Abstract 4496: Induction of immunogenicity in tumor cells by small molecule drugs that destabilize nucleosomes
Authors: Leonova Katerina , Safina Alfiya , Gudkov Andrei V. , Gurova Katerina V. 
Published: September 2020

Abstract
Curaxins are DNA binding small molecules that bind genomic DNA with high affinity and disrupt DNA-histone interactions, leading to dose-dependent nucleosome disassembly and chromatin decondensation in cells. Curaxins have anti-cancer activity against multiple mouse cancer models, and lead curaxin CBL0137 is currently being tested in several clinical trials. During preclinical testing, we observed that CBL0137 caused complete regression of spontaneous tumors in many transgenic mice but only inhibited tumor growth in xenograft models. One of the hypotheses to explain this difference is that the immune system, which is intact in transgenic mice but compromised in mice with xenograft tumors, may play an important role in the anti-cancer activity of curaxins. To test this hypothesis, we compared the growth of the same tumor cells (mouse 4T1 breast cancer cells) in syngeneic, immunocompetent BALB/c mice and immunocompromised SCID mice. CBL0137 had a much stronger inhibitory effect on tumor growth in BALB/c compared to SCID mice. There were also fewer suppressor cells and more active lymphocytes in tumors from BALB/c mice treated with CBL0137 compared to those treated with vehicle. Furthermore, CBL0137 substantially increased the abscopal effect of ionizing radiation. To understand the relationship between the immune system and CBL0137, we measured changes in gene expression in normal mouse organs and tumors upon treatment with CBL0137. The most prominent effect of CBL0137 observed was the induction of the type I interferon response (IFN-I). The same effect was also detected in PBMC from the blood of healthy volunteers treated ex vivo with CBL0137 and clinical trial cancer patients after a single IV injection of CBL0137. In this study, we aimed to establish how chromatin decondensation leads to IFN-I and increased immunogenicity of tumor cells. We identified several complementary mechanisms: (i) bi-directional expression of constitutive heterochromatin, leading to the accumulation of double-stranded RNA, known trigger of IFN-I; (ii) reactivation of facultative heterochromatin and expression of embryo-specific antigens, such as NY-ESO-I, recognized as a foreign antigen by T cells; (iii) increased expression of epigenetically silenced MHC-I proteins in tumor cells; (iv) departure of architectural chromatin proteins, such as HMGB1, from chromatin, which normally serve as a ligand-damage associated molecular pattern (DAMP) receptor. Thus, chromatin decondensation serves as a potent inducer of tumor cell immunogenicity. An immune response may significantly improve the anti-cancer activity of CBL0137, and the presence of an intact IFN-I could serve as a potential predictive marker of patient response to curaxin treatment.
Citation Format: Katerina Leonova, Alfiya Safina, Andrei V. Gudkov, Katerina V. Gurova. Induction of immunogenicity in tumor cells by small molecule drugs that destabilize nucleosomes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4496.