Omomyc as a novel therapeutic strategy against metastatic triple-negative breast cancer, alone and in combination with the standard of care

Abstract

This thesis advances our understanding of MYC inhibition as a therapeutic strategy in triple-negative breast cancer (TNBC), an aggressive disease with poor prognosis and limited treatment options. MYC is a transcription factor dysregulated in most human cancers, being disproportionately elevated in TNBC compared to other breast cancer molecular subtypes. It functions as a key driver of tumorigenesis and a modulator of DNA damage response (DDR) mechanisms. Our laboratory developed Omomyc, the first direct MYC inhibitor to reach a Phase II clinical trial, but also an important research tool in MYC biology. Having previously demonstrated that MYC inhibition through conditional expression of an Omomyc transgene was efficacious against metastatic breast cancer, we now show that, in TNBC models, direct administration of the Omomyc mini-protein is superior to the transgene in shutting down MYC's transcriptional programme and exhibits potent antitumour and antimetastatic properties. On one hand, in vitro, we identify a panel of genes that could explain Omomyc's anti-metastatic effects, have prognostic value in TNBC and demonstrate Omomyc's mechanism of action and target-engagement through in situ proximity ligation assay (isPLA). On the other, in vivo, we show that the Omomyc mini-protein effectively prevents TNBC metastatic seeding and tumour growth. The powerful effect of the mini-protein as monotherapy then prompted us to test its efficacy in combination with standard of care treatments for TNBC. We began by combining Omomyc with chemotherapy, particularly taxanes, where MYC is regarded as a mechanism of resistance. Our results demonstrate that the mini-protein synergizes with chemotherapy in all cell lines tested, contributing to increased cell death and enabling reduction of chemotherapy dosing. Additionally, we reveal a novel mechanism whereby Omomyc downregulates DDR genes in TNBC, causing DDR defects and inducing DNA damage itself. This creates a unique opportunity for therapeutic combinations in the DDR context. Indeed, when combined with PARP inhibitors (PARPi), the standard of care for germline BRCA-mutated TNBC, Omomyc enhances DNA damage and overcomes both intrinsic and acquired PARPi resistance in various models. Importantly, using patient-derived models and clinical samples, we identify MYC transcriptional activity as a potential predictive biomarker of PARPi resistance. This provides a rational basis for patient stratification and treatment selection. In the final section of this thesis, we present preliminary evidence that the Omomyc-PARPi combination is effective not only in BRCA-mutated TNBC but also in BRCA-wildtype TNBC models. Furthermore, we explore the therapeutic potential of this combination in other BRCA-related malignancies, including pancreatic and ovarian cancers, suggesting broader applications for this treatment strategy. Our findings highlight the therapeutic potential of Omomyc and establish a compelling rationale for combining MYC inhibition with PARPi, particularly in PARPi-resistant TNBC. This combination strategy represents a promising approach for addressing an unmet clinical need in these aggressive breast cancers and beyond.

Date of Award	25 Jun 2025
Original language	English
Supervisor	Laura Soucek (Director) & Daniel Masso Valles (Director)