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Harnessing the Immune System to Fight Pediatric Cancer: Discovering Novel Inducers of Immunogenic Cell Death

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While anthracyclines are known toinduce ICD in the laboratory, clinically this effect is not observed. Our data indicates this is due not only to immunosuppression caused by high doses but also the fundamentally unique gene expression programs induced by high vs. low doses. Our hypothesis, supported by preliminary data, is that low-dose anthracyclines induce ICD in therapy-resistant cancer cells by altering gene expression to initiate an ICD program, including T cell regulatory pathways and ICD markers such as HMGB2. Thus, discovering genes that inhibit or synergize with ICD induction will identify targets that can be activated or inhibited to enhance clinical efficacy of anthracyclines and other ICD-inducers at low concentrations that are not toxic to healthy tissues. Recent advances using CRISPR-Cas9 gene editing technology have made whole genome screens a practical reality, which we will employ to achieve the following:

Specific Aim1: To construct and validate a chemical-genetic strategy for identifying ICD inducers. We will employ combined genome-wide repression (using CRISPRi) and overexpression (using CRISPRa) screening on leukemia cells treated with low and high doses of anthracyclines to discover genes that antagonize and synergize with ICD induction vs. drug resistance.

Specific Aim 2: To evaluate ICD inducers and synergy between low vs. high doses of anthracyclines using leukemia models of immunotherapy resistance. Lead screening target hits with available small molecule activators and/or inhibitors of ICD and resistancewill be functionally assessed. This project will use cutting-edge genome editing techniques to conduct whole genome and targeted validation screens to identify genetic targets that can be activated or inhibited to induce ICD, thus overcoming therapy resistance and immune escape.

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