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Towards rational combination therapies in cancer: Understanding tumor evolution during therapy response and resistance


Organizer: IRB Barcelona

Date / Time: Friday, April 22, 2022 at 12:00pm  

Place: Auditorium

Speaker: Dr. Anna Obenauf - Group Leader at the Research Institute of Molecular Pathology (IMP) in Vienna.

Title: "Towards rational combination therapies in cancer: Understanding tumor evolution during therapy response and resistance"

Host: Dr. Cristina Mayor-Ruiz, Junior Group Leader - Targeted protein degradation and drug discovery Lab. - IRB Barcelona - Mechanisms of Disease Programme.



Targeted therapies and immunotherapies have transformed the clinical care of patients with metastatic cancer. By optimizing treatment with combinations of different therapies, a cure appears within reach for many cancers. However, achieving this goal will require more detailed knowledge of the mechanisms of therapy resistance and immune evasion and, importantly, of the impact of therapies on tumor evolution, which may promote or prevent subsequent therapy responses. The vision of my lab is to build and exploit this knowledge to identify rational combinations of existing and emerging therapies by understanding the complex and dynamic biology of cancer cells and the tumor microenvironment in all phases of therapy. 

Recent work includes the discovery that acquired resistance to targeted therapy leads to cross-resistance to immunotherapy, despite their entirely different mode of action (Haas et al., Nature Cancer, 2021), or that resistance to targeted therapy, including the resistance-conferring mutations and epi-genetic mutations are frequently acquired during therapy exposure (Umkehrer et al. 2020, Nature Biotechnology), and we have identified novel therapeutic approaches for rare cancers, such as Merkel cell carcinoma (Leiendecker et al., EMBO MM, 2020). In earlier work we identified the therapy-induced secretome as a novel driver of therapy resistance and tumor progression (Obenauf et al., 2015, Nature) and mediators of metastasis. To break new ground, a key effort in our lab is to develop and apply innovative technologies to gain insight into complex response and resistance mechanisms in vivo. We, for example, recently developed a functional lineage tracing approach termed CaTCH (CRISPRa tracing of clones in heterogeneous cell populations, Umkehrer et al. 2020, Nature Biotechnology), which allows to trace clones through evolutionary bottlenecks, but also allows to “go back in time” to retrospectively isolate founding clones from millions of cells prior to evolutionary selection. Thus, CaTCH has the potential to give unprecedented insights into tumor evolution and we are applying it to various biological problems.


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