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Biological programs that suppress tumor formation, like apoptosis and senescence, are frequent mutational targets in human cancer implying their critical importance in limiting tumor development and suggesting a therapeutic potential for restoring these mechanisms. The exact nature of these lesions has a dramatic impact on the susceptibility to treatment and may contribute to the range of responses seen in the clinic. For example, inactivation of the tumor suppressors p53 or PTEN hampers responses to a wide variety of treatments both in cancer models and in the clinic, while loss of other tumor suppressor genes appears less critical to therapy. Conversely, strategies directly aimed at the central players of tumorigenesis may be highly effective against those tumors relying on the targeted gene or pathway, but less so against others. Cancer is a genetically heterogeneous disease and understanding the interaction of genetics and treatment will optimize existing therapies and lead to novel approaches.
Our work centers on cancer genetics. We model relevant genetic changes found in human cancer specimens in cell culture and in accurate mouse models. A particularly successful approach has been the technique of adoptive transfer of retrovirally transduced hematopoietic stem cells (HSCs) (Fig. 1) to generate hematological malignancies that harbor defined genetic changes in vivo. This approach is uniquely fast, versatile and can be adapted to both overexpression or knockdown experiments and also unbiased screens. Thus we can rapidly produce genetically heterogeneous diseases in a physiological setting and study the resultant phenotypes, the underlying mechanisms and therapeutic consequences.
Fig. 1 Modeling Tumor Genetics &Treatment Response
Specific aims of our work are:
(i) The Akt survival pathway in cancer
(ii) Targeted therapies and genetics
(iii) Modeling tumor suppression with RNAi
(i) The PI3K/Akt survival signal is frequently activated in human cancers of various origins. The pathway is engaged following loss of the PTEN tumor suppressor or activation of various oncogenic kinases. Consequently, reduction of the Akt signal corresponds to the ability of many targeted agents to inhibit an oncogene. Thus the Akt pathway is a rational target for cancer therapy. This survival pathway has myriad effects on cellular biology and we will analyze the contribution of different components of this pathway to tumorigenesis and treatment response. The goal is to define the critical processes and effectors of this pathway in cancer. Conceptually, disrupting these should enhance tumor selective therapy.
(ii) Targeted therapeutics, e.g. Imatinib or EGFR inhibitors, hold great promise in cancer therapy. Their antitumor effectiveness implies a continued dependence for tumor cell maintenance on the activities targeted by these compounds. The downstream mediators of this dependence are largely unknown. We are using genetic studies to pinpoint downstream effectors of targeted therapeutics, define their role in determining sensitivity to these agents and explore ways to enhance therapy.
(iii) RNAi technology provides a new means of modeling cancer genetics in vivo. We are using stable RNAi expression to knockdown tumor suppressor genes in a target tissues, this approach minimizes the potential for compensatory events and allows for a stepwise reduction in gene dosage thus increasing our ability to recreate in vivo the complexity of gene inactivation patterns in human cancer. Additionally, stable or conditional knockdown of gene expression can mimic the effects of a targeted therapeutic. The latter should inform the development of pharmacological inhibitors.