A SABCS session presented targeting the “undruggable,” primarily in triple negative breast cancer (TNBC), a heterogeneous disease that responds poorly to therapy and progresses rapidly. Some strategies discussed here may fail in TNBC, yet prove effective in other types of breast cancer or other tumors.
Celina G. Kleer, MD, discussed EZH2, a histone methyltransferase that downregulates tumor suppressor genes, upregulates oncogenes, and is associated with tumor initiation, progression, metastasis, and poor prognosis. EZH2 inhibitors that modulate EZH2 methyltransferase activity are in multiple clinical trials, and are approved for epithelioid sarcoma and refractory follicular lymphoma.
EZH2 is a promising breast cancer therapy, and requires elucidation of its oncogenic mechanism in different breast cancer subtypes for effective targeting. EZH2 inhibitors may prove to be more effective in breast cancer in combination with p38 MAPK inhibitors or chemotherapy. Other strategies to improve efficacy could include screening patients for predictive biomarkers, such as phosphoEZH2 T267 or phospho-p38, to select those suitable for EZH2-targeted therapy.
Trey Westbrook, PhD, discussed RNA splicing dysregulation as a hallmark of breast cancer that is providing a new, rapidly-developing target space. RNA splicing defects are heterogeneous across patients.
Splicing-targeted therapies (STT) can act as immuno-oncology agents via different pathways. Preclinical data indicate that STT with different mechanisms of action elicit different neo-antigens derived from mis-spliced RNA. These neo-antigens are immunogenic, eliciting anti-tumor responses. An alternative mechanism of STT acts by viral mimicry, wherein mis-spliced RNAs form double stranded molecules and trigger anti-viral responses, e.g., production of inflammatory cytokines, that lead to anti-tumor responses.
It remains to be determined which STTs best activate these pathways, which tumor types are most likely to respond, and if STTs can be combined with immune modulators like checkpoint inhibitors.
David W. Cescon, MD, PhD, discussed novel epigenomic targets in TNBC. There is a growing menu of “epidrugs,” such as a PRMT5 inhibitor being tested in solid tumors with a TNBC cohort. Epidrugs could be combined with chemo- or targeted therapies, although toxicity will need to be determined. Finally, characterization of acquired treatment resistance is an unmet need in TNBC, and represents another research opportunity.
Dr. Lederman has no conflicts of interest to report and is a contributor for Doximity.
Illustration by Jennifer Bogartz
