Novel senolytic drugs as anticancer therapies

Lead Research Organisation: Imperial College London
Department Name: Dept of Chemistry

Abstract

Senescence is a stable growth arrest that impairs the replication of damaged, old or
preneoplastic cells. In addition to becoming cell cycle arrested, senescent cells undergo a
number of changes, the most notorious being the secretion of a complex mixture of mostly
pro-inflammatory factors collectively referred as the senescence-associated secretory
phenotype (SASP) [1].
Evolutionarily speaking, senescence is a beneficial response: it protects against cancer,
facilitates tissue homeostasis and limits fibrosis. However, the chronic accumulation of
senescent cells contributes to aging, disease and, paradoxically, cancer [2]. Interestingly,
eliminating senescent cells (using so called, 'senolytic' drugs) increases healthspan and
lifespan, and mitigates pathologies as diverse as atherosclerosis, osteoarthritis or
neurodegenerative diseases [3].
While initial interest has been centred on the use of senolytic against age-related diseases,
targeting senescent cells is rapidly gaining traction as an anticancer therapy [4]. Existing
cancer treatments (including chemo-, radio- and targeted therapies) are known to induce
senescence of cancer cells. Sequential treatment with senolytics (so-called "one-two punch"
approaches) have been suggested as anti-cancer therapies. Proof of concept for this
approach has been provided by us [5] and others [6]. As a result, key funders including the
US National Cancer Institute have started to explore the use of senolytics as anticancer
therapies by promoting workshops [7] In addition, both NCI and CRUK are expected to
announce shortly a 'Cancer Grand Challenge' on senescence and cancer.
3
Here we propose to take a convergent multidisciplinary approach, applying chemistry
technologies developed in the Tate lab to the novel cancer senescence models and screens
of the Gil lab to validate novel anti-senescence targets and pathways in cancer, and drive
the potential of anti-senescence therapy towards preclinical development. This will build up
in a successful collaboration on the potential of NMTi as senolytic already in placebetween
the Gil lab, the Tate group and CRUK & Imperial oncology spinout Myricx Pharma.
1. Herranz, N. and J. Gil, Mechanisms and functions of cellular senescence. J Clin Invest,
2018. 128(4): p. 1238-1246.
2. Munoz-Espin, D. and M. Serrano, Cellular senescence: from physiology to pathology.
Nat Rev Mol Cell Biol, 2014. 15(7): p. 482-96.
3. Ovadya, Y. and V. Krizhanovsky, Strategies targeting cellular senescence. J Clin
Invest, 2018. 128(4): p. 1247-1254.
4. Sieben, C.J., et al., Two-Step Senescence-Focused Cancer Therapies. Trends Cell
Biol, 2018. 28(9): p. 723-737.
5. Guerrero, A., et al., Cardiac glycosides are broad-spectrum senolytics. Nat Metab,
2019. 1(11): p. 1074-1088.
6. Wang, C., et al., Inducing and exploiting vulnerabilities for the treatment of liver cancer.
Nature, 2019. 574(7777): p. 268-272.
7. https://ncifrederick.cancer.gov/events/conferences/radiation-senescence-and-cancerconference

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/S023518/1 30/09/2019 30/03/2028
2597912 Studentship EP/S023518/1 01/10/2021 29/09/2025 Matthew Edward WHITE