Towards Rational Combination Therapies: Understanding tumor evolution during therapy response and resistance

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• Anna Obenauf, IMP Vienna
• Thursday 18 April 2024, 13:00-14:00
• CRUK CI Lecture Theatre.

If you have a question about this talk, please contact Kate Davenport.

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 crossresistance to immunotherapy, despite their entirely different mode of action (Haas et al., 2021, Nature Cancer), or that resistance to targeted therapy, including the resistance-conferring mutations and epigenetic mutations are frequently acquired during therapy exposure (Umkehrer et al. 2020, Nature Biotechnology). Moreover, we have identified novel therapeutic approaches for rare cancers, such as Merkel cell carcinoma (Leiendecker et al., 2020, EMBO MM ) and a new oncogenic virus as the cause of a human skin cancer (Leiendecker et al. 2022, Cancer Discovery). 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 decipher mechanisms underlying therapy resistance, metastasis and immune evasion. In my talk I will focus on our newest discoveries providing a mechanistic understanding of how cancer cells orchestrate an immune-evasive TME and discussrational combination therapies that could extend the benefit of immunotherapy to a larger number of patients

This talk is part of the Cancer Research UK Cambridge Institute (CRUK CI) Seminars in Cancer series.

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