Interfering with cancer cells' survival pathways

Research Interest

Several factors render tumors resistant to conventional treatment such as inoperable location or insensitivity to systemically administered drugs. Since oncolytic viruses naturally target and kill malignant cells and are non cytopathic towards healthy tissues, they harbor the potential to overcome these limitations for conventional cancer treatment and are therefore scrutinized for possible clinical applications.

Research Projects

Conventional cancer treatments based on toxicity towards dividing cells (eg. chemotherapy) or on the induction of death by soluble molecules (eg. TNFalpha or TRAIL) are often limited by the fact that tumor cells are naturally or quickly become resistant to the induction of death. Multiple signaling pathways that protect tumor cells against these apoptotic death stimuli have been identified. Molecules like Flip, Akt or Bcl2 interfere with the activation of caspases; inhibitor of apoptosis proteins (IAP) interact with activated caspases that they inactivate. A challenge in cancer research is to neutralize these survival pathways and/or to find alternative death pathways that can be specifically activated in tumor cells.
Understanding the induction of death by parvovirus infection has multiple interests in cancer therapy. Parvoviruses may be used to directly eliminate cancer cells resistant to conventional treatments by neutralizing survival pathways or activating alternative death pathways.

Aims

(1) to identify the genetic alterations necessary to sensitize normal cells to H-1PV cytotoxic effect.

(2) to characterize the death signaling pathways activated by H-1PV infection in human cancer models (SCC, gliomas).
(3) to analyze the interference of H-1PV with integrin signaling, in particular in relation with tumor cell survival and invasiveness

Study Models

Gliomas and Astrocytomas isolated by surgery of cancer patients (Collaboration with the neurosurgery department of the University of Heidelberg)

Primary keratinocytes and Ras transformed derivatives, as well as cells isolated from non melanoma skin cancer (Squamous Cell Carcinoma).

Collaborations

Karsten Geletneky and Neurosurgery Department (University Heidelberg): Gliomas cells from patients, mouse model
Neurosurgery Department and Children Hospital (University Heidelberg): Cases studies
Dirk Breitkreuz (DKFZ): SCC cells and mouse models

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