# Direct targeting of HIF1a-driven transcription in TNBC with engineered STRs > **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2024 · $667,792 ## Abstract Project Summary: Tumor cells are exposed to a wide array of stressors ranging from hyperactive protein synthesis and metabolism to nutrient and oxygen starvation in the tumor microenvironment; these stimuli require tumor cells to activate protective transcriptional programs that promote tumor cell survival and growth. X-box binding protein 1 (XBP1) and hypoxia-inducible factor 1 alpha (HIF1a) are two of the most important stress- induced transcription factors (TFs), activate oncogenic and metastatic gene expression programs by assembling into complexes at unfolded protein response (UPRE) and hypoxia-induced response (HRE) elements, respectively. These target DNA sequence ‘motifs’ overlap in many target genes. Triple negative breast cancer (TNBC), the most aggressive and metastatic subtype of breast cancer, is heavily dependent on strong upregulation of XBP1s (the spliced, active form of XBP1), HIF1a and their downstream stress-responsive gene expression networks. Despite the profound need for targeted therapies against these and other oncogenic TFs, they remain largely untapped as drug targets due to the challenges of targeting protein-protein and protein-DNA interactions. Therefore, our team recently developed a modular strategy to create fully synthetic transcriptional repressors (STRs) to directly inhibit the oncogenic activity of TFs by blocking their ability to bind and regulate specific DNA sequences. Using this synthetic platform, we have designed potent (low nM), highly specific, cell permeable, and in vivo active inhibitors of HRE/UPRE-driven transcription. Our lead STRs directly antagonize XBP1/HIF1a for DNA binding in vitro and in cells, resulting in potent, global inhibition of hypoxia-induced gene expression programs, blockade of hypoxia-induced aggressive phenotypes, such as cell invasion, and anti- proliferative effects only under conditions of hypoxia. In animal studies, administration of lead STRs significantly inhibits tumor growth and hypoxia-induced gene expression, validating on-target activity in animals. The proposed project will test the hypothesis that XBP1/HIF1a transcriptional responses can be tightly controlled by optimized STRs that directly target their shared DNA binding sites. This will be accomplished through three complementary Aims: 1) Develop ultra-potent, pharmacologically stable STRs for cell based and animal studies; 2) Map STR-based reprogramming of hypoxia-induced, XBP1/HIF-dependent gene expression and oncogenic phenotypes in TNBC; 3) Test efficacy of optimized STRs in inhibiting TNBC growth, metastasis and chemoresistance using in vitro and in vivo models. These studies will provide fresh insight into the molecular underpinnings and pathogenesis of adaptive stress responses in TNBC, determine the effects of blocking XBP1/HIF1a -DNA binding at the level of chromatin and transcriptional dynamics and establish the efficacy of targeting hypoxia-dependent gene expression on TNBC tumor growth, metastasis and c... ## Key facts - **NIH application ID:** 10944153 - **Project number:** 1R01CA292876-01 - **Recipient organization:** UNIVERSITY OF CHICAGO - **Principal Investigator:** Raymond E Moellering - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $667,792 - **Award type:** 1 - **Project period:** 2024-06-01 → 2029-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10944153 ## Citation > US National Institutes of Health, RePORTER application 10944153, Direct targeting of HIF1a-driven transcription in TNBC with engineered STRs (1R01CA292876-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10944153. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*