Oncology
Basel, Switzerland
p53 is a sequence-specific transcription factor that activates the expression of genes that promote cell cycle arrest or cell death in response to multiple forms of cellular stress, such as DNA damage, oxidative stress, or oncogene activation. Because of its growth inhibitory activities, p53 actions are kept tightly in check under most physiological conditions. In ≥50% of all human cancers, the tumor suppressor p53 is either mutated or deleted. In the majority of remaining cases, wild-type p53 is inactivated by other means, such as through amplification and/or overexpression of MDM2 and MDM4 that antagonize p53 function. Aberrant expression of MDM2 and/or MDM4 has been observed in a number of tumors, especially in those that retain wild-type p53.
Re-establishing wild-type p53 functionality in the context of genetic deletion or mutation is challenging. However, when wild-type p53 is present, targeting its negative regulators holds promise to reinstate the p53 tumor suppressor pathway. Academic and industry efforts have led to the development of a series of small molecules and peptides that target the p53-binding pocket of MDM2 and/or MDM4, disrupt the p53-MDM interaction, stabilize p53, and thereby reduce cancer cell viability. However, some p53-wild type tumors have intrinsic resistance to MDM2-p53 inhibition (e.g. Nutlin-3a). Our laboratory is interested in characterizing the role of other p53 family members - namely p63 and p73- in tumor cells, including the role of their transcriptionally regulated genes, particularly when activated in response to the p53-MDM inhibition. We are also interested in understanding the mechanisms of either intrinsic sensitivity or resistance to p53 reactivation
Selected Publications
M2 isoform of pyruvate kinase is dispensable for tumor maintenance and growth.
Cortés-Cros M, Hemmerlin C, Ferretti S, Zhang J, Gounarides JS, Yin H, Muller A, Haberkorn A, Chene P, Sellers WR, Hofmann F.
Proc. Natl. Acad. Sci. U S A. 2013 Jan 8;110(2):489-94.
The path to oncology drug target validation: an industry perspective.
Cortés-Cros M, Schmelzle T, Stucke VM, Hofmann F.
Methods Mol. Biol. 2013;986:3-13.
Aiolos is required for the generation of high affinity bone marrow plasma cells responsible for long-term immunity.
Cortés M, Georgopoulos K.
J. Exp. Med. 2004 Jan 19;199(2):209-19.
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