CHD1Li Targeted Combinations with Chemotherapy to Address Unmet Needs in Colorectal Cancer Treatment

PROJECT SUMMARY/ABSTRACT Cancer therapy has made important advancements in the treatment of aggressive and resistant to standard-of-care tumors. This progress can be attributed to the significant success of drug combination therapies in multiple cancer types. Drug combinations have benefitted from our increased knowledge of the mechanisms of resistance, drug metabolism, and genetic variability observed during tumor progression. Notably, the combination of FOLFIRI (FOLinic acid, 5FU, and IRInotecan) and bevacizumab (VEGF inhibitor) is used to treat advanced metastatic colorectal cancer. Herein, we propose the combination of FOLFIRI and Chromodomain Helicase DNA binding Protein 1-Like (CHD1L) inhibitors (CHD1Li) as a novel synergistic mechanism that will not only decrease the malignant properties of tumor cells, but also sensitize them to the effects of chemotherapy and other targeted therapies. CHD1L, also known as amplified in liver cancer 1 (ALC1), has been implicated, through clinical and basic research studies, as an oncogene that affects the outcomes of patients in many types of cancer. CHD1L is a chromatin remodeling enzyme, and its aberrant function can facilitate tumor progression and tumor cell survival. In cancer cells, CHD1L promotes malignant gene expression, which leads to an increase in metastatic potential and tumor heterogeneity. In addition, CHD1L is essential in the DNA damage response and repair, and directly inhibits programmed cell death mechanisms, enabling tumor cell survival and MDR. These functions of CHD1L, when unregulated in tumor cells, can significantly lead to an increase in cancer patient mortality. Onconaut Therapeutics Inc. has designed and optimized a series of first-in-class lead drugs (OTI-600 series) that inhibit CHD1L and display antitumor activity as single agents, but also synergize with standard of care chemotherapy and targeted therapy. Preliminary data with one of our lead CHD1Li (OTI-611) demonstrates an excellent pharmacokinetic profile, oral bioavailability, and no observed toxicity in major organs of tumor bearing mice as a single agent or in combination with chemotherapy. In this fast-track STTR proposal we will develop and prioritize the best CHD1Li lead drug to enable its transition to an investigational new drug (IND) with an initial target market of colorectal cancer (CRC). Phase I of this project will focus on performing a comprehensive in vitro cytotoxicity efficacy assessment of OTI-600 series drugs in patient-derived tumor organoids with diverse genetic backgrounds as single agents and in combination with FOLFIRI. In tandem, these CHD1Li will be tested for their pharmacokinetic and toxicologic profiles as single agents and in combination with FOLFIRI in mice. In Phase II, the best two OTI-600 series drugs will be tested for their efficacy in combination with FOLFIRI in mouse xenografts. Finally, the best lead drug CHD1Li will undergo scale up synthesis (2 kg) to facilitate preclinical IND-enabling studies.