Project-3: Targeting Hedgehog Signaling Pathway in Breast Cancer Therapy

Due to chemo-resistant metastases, breast cancer (BrCa) chemotherapy often fails after promising results. In 2023, the American Cancer Society predicted 43,700 BrCa deaths, an increase of 0.5% from the previous year. Due to its proliferation, frequent acquisition, chemotherapy resistance, and spread, BrCa has a high mortality rate. Advanced triple-negative breast cancer (TNBC) has the worst chemotherapy outcomes of all BrCa subtypes, with a nine-month survival rate. The high resistance and recurrence rate (30%), lack of effective targeting therapy (ER-, PR-, or HER2-), and poor prognosis render TNBC a poor treatment option. TNBC is challenging to treat due to toxicities from traditional chemotherapies like docetaxel and paclitaxel, poor bioavailability of anti-cancer drugs, and lack of tumor cell specificity. We need new molecular targets and cancer cell-targeted anti-cancer drugs. Recent studies suggested that organs, tissues, and cells rely on Hedgehog (Hh) proteins for their growth, survival, and organization. Therefore, targeting the Hh signaling pathway could offer a safe and curative option for patients with specific subtypes of BrCa. Many cancers, including human BrCa, have been associated with dysregulation of the Hh signal pathway involving the Sonic Hh (SHH) molecule. Alleviated SHH expression reduces the inhibitory impact of Smoothened (SMO) by attaching to its membrane receptors, Patched1 (PTCH1) or PTCH2, thereby activating transcription factors, Gli1, Gli2, and Gli3, to transcribe target genes and enrich the tumor microenvironment for growth and progression. Due to SHH oncogenic properties and potential for inhibition, targeting SHH signals directly is a promising BrCa treatment. Although natural compounds show promise in vitro, their low bioavailability limits in vivo efficacy. One of the best-studied anticancer natural compounds is honokiol, a dietary photochemical isolated from Magnolia officinalis bark. It has antioxidant, anti-inflammatory, and anti-microbial properties and is used in traditional medicine. Our initial findings strongly suggest targeting the Hh signaling molecule for TNBC treatment. This study will evaluate a new BrCa treatment method using honokiol alone or with docetaxel. Targeted delivery through gold nanoparticles may improve honokiol's low bioavailability and tumor cell non-specificity. This combination therapy should reduce docetaxel dosage synergistically. This research will allow honokiol to be used in pre- or clinical chemoprevention. Project Number: 5U54CA118638-20 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Brian Rivers (+2 co-PIs) | Institution: MOREHOUSE SCHOOL OF MEDICINE, ATLANTA, GA | Award Amount: $146,725 | Activity Code: U54 | Study Section: ZCA1-SRB-2(A1)S View on NIH RePORTER: https://reporter.nih.gov/project-details/11400487