Targeting CDK7-dependent transcription in cancer-associated fibroblasts to overcome therapeutic resistance in peripheral T cell lymphoma (PTCL)

• Applicant: Dr. Khouloud Kouidri
• Subject Area: Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 544872758

Despite revolutionary advances in the treatment of human lymphomas such as the development of targeted therapies, immunotherapies and novel cell therapies, the outcome for most peripheral T cell lymphoma (PTCL) patients remain poor. There is an unmet clinical need of effective treatment options, particularly in relapsed disease. Recognizing the emerging significance of the lymphoma microenvironment (LME) in sustaining tumor growth and treatment response, our objective is to understand the bi-directional communication of the most demonstrably relevant stromal cell type, cancer associated fibroblasts (CAFs), with lymphoma cells in PTLC. CAFs are known for producing the extracellular matrix (ECM) that is responsible for the microarchitecture, biomechanical properties and biochemical composition of the LME. Conversely, lymphoma cells, along with LME cells, continually adapt to these conditions to sustain proliferation while evading immune responses. Preliminary findings from the Cerchietti research group indicate that CDK7-dependent transcriptional programs play a pivotal role in driving the pro-lymphogenic phenotype of CAFs and conversely, that treatment with novel specific CDK7-inhibitors reprograms the CAF phenotype to a non-tumor-permissive state in PTCL. Our goal is to further elucidate the role of CDK7 in establishing pro-tumor phenotypes in CAFs. We will develop CDK7 based therapeutic strategies for PTCL by using novel combinatorial approaches. We will take advantage of patient-derived-tumor-xenografts (PDTXs), developed in the Cerchietti laboratory as well as lymphoma organoids. This will allow us to mechanistically and therapeutically define and target stromal-tumor cell interactions contributing to lymphoma growth and survival. Furthermore, these unique in vivo models will offer relevant predictive insights into clinical outcomes when evaluating the efficacy of the proposed anti-PTCL therapies.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Leandro Cerchietti