1999 — 2001 |
Schroeder, Joyce A |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Muci Effects On Breast Development and Tumorigenesis @ Mayo Clinic Coll of Med, Mayo Clinic Az
cell cell interaction; laboratory mouse
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0.907 |
2005 — 2010 |
Schroeder, Joyce A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Effects of Muc1 Expression On Erbb Activity in Neoplasia
DESCRIPTION (provided by applicant): Ligand independent activation of overexpressed growth factor receptors frequently results in unchecked mitogenesis and inhibition of apoptosis during breast cancer progression. The erbB transmembrane tyrosine kinases are commonly overexpressed in breast cancer tissues and have a potent mitogenic and anti-apoptotic effect. The tumor antigen MUC1 is also commonly overexpressed on breast cancer epithelium, associates with and is phosphorylated by erbB receptor kinases and can potentiate erbBdependent Map Kinase activation. Importantly, interactions between MUC1 and the erbB receptors are observed primarily in tumors and lymph node metastases from infiltrating ductal breast adenocarcinoma patients, and not in normal breast epithelium. We hypothesize that a functional interaction between MUC1 and erbB receptor kinases results in tumor growth and metastatic progression, and acts to drive cells into growth factor-independent mitogenesis and resistance to apoptosis. We intend to investigate the functional significance of molecular interactions occurring between MUC1 and the erbB receptors in the WAP-TGFalpha and MMTV-MUC1 transgenic mouse models of breast cancer. We will determine if erbB kinase activation is required for MUC1-induced tumorigenesis, and if MUC1 expression promotes erbB-induced tumorigenesis by crossing these transgenics onto a Muc1 null and erbB-mutant background, respectively. We will determine if MUC1 and erbB receptor complex formations are tumor-specific, what erbB-specific signaling pathways are activated in tumors, and how downstream effects such as growth, inhibition of apoptosis and invasion are affected by MUC1 and erbB receptor functional interactions. The utilization of mouse models allows us to gain a more comprehensive understanding of both the molecular events occurring in the cell, and how those events contribute to the growth of a spontaneous tumor that is fully affected by the microenvironment. We will next dissect the mechanism by which MUC1 expression affects erbB receptor function in breast cancer cell lines. We will determine if MUC1 expression promotes the recruitment of adapter molecules to erbB receptors, what is the functional outcome of this biochemical interaction and how the expression or ablation of MUC1 affects erbB-dependent signaling. We will also determine if MUC1 expression affects erbB receptor endocytosis, by promoting erbB receptor retention at the plasma membrane or in signaling endosomes, thereby potentiating erbB signaling during transformation.
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1 |
2009 — 2012 |
Zohar, Yitshak [⬀] Jiang, Linan Schroeder, Joyce |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Eager: Nanoparticle-Based Integrated Microsystem For Selective Targeting of Bio-Species in Flowing Suspensions
The objective of this research is to develop a high-performance system to target individual bio-species with dramatically enhanced specificity and sensitivity. The approach is based on utilizing smart nanoparticles, encapsulating various chemicals and equipped with homing features, to provide a vehicle for pin-point delivery of payloads at a nanoscale with high efficiency. Current systems utilize drugs with very low specificity resulting in serious side effects and poor system response. Organic-inorganic nanoparticles will be functionalized with antibodies for specific binding to circulating tumor cells flowing in complex mixtures to improve the system performance. The intellectual merit lies in the goal of selectively capturing a rare moving bio target that is still a tremendous engineering challenge. Metastatic cancer cells circulating in the blood stream will be targeted. To meet this challenge, unique trans-membrane cell-cell adhesion molecules are used as receptors. The antibodies on the hybrid nanoparticles, having a liposomal bilayer structure and a silicate surface, are used as homing ligands for selective binding to the target cell receptors.
The project could have a major impact by applying the proposed methodologies not only to detection but also diagnosis, monitoring and treatment of diseases. An automated immunoassay employed at the point-of-care with enhanced specificity will increase the efficacy of patient treatment helping eradicate diseases such as cancer. The proposed project directly supports the Bio-MEMS educational program currently under development; it incorporates workforce development by providing an opportunity for students to carry out advanced interdisciplinary research. Science education outreach for K-12 and general communities will also be arranged.
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0.915 |
2013 — 2014 |
Camenisch, Todd D [⬀] Schroeder, Joyce A |
R41Activity Code Description: To support cooperative R&D projects between small business concerns and research institutions, limited in time and amount, to establish the technical merit and feasibility of ideas that have potential for commercialization. Awards are made to small business concerns only. |
Decoy Peptides: Development of a Novel Therapeutic For Metastatic Cancer @ Arizona Cancer Therapeutics, Llc
DESCRIPTION (provided by applicant): Arizona Cancer Therapeutics LLC (ACT) proposes a two-year, preclinical research project in cooperation with the University of Arizona Cancer Center to develop the novel anti-tumor therapeutic, Protein transduction domain-MUC1 Inhibitory Peptide (PMIP). PMIP is an intracellular MUC1 peptide that acts as a decoy to block the MUC1- oncoprotein interactions that drive breast cancer growth and metastasis. Utilizing a protein transduction domain to allow for transmembrane cellular uptake, PMIP can freely enter the cell and interact with intracellular target proteins. Laboratory research at the University of Arizona over the past nine years has examined the ability of MUC1 and an oncogenic partner, epidermal growth factor receptor (EGFR), to synergistically drive breast cancer progression. To block these tumor-specific, intracellular interactions, the first-in-class peptide-based cancer therapeutic, PMIP, was developed. Studies in tumor-bearing mouse models demonstrate that PMIP blocks tumor growth and metastasis and is nontoxic and tumor specific, making it an excellent anti-tumor drug candidate to carry forward through preclinical studies and clinical trials. Over 40,000 Americans die annually from metastatic breast cancer and, in greater than 90 percent of human breast carcinomas and metastases, MUC1 is over-expressed. This project represents critical steps in preclinical studies in drug dosing, absorption, distribution, metabolism and toxicity. The project will also investigate the benefits of PMIP when used in combination with FDA-approved chemotherapies for breast cancer. PMIP represents a unique approach to targeting MUC1 activities in cancer - other clinical trials targeting MUC1 have been designed to elicit anti-MUC1 immunity, and have been largely ineffective. Unlike these approaches, PMIP does not rely on activation of the immune response, but instead directly blocks tumor-promoting intracellular interactions. If successful, PMIP can substantially enhance the effective treatment options for metastatic breast cancer patients. This project aligns to NIH's mission to enhance health, lengthen life, and reduce the burdens of illness and disability by researching a new and unique anti-tumor drug to treat, effectively and with low or no toxicity, metastatic breast cancer.
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0.925 |
2016 |
Camenisch, Todd D [⬀] Schroeder, Joyce A |
R41Activity Code Description: To support cooperative R&D projects between small business concerns and research institutions, limited in time and amount, to establish the technical merit and feasibility of ideas that have potential for commercialization. Awards are made to small business concerns only. |
Combinatorial Inactivation of Erbb Receptors in Breast Cancer Using Therapeutic Stapled Peptides @ Arizona Cancer Therapeutics, Llc
? DESCRIPTION (provided by applicant): In metastatic breast cancer, the Epidermal Growth Factor Receptor family of transmembrane tyrosine kinases (ErbB) drives proliferation and metastasis. EGFR, HER2 and ErbB3 are known to be highly expressed and active in both the HER2+ and Triple Negative/Basal subtypes of breast cancer, and have been targeted with varying effectiveness. Importantly, targeting of a single receptor member typically results in activity in the remaining receptor members, making simultaneous targeting of all receptors a needed therapeutic development. Furthermore, while the tyrosine kinase domain of these receptors is a significant driver of transformation, kinase inhibitors fail to induce cell death, indicating that a non-kinase function of the ErbB receptors is important in driving cancer progression. While the tyrosine kinase activity of these receptors is well known, less appreciated are the non-canonical activities of this family, including the modulation of mitochondrial function calcium signaling and nuclear translocation and activity as transcriptional co-factors. These functions are regulated simultaneously by the juxtamembrane domains (JD) of the ErbB receptors, which are also responsible for active homo- and hetero-dimerization. The non-kinase JD forms anti-parallel dimers between the receptors upon ligand binding, resulting in receptor transphosphorylation, Calmodulin activation, intracellular trafficking of the receptors and signal transduction. These functions drive ErbB-dependent survival, migration, growth and therapeutic resistance. We have previously demonstrated that peptides mimicking this JD can act in a dominant-negative fashion, promoting the formation of non-functional ErbB dimers (consisting of EGFR, HER2 and ErbB3) that induce rapid, ErbB-dependent cell death. Using Cell Penetrating Peptides synthesized in tandem with the JD (EJ1), peptides rapidly cross the plasma membrane, bind the ErbB receptors, and induce cell death in cell lines and PDX lines grown in culture. Death results from a combination of apoptotic and necrotic mechanisms, due to inactivation of ErbB kinases, and modulation of mitochondrial and calcium signaling. Initial results showed that, although these peptides display rapid ErbB-dependent cell death in vitro, the peptides have moderate efficacy in vivo. To stabilize in vivo activity, the active peptide (which is an alpha-helix) was stabilized with hydrocarbon staples (SAH- EJ1), resulting in a 10-fold increase in the activity of the peptide. Based on these data, we hypothesize that SAH-EJ1 will serve as an effective and stable therapeutic for the treatment of ErbB- dependent breast cancer. We plan to investigate this hypothesis by 1) Performing the preliminary in vivo Pharmacokinetics studies for SAH-EJ1, and 2) Determining the activity of SAH-EJ1 in PDX models of metastatic breast cancer that express EGFR, HER2, and/or ErbB3.
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0.925 |