ITX-0121: A therapeutic strategy for transcription-coupled repair-deficient cancers.

e15149 Background: Cells possess a complex DNA damage response (DDR) system to prevent detrimental mutations from accumulating. The genes encoding various DDR components are frequently mutated in cancer cells and provide potential sites for therapeutic intervention. DNA damaging agents, with one exception, are repaired by the global genome nucleotide excision repair (GG-NER) pathway. Our novel class of drugs, Illudins, are the exception as Illudin-induced DNA damage is not recognized by GG-NER and can only be repaired by the transcription-coupled nucleotide excision repair (TC-NER) pathway. Studies utilizing isogeneic cell lines completely deficient in specific TC-NER proteins (e.g. homozygous ERCC6 knockout) indicate these cells are extremely sensitive to Illudins (up to 30-fold). In contrast, cells deficient in GG-NER activity are not sensitive to our drugs. Moreover, non-replicating or normal cells are minimally affected by Illudins, as evidenced by the lack of systemic toxicity in humans treated with one of our drugs. In TC-NER deficient cancer cells, however, our drug ITX-0121 blocks the TC-NER polymerase complex, which disengages from DNA, and initiates the irreversible process of apoptosis or cellular suicide. Many cancers exhibit deficiencies in DDR mechanisms and cannot properly repair DNA damage. Methods: Analysis of the GENIE Database indicates that the overall incidence of TC-NER deficient cancers in solid tumors is ~10%, and includes all major histological classifications (breast, ovarian, endometrial, prostate, renal, bladder, bone, colorectal, liver, lung, skin, pancreatic, thyroid, etc.) or ~175,000 new patients annually. These cancers, however, possess monoallelic mutations, as opposed to biallelic, and thus have some residual TC-NER functionality. To determine the relative sensitivity of cancers with monoallelic alterations in TC-NER genes, we generated colorectal HCT-116 cells with a monoallelic deletion in a single TC-NER gene. For example, we are generating daughter cell lines with small monoallelic deletions in ERCC2, ERCC3, ERCC4, ERCC6, and ELOF1 genes. Results: We are comparing sensitivity of these daughter lines to our lead drug ITX-0121, as well as to other DNA damaging agents such as cisplatin. Preliminary results indicate a monoallelic alteration in a TC-NER gene can confer > 6-fold sensitivity to ITX-0121, which is clinically relevant based on PK results. Based on these PK results, we believe the maximum tolerated dose (MTD) of ITX-0121 in patients to be > 1.2 mg/kg; yet only 0.4 mg/kg will be sufficient for clinical efficacy against cancers that are phenotypically TC-NER deficient. Conclusions: Thus, despite the administration of a cytotoxic agent, TC-NER deficient cancer patients can be treated at a non-toxic dose; if toxicity occurs, it should be limited to transient thrombocytopenia, as indicated by prior studies.