Abstract 60P
Background
Triple-negative breast cancer (TNBC) is among the most aggressive and clinically challenging breast cancer subtypes, marked by high metastatic potential, poor prognosis and limited treatment options. This underscores the urgent need to identify novel molecular targets for effective therapies. Aldehyde dehydrogenase 1 (ALDH1) enzymatic activity is a hallmark of cancer stem cells (CSCs), strongly associated with drug resistance, tumor aggressiveness, and metastasis, making it an attractive therapeutic target. However, the distinct roles of ALDH1 isoforms, particularly ALDH1A1 and ALDH1A3, remain poorly understood, hindering the rational design of selective inhibitors.
Methods
This study integrates bulk RNA-seq data from 1,103 primary breast tumors, 50 breast cancer cell lines, and single-cell RNA-seq data from 26 patients to characterize ALDH1 isoform expression across molecular subtypes and the tumor microenvironment.
Results
ALDH1A3 was predominantly expressed in basal-like TNBC tumors, primarily by epithelial tumor cells, while ALDH1A1 was enriched in stromal components, including myeloid cells and cancer-associated fibroblasts, implicating this isoform in immune suppression and metastasis.
Building on this insight, we developed a novel ALDH1A3-selective inhibitor derived from DIMATE, an ALDH1A1 inhibitor currently in clinical trials for AML. Structure-activity relationship studies identified a lead compound with enhanced selectivity for ALDH1A3, sparing the critical ALDH2 and ALDH3. Functional assays revealed that this inhibitor selectively induced apoptosis in ALDH1A3-expressing basal-like TNBC cell lines. Furthermore, it suppressed metastasis by inhibiting IL-6/JAK2/STAT3 and tPA/Src/FAK signaling pathways, potentially via a regulatory mechanism involving modulation of retinoic acid production mediated by ALDH1 in both tumor cells and the microenvironment. Preclinical TNBC models demonstrated its efficacy in reducing tumor growth and preventing distant metastases.
Conclusions
This work establishes ALDH1A3 as a promising biomarker and therapeutic target in basal-like TNBC, offering a promising approach to address unmet clinical needs in aggressive TNBC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Advanced BioDesign.
Funding
Advanced BioDesign.
Disclosure
G. Fournet: Financial Interests, Personal, Stocks/Shares: Advanced BioDesign. G. Martin, I. Ceylan, M. Perez: Financial Interests, Personal and Institutional, Member of Board of Directors: Advanced BioDesign. All other authors have declared no conflicts of interest.