Dr. Ali Nowrouzi

Clonal Tumor Evolution and Functional Genomics

During the development of cancer the accumulation of mutational events lead to tumors which are composed of genetic and phenotypic heterogeneous cell populations. Most cancer entities may share mutations in so called “driver” genes however the majority of mutations identified in individual tumors are personalized and unique between patients. The molecular function of such mutations and their response towards radiotherapy and particle therapy are not fully understood to the present. Therefore, experimental platforms predicting the response of cancer specific mutations to radiotherapy and multimodal therapies consisting of radio-(chemo)-therapy are urgently needed.

The “Clonal Tumor Evolution and Functional Genomics” group is seeking to functionally annotate the response of cancer specific mutations to multimodal therapies consisting of radio-(chemo)-therapy and targeted agents with the goal of developing prognostic biomarkers and identifying synthetic lethal interactions in radiotherapy and particle therapy. Further we want to understand the dynamics of tumor evolution on the clonal level during the initiation of local recurrences and the development of metastasis post RT in xenogeneic and syngeneic mouse models. Therefore we are using diverse molecular and cell biological tools such as CRISPR/Cas9 functional screens, clonal barcoding/tracing technologies, longitudinal tracing of DNA double strand signatures and single cell OMICS in combination with preclinical in-vitro/in-vivo models.

Our current research activities are focused on the following objectives:

  • Identification of synthetic lethal and resistance promoting genetic interactions in radiotherapy of HNSCC.
  • Understanding molecular processes and biological mechanisms leading to the development of local recurrences and metastasis post-surgery or RT.
  • Deciphering the clonal dynamics of tumor evolution and consequences of functional intratumoral heterogeneity and RT- induced cellular plasticity.
  • Genomic mapping and longitudinal clonal tracing of radiation induced DNA double strand breaks in single nucleotide resolution.

Our long term goal is that our activities pave way towards the identification of novel molecular biomarkers and candidate therapeutic targets for personalized radiation oncology. Since 2016, this group has joined the tight collaboration between the German Cancer Research Center, the University of Heidelberg Medical School and the Merck-DNA-repair cluster analysing the efficacy of newly developed DNA repair inhibitors. Our particular focus in this joint venture is provided by our established platforms and infrastructure for performing functional genomic screens in preclinical cancer models of radiotherapy. We are identifying synthetic lethal genetic interactions with DNA repair inhibitors and radiotherapy. Further, we are deciphering resistance mechanisms to combined radiotherapy with DNA repair inhibitors.

Team Members:
Mahdi Akbarpour, DVM,  PhD candidate
Anne Wursthorn, PhD candidate
Fatma Pinar, MsC student

 

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