Wednesday, May 21, 2025
5/21/2025
Induction of interferon response by chromatin damaging anti-cancer therapy - Abstract. DNA-targeting drugs are a mainstream therapy for cancer, but it is becoming clearer that some of their anti-cancer activity is due not only to DNA damage, but also chromatin decondensation, which we call chromatin damage (CD). Moreover, it has been shown that some drugs cause only CD without DNA damage, and these CD-only drugs are as potent anti-cancer drugs as compounds causing both CD and DNA damage, but lack the toxicity associated with DNA damage. The focus of our study is to understand how CD activates IFN, and how this property can be used in the clinic to gauge the potency of CD drugs. Our ultimate goal of our research is to show that CD is a superior mechanism to DNA damage for the next generation of anti-cancer chemotherapy, which is more effective, less toxic, and more powerful in activating an anti-tumor immune response. To achieve this goal, we have developed a new group of CD-only chemicals, curaxins. The anti-cancer activity of curaxin clinical lead, CBL0137, has been demonstrated in multiple mouse models. Phase I trial has shown manageable toxicities and evidence of antitumor activity. These studies confirmed induction of IFN signaling by CBL0137 in mice and humans. Notably, curaxins cause stronger and faster IFN induction than DNA damaging agents, DNA methyltransferase inhibitors, and HDAC inhibitors. It is well established now that IFN induction significantly improves their anti-cancer efficacy of DNA damaging therapy. CD causes IFN induction via different mechanisms, but our data showed that IFN activation enhances anti-cancer efficacy of CD. Therefore, we propose that anti-cancer activity of CD agents is mediated in vivo via two complementary mechanisms: direct killing of tumor cells and engagement of anti-tumor immune attack. This proposal focuses on the hypothesis that IFN signaling in tumor and/or non-tumor cells is induced by CD via a mechanism different from DNA damage and potentiates the anti-cancer activity of CD drugs. We will focus on triple negative breast cancer (TNBC), a challenging disease to treat due to its aggressive behavior and lack of actionable targets. Our specific aims are: 1. Determine the impact of the IFN activation in tumor and non-tumor cells on the anti-tumor activity of CD therapy. 2. Define the mechanisms of IFN activation by CD agents. 3. Develop strategies for reversing the immune suppressive environment in triple-negative breast cancer using CD agents.
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