A. Soragni, N. Phan, D. Eisenberg
Jul 1, 2017
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Cancer Research
Abstract
Li-Fraumeni syndrome (LFS) is a rare, dominant cancer predisposition disorder. The majority of LFS cases are brought about by germline p53 mutations. Individuals affected develop a spectrum of cancers occurring since childhood or early adulthood (Mai et al, 2012). Tumors associated with LFS include but are not limited to sarcomas, lymphomas and leukemias, breast cancers, brain tumors, etc (Olivier et al, 2010; Mai et al, 2012). p53 is a tumor suppressor gene that regulates many cellular processes and prevents cancer formation, growth and dissemination. When inactivated by mutation, it not only loses its tumor suppressive function, but also acquires oncogenic properties. Mutations of p53 promote destabilization of its three-dimensional structure, which can cause p53 to partially unfold, aggregate and accumulate in cells (Xu et al, 2011). We developed a peptide, ReACp53, to arrest p53 clumping and accumulation, chaperone p53 to a functional state and promote its degradation, hence arresting tumor proliferation (Soragni et al, 2016). ReACp53 can also target p63 and p73 (Zheng et al, 2016). It has shown good tolerability and a favorable safety profile in vivo. In LFS patients and LFS animal models, p53 is undetectable in normal tissues. However, the protein starts to accumulate in tumors and pre-cancerous lesions (Lang et al, 2004; Soragni et al, unpublished data). As p53 accumulation is correlated with aggregation (Xu et al, 2011; Soragni et al, 2016), we postulated that, by periodically administering ReACp53, we could target this initial event early on, and prevent p53 accumulation and/or push the p53 aggregates-ridden cells into apoptosis (Soragni et al, 2016). Here, we tested ReACp53 as a tumor preventive agent, by administering it twice a week from weaning to LFS mice carrying the aggregation-prone R172H mutation (R175H in humans). ReACp53 delayed cancer onset resulting in a significant increase in overall survival (OS). The homozygous cohort (n=16/group) showed a 50% increase in median survival in ReACp53-treated mice (median OS 15.79 vs 23.93 weeks for vehicle vs ReACp53, p=0.005; HR=2.6). Heterozygous mice (n=8/group) showed a 36% increase in OS with a median of 58.86 vs 80.50 weeks for vehicle vs ReACp53 (p=0.03, HR=2.6). No long-term side effect was observed upon ReACp53 administration. The tumor spectrum reported differed between the two groups. Activation of a functional p53 response in mouse cells and LFS patient cells treated with ReACp53 is undergoing. Overall, our study supports ReACp53 therapy as a potential approach to tumor prevention in LFS. Citation Format: Alice Soragni, Nhan Phan, David Eisenberg. Targeted tumor prevention in Li-Fraumeni syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-169. doi:10.1158/1538-7445.AM2017-LB-169