Walczak, Henning - A 07

Resistance to apoptosis remains a major barrier in the effective treatment of many cancers, including haematological malignancies. Additionally, haematological malignancies often develop resistance to standard-of-care therapies, underscoring the urgent need for novel, effective treatments. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown promise as a cancer-selective therapeutic, but clinical efficacy has been limited by widespread TRAIL resistance in primary tumours. We previously found that CDK9 inhibition (CDK9i) can selectively sensitise TRAIL-resistant cancer cells to TRAIL-mediated apoptosis by concomitantly downregulating the anti-apoptotic proteins Mcl-1 and cFLIP. Importantly, we recently found that the combination of TRAIL with CDK9i (TRAIL–CDK9i) was also highly effective at overcoming cancer cell resistance to both, standard-of-care chemotherapy and various targeted therapeutic approaches. Intriguingly, therapeutic efficacy of allogeneic haematopoietic cell transplantation (allo-HCT) afforded by MDM2 inhibition (MDM2i) requires TRAIL-R expression on leukaemia cells. This project aims to identify novel, highly effective anti-cancer therapies that build upon our knowledge of sensitization to TRAIL induced cell death and could rapidly translate into the cancer clinic, offering new hope for patients with relapsed or refractory lymphomas or leukaemias, thereby potentially transforming the therapeutic landscape for these cancers.

This study addresses a critical unmet need in cancer therapies: overcoming cell death resistance in haematological malignancies. By integrating agents that modulate transcription elongation, restore tumour suppressor function, and directly trigger extrinsic apoptosis, this strategy targets multiple vulnerabilities in haematological malignancies. Furthermore, biomarker discovery could enable patient stratification, maximising therapeutic benefit while minimizing toxicity.

To find novel pro-apoptotic combination therapies for therapy resistant haematological malignancies we will:

1. Systematically evaluate the efficacy and mechanism of TRAIL–CDK9i therapies in haematological malignancies and determine the combinatorial impact of adding MDM2i.
2. Assess the effectiveness of such TRAIL-comprising therapies across drug-resistant variants of haematological cancers and elucidate its underlying molecular mechanisms
3. Evaluate the therapeutic efficacy and safety of the most effective of these novel anti-cancer-therapies build upon our knowledge of sensitization to TRAIL-induced cell death in different mouse models of haematological malignancies

For more information, please check Professor Walczak´s research website. 

• Center for Molecular Medicine Cologne (CMMC)
• Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931, Cologne, Germany
• Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK
• CECAD Cluster of Excellence, University of Cologne, 50931 Cologne, Germany