Phenotypic Therapy and Immune Escape in Cancer
Project 5Impact of the PI3K/AKT signaling pathway on epigenetic circuitry to generate immune and targeted therapy resistant melanoma phenotypes
Despite the encouraging therapeutic progress recently made for advanced melanoma, primary or acquired resistance is still a problem. Resistance to targeted and immune therapies may be both driven by genetic evolution and/or by adaptive plasticity. For example, deregulation of the PI3K/AKT signaling pathway can be caused by oncogenic activating and inactivating mutations as well as epigenetic mechanisms. Moreover, for uveal melanoma there was very limited therapeutic improvement, which is in part due to limited preclinical models for this tumor, but may also be caused by the notoriously constitutive activation of the PI3K/AKT pathway. While the critical relevance of PI3K/AKT pathway activation for the carcinogenesis of the majority of cancers is undoubted, the exact contribution of the mode of action of its activation (e.g. by PTEN loss, PI3K/AKT hot spot mutations or overexpression) is not yet completely understood. Based on our preliminary work, our overall hypothesis is that PI3K/AKT pathway activation by PTEN loss plays a key role in resistance to immunotherapy of melanoma; notably, however, the modus operandi is likely to go beyond canonical PI3K/AKT activation as it also involves both direct epigenetic changes in the tumor cell as well as indirect effects caused by immune selection. In previous work, we have established the relevant in vitro and in vivo models. For example, we have generated a spontaneous murine model resembling uveal melanoma to study the effects of PI3K/AKT pathway activation on the immunogenicity of melanoma cells including the possibility to include (i.e., PTEN k.o. in vivo before the development of visible tumors) or exclude (i.e. PTEN k.o. in vitro or in vivo after visible tumors have developed) previously unaddressed indirect effects caused by immune selection. The particular setting of collaborations and research goals proposed in the Clinical Research Unit PhenoTImE would serve as an ideal platform to scrutinize the effects of PI3K/AKT activation by PTEN loss on the carcinogenesis and immunogenicity not only of melanoma but also on other cancer entities. The detailed and mechanistic analysis of this cellular escape strategy allows us to conceptualize future concepts to target therapy and immune (cross-)resistance also in the clinical context. For this purpose, profound understanding of transcriptional, epigenetic, phenotypic, and metabolic alterations is necessary; a task, which can only be mastered in a consortium like PhenoTImE bringing together different areas of expertise. The close cooperation of basic, translational, and clinical researchers will allow us to rapidly confirm the preclinical findings in patients and to translate these into innovative therapeutic approaches.
Prof. Dr. med. Jürgen Becker
Department Translational Skin Cancer Research (TSCR)
German Cancer Consortium (DKTK)
University Hospital Essen