Combating Breast Cancer with the Wellderly Immune Repertoire
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Note: this project is a continuation of an earlier IDEA grant to the PI funded by the CBCRP from 2009-2010.
 
 
 
 
 
 The “Wellderly” is a group of 1000 healthy people in their eighties who never had cancer or any other chronic disease. Our idea is that many of these people have a strong immune system, and that some may have had developing breast cancer cells in their bodies, at some point in time, but successfully produced antibodies that prevented tumor establishment. Our project will tap into the genes of the “Wellderly” by using a “library” from their immune cells that we generated. The library will be used to fish out antibodies that can inhibit breast cancer cells, particularly those that cause inflammatory breast cancer, the most aggressive form of this disease.
 
 
 
 
 
 
 
 For these studies we established a unique new model of triple-negative, inflammatory breast cancer that reflects progression of a particularly treatment-resistant tumor type seen in the clinic. This model comprises cell lines from the primary tumor, local recurrence and pleural effusion that a young patient developed despite extensive regimens of chemotherapy and radiation. We are studying the immune repertoire of the Wellderly to detect antibodies that can block breast cancer growth and progression to an invasive phenotype. We are further performing genetic analyses of the increasingly aggressive and therapy-resistant tumor cells in our model to understand the underlying molecular basis related to breast cancer metastasis.
 
 
 
 
 
 In more technical terms, we will: (1) use a combinatorial phage display scFv antibody library that we generated from the “Wellderly”, to identify new antigens expressed by the increasingly aggressive breast cancer cells during their epithelial-to-mesenchymal transition (EMT) which we established as a disease driving pathway in our breast cancer progression model; and (2) utilize a high-throughput screening platform for identifying growth inhibitory and EMT reversing scFvs. We have expanded the genetic analyses of our progression model and are beginning to understand gains and losses of chromosomal regions in relation to gene expression regulation. Our comparisons of the aCGH (comparative genome hybridization) and gene expression data, as well as functional network analyses will enable us to generate a synopsis for understanding gene regulation in the progression of a very aggressive and treatment resistant form of breast cancer.
 
 
 
 
 
 Our hope is that Information on antigens against which growth inhibitory and EMT reversing antibodies are directed, and results from gene expression and chromosomal aberration analyses of our model, will identify novel therapeutic targets in aggressive breast cancer. Human antibodies from the “Wellderly” might be directly used in patients, or could be optimized for efficient therapy and combination treatments. Future study on if and how results from this work relate to triple negative, basal type breast cancers in general, may help find treatments for very aggressive and rapidly progressing types of breast cancer.