targeting systems; new analytical tools for acute characterization. To do so, TACT relied on a European network composed of nine research groups and companies located in five countries with expertise covering all research fields dealing with PDC. Finally, this training programme also intended to raise awareness of groundbreaking progress in the field of anti-cancer therapy among the non-scientific audience through original communication approaches.
After four years, the TACT programme has fulfilled its ambitions and managed to develop innovative treatment options and form experts in the field – all ESR who finished their thesis are now pursuing a scientific career either in academia or in pharmaceutical companies. Through the production of 3 animated movies and a graphic novel, TACT also kept its promise of developing original communication content aimed at the general public.
The good progress of the project was first impeded by the sanitary situation in Europe but could finally proceed as originally planned 2 years after its start. All management structures were set up at the beginning of the project, quickly agreed on the Consortium agreement and finalized all recruitments. The recruitment procedure completely decentralized to match the travel restrictions imposed by the pandemic, with each beneficiary conducting the interviews separately before validating the eligibility of the successful candidate with the coordinator. Having to suffer from two resignations midway through the project – the PM and 1 ESR –, the same procedure was applied to ensure a rapid recruitment procedure and minimize detrimental effects.
Most of the 11 ESR started their positions in month 7, with two starting month 8 and the last one in month 10 due to visa issues or sanitary checks. At the present, 5 ESR have had their viva and are pursuing their careers in the field of PDC, whether in academia or in pharmaceutical companies (Lonza, ADC Therapeutics). The rest of the ESR are now finishing their theses and most of them should have their viva by the end of the year. This follows key findings made by the ESR during their main project or through their secondments at participating institutions. Ilias Koutsopetras (UNISTRA) developed a site-selective variation of the Ugi reaction for the conjugation of proteins; Lorenzo Turelli (UNISTRA) worked on the successful development of a new family of cytotoxic antibody conjugates; Rania Benazza (CNRS) developed several mass spectrometry techniques for the characterization of either intact or denatured proteins; Irene Shajan (WUR) managed to develop a chemoenzymatic site-selective conjugation of antibodies, used for the production of potent bispecific antibodies; Bianka Jackowska (QUB) produced new nanoparticles decorated with antibodies and loaded with cytotoxic drugs for the treatment of pancreatic cancer; Ana Carvalho (QUB) developed another family of nanoparticles, loaded with 2 drugs with complementary modes of action against leukemia; both Carmen Longo and Yagmur Ersoy (TUM) participated in the production of new formats of targeting proteins – i.e. anticalins – directed against several surface antigens; Thomas Favraud (AD) exploited the principle of Protein Trans Splicing to generate a series of bispecifics and their corresponding ADC; Léa Rochet (UCL) used a dibromo-pyridazinedione platform to produce novel formats of targeting agents, such as dual-binder antibody-nanoparticle conjugates; Alessandra Totti (HDPR) produced detoxifiable analogues of the highly cytotoxic drug α-amanitin, in order to minimize the side-effects of ADC; Loïc Herter (SPC) developed drugs bearing bioisostere motifs and successfully incorporated them in selective and potent ADC. This research activity led so far to 18 peer-reviewed publications and 2 pre-prints, 1 patent, and more than 20 participations to international scientific conferences from the ESR.
Besides this research training, ESR also benefited from network-wide meetings, during which they were trained on numerous topics, from drug development to patient and public involvement, and had the opportunity to network with several actors (European institutions, start-ups, academics, pharmaceutical companies).
Finally, TACT also led to the development of original communication activities, with 3 animated movies entitled ‘History of the fight against cancer’ (https://www.youtube.com/watch?v=pjqVawLBiBI) and a 32-page long graphic novel describing the therapeutic journey of a cancer patient, as well as the 11 research projects of the ESR.
This project led to the development of dozens of new formats of targeted therapies, most of which having shown promising results in vitro, up to in vivo for three of the more advanced compounds. This programme also opened new avenues in the field of targeted therapies: detoxifiable ADC, bioisostere-containing drugs, dual-drug conjugates. With already one patent filed, TACT research is still being pursued, with the aim of creating a start-up company in the next years. The ESR that benefited from this unparalleled training and who already graduated are continuing their careers in this field Europe. Finally, by creating a graphic novel and 3 movies dedicated to the popularization of cancer and its treatment, TACT filled an existing gap in this domain, for which very few works are currently available to the general public. This has been noted during our interactions with media and at our exhibition that gathered 60 participants.
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