Abstract IA002: Targeting senescence heterogeneity against cancer therapy-resistance and metastases
Authors: Putavet Diana A. , Lehmann Johannes , Subtil Beatriz , Hofman Damon , Baar Marjolein P. , de Keizer Peter L.J. 
Published: March 2021

Therapy resistance of metastatic tumor cells poses a major limitation to the cure of cancer. Aside from cell-intrinsic processes, the tumor microenvironment is a contributor to this problem. Senescent cells can originate from healthy cells that accumulate irreparable damage. Senescent cells cease to divide, but chronically secrete a wide range of factors that permanently alter their environment. As such, they are thought to impair tissue function and, when part of a tumor microenvironment, they are thought to accelerate tumor progression, metastazation and therapy resistance. Today, I will discuss how we identified that therapy-surviving cancer cells can develop a stem-like state, which is, at least partially, driven by exogenous signals from senescent cells. In addition, I will show how therapy-surviving cancer cells can develop a senescence-like state of their own, including an associated pro-inflammatory secretory phenotype. Given the importance of cancer stemness in therapy resistance, both senescent stromal cells and senescence-like cancer cells pose exciting candidates for therapeutic removal. When designing therapies for elimination of, we ran into a problem, which is that there is no such thing as (just) senescence. Instead, there are distinct subtypes, which are not merely caused by noise. I will show how we investigate these subtypes of senescence and how this is important for their targeted elimination. More specifically, I will highlight interaction between the damage-associated proteins FOXO4 and p53 as a pivot in the viability of a damaged type of senescence, which we call now call “scarred” senescence. We had already shown in the past (Baar .. de Keizer, Cell, 2017) that inhibition of FOXO4, or interference with its interaction with p53 using cell penetrating peptides could selectively eliminate senescent cells and target signs of aging in vivo. Today, I will show how we can use FOXO4-TP53 inhibitors against at least some therapy-surviving cancer cells. Last, I will show how we invested in optimization of these compounds to develop them towards clinical translation and how we can now very effectively eliminate certain types of therapy-surviving cancer cells. Altogether, this adds to a model where a senescent TME, as well as senescence-like cancer cells, can also promote cancer progression, migration, and therapy resistance by locally enforcing a state we called (cancer) “stem-lock”. And specific TP53-FOXO4 inhibitors may overcome this problem, thereby adding to a yin-yang treatment of damaging chemo-radiotherapy, followed by FOXO4-TP53-based anti-senescence treatment.

Citation Format: Diana A. Putavet, Johannes Lehmann, Beatriz Subtil, Damon Hofman, Marjolein P. Baar, Peter L.J. de Keizer. Targeting senescence heterogeneity against cancer therapy-resistance and metastases [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA002.