Combating Breast Cancer with the Wellderly Immune Repertoire
|Institution:||Scripps Research Institute|
Brunhilde Felding-Habermann , Ph.D. -
|Award Cycle:||2011 (Cycle 17)||Grant #: 17NB-0058||Award: $473,750|
|Award Type:||IDEA Competitive Renewal|
|Innovative Treatments>Immune therapy: mobilizing the body's defenses|
Initial Award Abstract (2011)
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.
Progress Report 1 (2012)
Breast cancer diagnosis and treatment have much improved, but some tumor types resist therapy, recur early and progress to metastatic disease. Our goal is to understand hard-to-treat breast cancer and to develop more effective therapies. We established a unique new model of triple negative, metaplastic inflammatory breast cancer that reflects progression of the most aggressive type of this disease. The 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 “mined” the immune repertoire of healthy long-lived people (the Wellderly) for antibodies that react with breast cancer cells and point to new pathways that control breast cancer progression. We reasoned that many individuals in the Wellderly group may have encountered developing breast cancer cells in their bodies over the years, but remained clinically disease free over decades - in many cases despite non-favorable genetic disposition and risk factors encountered over a lifetime. We further hypothesized that genetic analysis of the progressively aggressive and therapy resistant tumor cells in our model will reveal critical information for understanding the disease and, together with the antibody strategy, provide a basis for new, effective therapies.
During the first year of this study, we focused on screening the Wellderly antibody library to derive antibodies from the Wellderly antibody (Fab) library that recognize the breast cancer cells of our new progression model. To relate the identified targets and tumor progression related pathways involved to our gene expression analyses, we interrogated expression levels of the target molecules and related pathway components. We were able to isolate three specific antibodies that bind highly relevant targets associated with our breast cancer progression model. The targets we identified reveal the importance of three distinct but functionally related molecules and pathways that apparently dominate a prominent part of the aggressive phenotype in breast cancer progression.
In the upcoming funding period we plan to advance our screening approach of the Wellderly library for identification of differentially expressed targets in our breast cancer progression model. We will explore potentially therapeutic antibodies for their function blocking properties and generate clinically relevant molecular formats of the most promising antibodies. We will also pursue new genomic approaches to more fully explore the genetic underpinnings of breast cancer progression in our model. The information and tools from this study provide novel, in some cases unexpected leads, as a basis for development of improved and effective therapies.