The first plenary lecture of SABCS 2022 looked at lineage-defined cell metabolism and the metabolic variability of breast cancer.

Rama Khokha, PhD, Princess Margaret Cancer Centre/University Health Network, University of Toronto, summarized findings from studies of epigenetic inhibitors, PARP inhibitors and metabolic inhibitors in her lecture, Lineage-Defined Metabolism of Normal Mammary Cells and Origins of Cancer Metabolic Heterogeneity on Wednesday, December 7.

Dr. Khokha said that prevention strategies have become a target for her research.

“While we are very good at identifying patients who are at risk of developing breast cancers,  the management modalities for these patients is stagnating in comparison,” she said. “So we are motivated to understand core biology that is unique to the high risk breast and identify candidates for early molecular interception.”

Findings on epigenetic drugs show they delay the onset of mammary tumors. Epigenetic inhibitors JQ1 and DAC inhibit mammary cell clonogenicity, whereas JQ1 also depletes bipotent mammary stem cells, Dr. Khokha reported.

Subsequent studies using multimodal data found that DNA damage repair capacity shows lineage distinctions, and that the basal lineage is hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibitors like olaparib.

In the study of PARP inhibitors, Dr. Khokha reported that homologous recombination was more proficient in luminal than basal cells, and both olaparib and talazoparib inhibited basal progenitors but spared luminal progenitors. Metabolism emerged as a core lineage distinction.

Oxidative phosphorylation pathways are dominant in luminal cells, while basal cells exhibit more glycolytic features, she said. From there, she turned her attention to mitochondrial form and function, which also showed differences in luminal cells than in basal cells.

In studying metabolic inhibitors, there was some overlap but also clear differences in luminal versus basal progenitor cell sensitivity to metabolic drugs. Dr. Khokha said the study also tested metformin in the assays and found that it only inhibits mature luminal cells while sparing both luminal and basal progenitors.

To conclude, Dr. Khokha’s lecture showed that the adult breast has unique progenitor cell populations, which are the purported cancer cells-of-origin. Molecular portraits of these progenitors have revealed actionable vulnerabilities, and her preclinical discovery-to-interception pipeline has pointed to promising drug categories.

“Exploiting the metabolism of breast cancer precursors may be an emerging Achilles heel in breast cancer interception,” she said.