SPOREs : Organ-Specific SPORE Programs : Breast

Vanderbilt University

Overall Abstract

Principal Investigator: Carlos L. Arteaga, MD

This Breast Cancer SPORE renewal application is submitted by the VICCC and VUMC. It is comprised of investigators with expertise in cellular signaling and molecular biology, breast pathology, medical, surgical, and radiation oncology, clinical trial design, epidemiology and population studies, mass spectrometry, biostatistics, and biomedical informatics. The SPORE application is built on established and newer Institutional strengths. The investigators in the SPORE are truly committed to reducing the incidence, morbidity and mortality of breast cancer. All four projects are translational and multidisciplinary as discussed below. They are led by co-investigators from multiple Departments in the School of Medicine and with complementary basic science and translational/clinical expertise.

Project 1: Resistance to antiestrogen therapy in hormone receptor-positive breast cancer. Aim 1 of this project will develop biomarkers of response combined therapy with the aromatase inhibitor letrozole and the HER2 tyrosine kinase inhibitor (TKI) lapatinib in patients with hormone receptor-positive breast cancers that overexpress the HER2 oncogene. This project will also test the hypothesis that tumors with high cell proliferation, as measured by Ki67 staining after a short period of hormonal therapy, harbor a hormone-independent RNA signature with overexpressed molecules or ‘pathways’ that are biomarkers of antiestrogen resistance or a cause of it. Therefore, Aim 2 will use the post-letrozole Ki67 in ER-positive/HER2-negative tumors to discover gene expression signatures associated with response or resistance to estrogen deprivation. Finally in Aim 3, this Project will investigate mechanisms by which loss of the phosphatase PTEN in hormone receptor-positive breast cancer cells results in activation of phosphatidylinositol-3 kinase (PI3K) and Akt signaling and generates autonomy from hormones and resistance to endocrine therapy.

Project 2: p63/p73 signaling axis as a target for treatment of triple negative breast cancer. This project will examine several hypotheses in breast cancers that lack hormone receptors and do not overexpress HER2, so called triple negative breast cancers. In triple negative tumors that express both p63 and p73, p63 promotes tumor cell survival through repression of p73. Therefore, the combined use of drugs that impinge on the p63/p73 signaling axis will have synergistic activity. In the remaining fraction of triple negative tumors that lack p63 expression but express p73, other pathways are selected for that abrogate p73 pro-apoptotic activity and thus promote tumor cell survival. The first Aim will determine the tumor response to neoadjuvant therapy with cisplatin, paclitaxel, and the mTOR inhibitor everolimus (RAD001) vs. cisplatin and paclitaxel in patients with triple negative breast cancer. In the second Aim, the applicants will use gene expression profiling to sub-classify triple negative cancers and identify p63 and p73 gene signatures that predict response to neoadjuvant therapy. The last Aim will return to preclinical studies to analyze a panel of insulin sensitizers for their ability to activate p73 and induce apoptosis alone or in combination with known chemotherapeutic agents in triple negative breast cancer cells and, in parallel, determine the mechanism by which p73 activity is stimulated.

Project 3: Cellular mechanisms of bone quality in metastatic breast cancer. This project will test the hypothesis that the biomechanical properties of bone at the tumor-bone interface in metastatic breast cancer is determined in large part by osteoblast differentiation. In breast cancer metastatic to bone, osteoblast differentiation and the ability to form new bone is impaired in major part by transforming growth factor (TGF) b. This alteration occurs regardless of the reduction of metastastic tumor cells with current therapies and thus limits their full impact on patients’ quality of life. Aim 1 will determine the effects of impaired TGFβ signaling on osteoblasts and fibroblasts by the use of mice with conditional knockout of the TGFβ type II receptor. This aim will provide direct information on the role of TGFβ signaling in osteoblasts and test the basic hypothesis. Aim 2 will examine the effects of neutralizing TGFβ antibodies on tumor burden in parallel with effects on bone quality, osteoblast differentiation, and bone structure in mice bearing human breast cancer cells to help in the design of clinical studies. Aim 3 will determine the effects of anti-TGFβ antibodies on parameters of bone turnover in phase I and II clinical trials in patients with breast cancer metastatic to bone.

Project 4: Genetic predictors of progression of premalignant breast disease. The objective of this study is to identify predictors of breast cancer by investigating how genetic variation within the ErbB and TGFb signaling pathways interact with histologically-defined preneoplastic mammary lesions to affect cancer risk. The project will study a unique cohort of 7,963 women who underwent biopsy for benign breast disease, 535 of whom have developed invasive breast cancer or ductal carcinoma in situ during a median follow-up of 16 years. Cohort projections indicate that the number affected by breast cancer will expand to 908 over the next 5 years. The cohort is accompanied by epidemiological data of established breast cancer risk factors, paraffin-embedded tissue blocks of the initial benign breast biopsy, and rigorous histological detail of both the initial biopsy and subsequent tumor. In the first two Aims, the role of genes in the ErbB and TGFb signaling pathways will be evaluated by linkage disequilibrium mapping. Aim 3 will identify candidate etiologic variants of haplotypes that are significantly associated with breast cancer risk in Aims 1 and 2. Aim 4 will focus on how genetic variation in the ErbB and TGFb signaling networks interacts with proliferative breast disease to affect breast cancer risk.

Core Resources. To support the research aims in the translational research projects, we propose five shared Core Resources. Each of these cores supports at least 3 projects in this competing renewal application (see F. Scientific Integration). They are Administration & Outreach, Tissue, Clinical, Biostatistics, and Imaging Cores. We should emphasize that these Cores do not duplicate pre-existing available resources at VICC or VUMC. The proposed Projects will require additional personnel and funded effort over the already maximally utilized personnel in equivalent institutional Core Resources.

Administration and Outreach Core

Director: Carlos L. Arteaga, MD, Core Co-Director, Anne Washburn, MPH

The Administration & Outreach Core supports SPORE projects and investigators by managing SPORE resources, communication and outreach, including fostering interaction among SPORE components and collaborators, other SPOREs, the patient and advocate community and the NCI. This management and support is accomplished through a series of oversight committees and organized administrative and scientific meetings of SPORE investigators, institutional representatives and external advisors. Specific functions of the Core include:

1. To monitor and manage financial resources
2. To create and prepare documents and reports to insure compliance with federal regulations and reporting requirements
3. To administer the Developmental Research (pilot project) and Career Development Programs
4. To organize all meetings, seminars, and travel related to Breast Cancer SPORE activities
5. To serve as a point of contact to all Cancer Center fund-raising related activities focused in breast cancer
6. To serve as a main point of contact to biotechnology and pharmaceutical companies

Tissue Core

Director: Melinda Sanders, MD, Core Co-Director, Bapsi Chak, MD

The primary mission of the Vanderbilt Breast SPORE Tissue Core is to provide investigators with human tissue samples collected and processed according to standard protocols. We also provide high quality histology services, including expertise in performance and interpretation of immunohistochemistry (IHC), construction of tissue microarrays, and bone histology.  The tissue core provides a centralized mechanism for performance of these services, preventing the inefficiencies of tissue acquisition by individual projects and the performance of IHC by inexperienced hands. We provide a direct link between surgeon, pathologist, and investigator.  

Specific Aims

To collect, process, bank, and distribute human breast tumor and matched normal tissue samples to investigators in the Vanderbilt-Ingram Cancer Center (VICC) Breast Cancer SPORE.

To perform quality control to ensure that the relevant tissue is supplied to the researcher and suitable for the planned research (not necrotic or involved by unsuspected disease processes).

To protect patient confidentiality through use of a pre-surgical consent form that specifically addresses use of extraneous tissue from a clinically indicated surgical procedure for research purposes through de-identification of specimens.

To work with the VICC Clinical & Research InformaticsResource to establish an informatics strategy for networking of requests, specimen tracking, extraction of clinicopathologic data relating to specimens of interest, and linkage to research data.

To provide expertise in bone histology and histomorphometry.

To provide laser capture microdissection services to Breast SPORE investigators.

To provide tissue microarray services to Breast SPORE investigators.

To provide expertise in developing, performing, and evaluating immunohistochemical (IHC) and FISH assays for Breast SPORE investigators, including IHC on tissue microarrays.

To provide expertise in evaluation of the histopathology of human breast tumor xenografts in mice.

Clinical Core

Director: Ingrid Mayer, MD

The distinctive feature of NCI’s SPORE program is its mandate to involve basic and clinical researchers in translational research. The Clinical Core provides the expertise and manpower required to ensure that clinical trials incorporate the latest insights into the biology of the disease into rigorously designed trials and to ensure that biological samples obtained from patients enrolled in these studies provide the greatest information possible. The Clinical Core builds upon the existing infrastructure of the Vanderbilt-Ingram Cancer Center (VICC) Clinical Trials Shared Resource (CTSR). The CTSR is dedicated to the research efforts of all VICC members. The VICC CTSR provides space and secretarial support for the Research Nurses, Regulatory Coordinator, Data Manager, and Tissue Procurement Specialist. It also provides a portion of the administrative and extra regulatory support that is necessary for all clinical trials. While facilities and equipment are available for the SPORE in Breast Cancer projects, personnel funded by the Cancer Center Support Grant (CCSG) are fully utilized. The Clinical Core personnel funded through the Breast Cancer SPORE will focus on the research activities described throughout this narrative. The intensive nature of the clinical trials conducted by the Breast Cancer SPORE - in terms of precisely timed interventions, the need for coordination of clinical intervention, radiological evaluation, specimen procurement, stabilization, and transport to the Tissue Core, and the need to ensure protection of patients safety and privacy while linking clinical and specimen databases - exceed the level of support provided by the VICC CTSR and necessitate a dedicated Clinical Core for the Breast Cancer SPORE. Accordingly, there is no overlap between CCSG and Breast Cancer SPORE funded personnel’s effort.

SPECIFIC AIMS

1. To provide assistance in the development and implementation of translational clinical trials conducted as part of the Vanderbilt Breast Cancer SPORE
2. To provide research nurse and data management support for these clinical trials
3. To ensure the safety of research subjects, adherence to institutional and federal regulatory requirements and compliance with protocol-specified activities
4. To oversee the timely and accurate entry of data into computerized data collection systems
5. To monitor accrual to the clinical trials conducted as part of this SPORE

Biostatistics Core

Director: Yu Shyr, PhD

The purpose of the Biostatistics Core is to provide professional expertise in statistics for all Vanderbilt University Breast Cancer SPORE projects, investigators, and participants.  Functions provided by this core include development of experimental designs, data quality control, statistical analysis and interpretation of findings, and collaboration on presentation of results.  To achieve these functions, the core director and core biostatisticians are constantly available to investigators, and are in regular contact with the project and pilot project leaders.

The Specific Aims of the Biostatistics Core are:

1. To provide study design and review all laboratory and animal studies, including feasibility assessment, power analysis, and sample size estimation.
2. To collaborate in projects data analysis, interpretation of results, and the writing of final study reports and manuscripts.
3. To work with the Clinical Core, Imaging Core, and Tissue Core in the development of research project database, to maintain data quality control and to ensure timely data capture.
4. To develop and evaluate statistical methods for experimental design and data analysis.

The Biostatistics Core support is required in all Breast Cancer SPORE studies.  Core personnel have worked and will continue to work closely with project leaders for assuring that Core provides state-of-the-art statistical support.

Imaging Core

Director: Thomas Yankeelov, PhD, Core Co-Director: Charles Manning, PhD

The overall goal of the Imaging Core is to develop, implement, optimize, and validate quantitative surrogate biomarkers of tumor treatment response.This Core will be dedicated to providing scientific and technical resources and support for non-invasive imaging of small animal models of cancer in vivo and is fundamental to the success of three of the four projects described in this application. Projects supported by the Imaging Core are directed at employing existing as well as novel, targeted therapies which will elicit molecular signatures that can be imaged via optical, SPECT, and PET methods and then complemented with the (downstream) physiological information obtained from ultrasound, MRI, and CT. In particular, Project 1 (PI: Arteaga) and Project 3 (PI: Pietenpol) will employ noninvasive molecular imaging metrics (FLT-PET, FDG-PET, Annexin-V microSPECT and optical) to assess tumor cell proliferation, glucose metabolism, and apoptosis in response to novel therapies. Project 2 (PI: Mundy) will employ noninvasive molecular imaging metrics (bioluminescence, fluorescence, and microSPECT/CT) to track breast cancer metastases to bone and assess bone quality.  In addition to providing the methods required by SPORE projects, the Imaging Core will develop techniques that can augment these studies as well as support developmental pilot projects.  The equipment and personnel needed to support research by investigators from within the SPORE will be provided by the Center for Small Animal Imaging (CSAI) (see Resources)). Funds obtained through the SPORE will support collaborations with expert imaging science faculty for the development and implementation of cutting edge imaging protocols; support for imaging system operators and technical staff who will handle animal preparation and monitoring as well as operate the instruments; support for data analysis and for quantitative image analysis customized to specific applications, including the co-registration and integration of multiple imaging modalities, histology and proteomics.

1. Provide non-invasive imaging metrics of tumor initiation, progression and treatment response to investigators in the Vanderbilt Breast SPORE.
2. Provide collaborations with expert imaging science faculty for the implementation of cutting edge imaging protocols to address each investigators goals. The Imaging Core will support experts in nuclear, optical, MRI, CT, and ultrasound imaging.
3. Provide support for data analysis and for quantitative image analysis customized to specific applications, including the co-registration and integration of multiple imaging modalities, histology and proteomics.

http://www.vicc.org/spores/breast/

The page is maintained by: Website Contact