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MULTIPLEXED ISOFORM QUANTIFICATION IN HER2-POSITIVE BREAST CANCER

HER2 阳性乳腺癌的多重异构体定量

基本信息

批准号：
10583566
负责人：
Amy Elizabeth Herr
金额：
$ 35.05万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-03 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583566
关键词：
Acceleration Address Articulation Assessment tool Automobile Driving Binding Biological Biological Assay Biological Markers Biology Biomedical Engineering Biometry Biopsy Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Breast Cancer cell line Breast biopsy Cells Chemistry Classification Clinical Computational Biology DNA DNA Sequence Alteration Detection Development Diagnosis Dimerization Drug Targeting Drug resistance ERBB2 gene ERBB3 gene Exhibits Extracellular Domain Fluorescence Resonance Energy Transfer Fluorescent in Situ Hybridization Genomics Goals Heterogeneity Homo In Situ Hybridization Individual Knowledge Length Life Malignant Neoplasms Mammary Gland Parenchyma Maps Measurement Measures Medicine Membrane Microfluidics Molecular Monitor Mutation Nature Nuclear Oncogenic PIK3CA gene Patients Pertuzumab Pharmaceutical Preparations Play Population Analysis Precision therapeutics Productivity Prognostic Marker Protein Family Protein Isoforms Proteins Proteomics Radiation therapy Recurrence Research Resistance Resolution Retinal blind spot Role Signal Transduction Specificity Surface Survival Rate Tissue Banks Tissue Sample Tissues Trastuzumab Variant Western Blotting biological heterogeneity cancer cell cancer drug resistance chemotherapy clinically relevant design dimer drug resistance development experience fundamental research improved individualized medicine malignant breast neoplasm multimodality mutant neoplastic cell news next generation novel therapeutics oncology program overexpression patient oriented precision medicine protein complex single cell analysis stem success targeted cancer therapy targeted treatment therapy resistant tool tumor heterogeneity

项目摘要

While targeted therapy increases overall survival rates in HER2-positive breast cancer patients, most patients will experience recurrence due to resistance to initially successful therapy (trastuzumab-based). Accordingly, there is an unmet, patient-driven need to understand and circumvent breast cancer resistance, to even targeted therapies. At the cellular level, cell-to-cell variation (heterogeneity) is a hallmark of cancer. Perhaps surprisingly, molecular heterogeneity is also a hallmark of HER2+ breast cancer. Spanning the outer membrane of a cancer cell, the large protein HER2 displays an extracellular domain, which is the target of ‘targeted therapies’ (vs. chemo- or radiation therapies). These HER2+ breast cancer targeted therapies include the landmark drug Herceptin® (trastuzumab). But the HER2 protein manifests as a family of proteins (called protein isoforms), not just a single molecular form. Regrettably, numerous of these HER2 isoforms lack the extracellular domain of the full-length HER2 protein, making the cell non-responsive otherwise powerful anti- HER2 targeted therapies. These smaller HER2 isoforms are known as ‘truncated isoforms’, with a 95 kDa form ‘P95HER2’ being especially potent in drug resistance. Until our previous R01 research, the ability to discern full-length HER2 from the truncated P95HER2 isoform was not readily possible with same-cell resolution. Consequently, to advance our knowledge of resistance to anti-HER2 targeted therapies, we propose to build on our team’s capacity to precisely distinguish P95HER2 from other HER2 protein forms to scrutinize the role of P95HER2 in: (1) the potent, signal-activating HER2 dimers that reside on the surface of each breast cancer cell and (2) potentially ultra-resistant breast cancer cell subpopulations that exhibit both the P95HER2 protein isoform and the resistance-driving DNA mutation (PIK3CA). These are two cellular ‘modes’ (P95HER2 homo/heterodimers; co-expression of P95HER2 and PIK3CA mutation) that no other tools can directly and with high-specificity concurrently measure in minute tissue samples, down to single-cell resolution. Our clinical, biostatistics, and bioengineering team will conduct research to yield tools that can perform these isoform- involved multimodal assays in tissues and cells from HER2-positive breast cancer patient biopsies (Stanford Breast Tissue Bank), after performing early development on well-characterized breast cancer cell lines. The ability to directly measure the truncated HER2 isoforms and interaction modes in sparingly available breast biopsy tissues and with single-cell resolution should yield a tremendous advantage for understanding and then assessing the potential for drug resistance. These studies will allow us to profile the cellular and molecular heterogeneity of HER2 to advance understanding of persistent breast cancer resistance to anti-HER2 targeted treatment and, ultimately, to identify approaches to reduce or eliminate recurrence.

虽然靶向治疗提高了her2阳性乳腺癌患者的总体生存率，但大多数患者