Skip to Content
Translational Research Program (TRP)
Contact CIP
Show menu
Search this site
Last Updated: 02/21/17

Translational Research in Breast Cancer

Baylor College of Medicine

Principal Investigator:
C. Kent Osborne, MD-PI

OVERALL ABSTRACT

Translational research, adapting new laboratory findings quickly to improve prevention, quality of life, and survival for breast cancer patients, has been the focus of the team now forming the Baylor Breast Center for over 30 years. In the early years of our previous SPORE, our tumor bank which made much of this rapid translation possible became a national resource, while basic cell and molecular biology research suggested new clinical implications for endocrine and chemotherapy resistance, breast cancer prevention, metastasis, and development of premalignant lesions.

Developmental projects ranged even further in seeking new translational possibilities. In this new SPORE proposal, we build on our earlier results and on new findings and technologies, in four projects and several support components. (1) We have discovered that the mevalonate pathway is upregulated by anti-HER2 therapy and can serve as an escape pathway, leading to treatment failure. But several already approved agents (statins and bisphosphonates) can inhibit this pathway, and we will explore their mechanisms and their potential to overcome this treatment failure, both in preclinical studies and a clinical trial. (2) The steroid receptor coactivator SRC-3 is frequently overexpressed in breast cancer and promotes growth and endocrine resistance, especially when HER2 is also active. Finding that inhibiting upstream kinases PKC and PKD that support SRC-3 activity can suppress tumor growth and restore endocrine sensitivity, we propose to dissect the functions of these kinases on SRC-3 in defined preclinical models, and test the efficacy and safety of a PKC inhibitor added to endocrine therapy in a clinical trial. (3) Chemoprevention of breast cancer has had limited acceptance due to expense and concerns about side effects of long-term continuous treatment with existing agents. But we have now discovered that activated pSTAT5 blocks the apoptosis that is typically induced as a protective mechanism by activation of oncogenes, and that even short-term suppression of pSTAT5 with agents like ruxolitinib can cause regression of premalignant breast lesions and prevent progression to cancer in mice. In both mouse models and an early clinical trial, we will investigate this approach for effective intermittent chemoprevention. (4) Though immunotherapy promises exquisite specificity and safety, results have been disappointing as tumor cells alter targeted antigens and generate an immunosuppressive environment to escape. Here we propose to adoptively transfer T cells engineered to attack two tumor-associated antigens rather than one, and to express a chimeric receptor that causes the repressive cytokine IL4 to promote T cell cytotoxicity instead. Our unique, widely used breast Tissue Resource/Pathology Core, along with Biostatistics and Administrative Cores give key support to this SPORE. Our highly successful Developmental Projects and Career Development programs will continue to encourage new ideas and new investigators in translational breast cancer research.

Project 1: Targeting the Mevalonate Pathway to Overcome Resistance to Anti-HER2 Therapy

Project Co-Leaders
Rachel Schiff, Ph.D.
C. Kent Osborne, M.D.
Mothaffar Rimawi, M.D. (clinical)

We recently showed in preclinical models and now in patients in our recent neoadjuvant trial, that antiHER2 drug combinations, such as the monoclonal antibody trastuzumab plus the dual HER1/2 kinase inhibitor lapatinib (LT regimen), more completely inhibit the HER receptor network, and are highly effective, achieving substantially high rates of pathological complete response even without chemotherapy. However, even when HER signaling is completely abrogated, many tumors still acquire resistance. Therefore, it is important to understand resistance mechanisms and to identify well tolerated therapeutic strategies that can overcome or prevent this resistance. In this project we will investigate a novel approach to overcome resistance to HER2-targeted LT therapy based on our laboratory discovery that the mevalonate (MVA) pathway is one of the escape pathways that is activated in LT-resistant breast cancer cells, in which HER2 remains inhibited. In addition to cholesterol biosynthesis, the MVA pathway, via isoprenoid intermediates, can also generate cell proliferative and survival signals. Interestingly, we find that blocking this pathway with relatively non-toxic statins leads to remarkable growth inhibition and death of LT-resistant cells, while parental cells are only modestly affected.

We therefore hypothesize that the MVA pathway can function as an escape route in HER2+ breast cancer with intrinsic or acquired resistance to potent antiHER2 treatments, by providing alternative survival and proliferative stimuli to bypass sustained HER2 inhibition. We further hypothesize that targeting the MVA pathway will provide a novel therapeutic strategy to overcome antiHER2 treatment resistance. In Aim 1 we will evaluate the role of the MVA pathway in antiHER2 resistance in our diverse in vitro and in vivo models of resistance to HER2 targeted therapies and will identify predictive biomarkers for response to inhibitors of this pathway. In Aim 2 we will elucidate the molecular mechanisms by which the MVA pathway mediates survival. In Aim 3 we will investigate the predictive value of the MVA pathway for the clinical outcomes in our unique set of tumor specimens from our LT neoadjuvant trials, will assess in the ALTTO trial whether patients taking statins along with antiHER2 treatment have a better outcome, and will conduct a clinical trial to test the efficacy of statin in patients with metastatic disease who are resistant to antiHER2 drug combinations. If this study is successful, targeting the MVA pathway could provide a valuable new therapeutic strategy to overcome antiHER2 treatment resistance.

Project 2: PKC-mediated Inhibition of SRC-3 for the Treatment of ER+ Breast Cancer

Project Co-Leaders:
Bert O’Malley, M.D.
Mothaffar Rimawi, M.D.

Co-Investigators:
Nicholas Mitsiades, M.D., Ph.D.
David Lonard, Ph.D., Project

Steroid receptor coactivator-3/amplified in breast cancer-1 (SRC-3/AIB1) is frequently overexpressed in breast carcinomas and can promote cell growth and resistance to endocrine therapies. In breast carcinomas overexpressing SRC-3, especially when in combination with activated HER2 signaling, the selective ER modulator (SERM) tamoxifen functions as an ER agonist. ER+/HER2+ tumors have a very poor response to tamoxifen treatment if SRC-3 is also overexpressed. Experimental targeting of SRC-3 can both a) augment the anti-estrogenic and anti-proliferative activity of tamoxifen in hormone-naïve breast cancer cell lines, and b) restore the anti-estrogenic and anti-proliferative activity of tamoxifen in refractory breast cancer cell lines. Therefore, targeting SRC-3 expression and/or function is expected to enhance the activity of first-line conventional therapy and restore sensitivity in treatment-refractory breast cancer. Unfortunately, up to this point, SRC-3 has been considered “undruggable” because it lacks a natural ligand-binding site that can be inhibited by small molecule compounds and protein:protein interactions are difficult to disrupt. Importantly, the stability and activity of the SRC-3 protein are strongly regulated via its post-translational modification (PTM) by upstream kinase signaling networks, including protein kinase C (PKC). PKC family members can phosphorylate and protect SRC-3 from proteasome-mediated degradation. Given the critical role of SRC-3 in breast cancer and the lack of FDA-approved SRC-3 targeting agents, this proposal represents an innovative hypothesis-driven approach, based on key basic research and robust preclinical evidence, to establish PKC SMIs as first-in-class inhibitors of SRC-3 expression and function and as targeted therapies for use in combination with conventional agents for ER+ breast cancer. Preliminary studies demonstrate that PKC inhibitors (including agents that have been well-tolerated in clinical trials in other diseases) can, at clinically achievable and tolerated concentrations, decrease SRC-3 protein expression, exert anticancer activity in SRC-3-overexpressing cell lines, enhance the anticancer activity of endocrine therapy in sensitive cells lines, and restore sensitivity to endocrine therapy in resistant breast cancer cell lines and xenografts.

Project 3: Intermittent Ruxolitinib to Target STAT5 Activation for Breast Cancer Prevention

Project Co-Leaders:
Yi Li, Ph.D.
C. Kent Osborne, M.D.

The overall goal of this proposal is to test a novel concept in breast cancer prevention. Reducing breast cancer incidence can theoretically have a profound impact on saving lives and reducing the huge cost of treatment. Antiestrogens can prevent breast cancer, but they require prolonged treatment and can have significant side effects. Therefore, new preventive therapy that does not require years of continuous treatment is urgently needed. Premalignant lesions of the breast sometimes but not always progress to invasive cancer — what causes this small subset of premalignant lesions to progress is not yet known. Studies in several tissue types indicate that apoptosis is activated in human premalignant lesions as a result of oncogene overexpression and oncogene-induced aberrant proliferation, providing a barrier to progression to malignancy. This barrier must be overcome for early lesions to develop into full-blown cancer. In our preliminary studies using mouse models, we have found that Jak2-STAT5 signaling may be a key pathway that can break this anticancer barrier. Therefore, we hypothesize that the JAK2-STAT5 pathway in human premalignant lesions promotes the progression to malignancy by lowering the apoptosis anticancer barrier; if so, inhibition of this prosurvival pathway could reduce the load of premalignant lesions in the breast and thus lower breast cancer risk. We predict that even transient or intermittent inhibition of this pathway in early lesions could devitalize them and lower the risk of invasive breast cancer, while the possible adverse effects, cost, and inconvenience to women would be small.

Three aims are as follows:

Aim 1: Determine if STAT5 activation accelerates tumorigenesis of premalignant lesions induced by major oncogenic events associated with breast cancer.

Aim 2: Determine whether in rodent models short-term or intermittent administration of ruxolitinib causes apoptosis in pSTAT5-expressing early lesions and effectively prevents their progression to cancer.

Aim 3: Determine whether in women with a premalignant lesion on core biopsy requiring subsequent surgical resection, short-term ruxolitinib blocks pSTAT5 and induces apoptosis in the lesion.

Project 4: Evading Immune Escape Mechanisms in Dual-Targeted T-cell Therapy For Breast Cancer

Project Co-Leader:
Juan Vera, M.D.
Malcolm Brenner, MB Bchir, Ph.D.

Breast cancer and its microenvironment can directly subvert cytotoxic T cell immune responses. Thus, previous efforts to induce cell-mediated anti-tumor responses in vivo by vaccination have had limited success. We propose instead to adoptively transfer T cells that are engineered ex vivo to target the tumor and the tumor environment, and are armed with countermeasures to a potent tumor immune evasion strategy. In this application we propose to: 1) generate bi-specific T cells that simultaneously target two tumor-associated antigens, Her2 and Muc1, through native and chimeric receptors, thereby minimizing the impact of antigen and MHC modulation as a means of evading T cell recognition. 2) Next, we will assess the safety and function of these adoptively-transferred binary T cells in patients with refractory breast cancer. 3) Finally, to protect these ex vivo generated bi-specific T cells from the hostile tumor microenvironment, we have developed a novel chimeric cytokine receptor (4/7R). Transgenic expression of this chimeric 4/7R molecule allows the engineered T cells to utilize the suppressive Th2 cytokine IL4, produced at the tumor site, to instead promote the T cells’ expansion, persistence, and cytotoxic activity in vivo. The safety and anti-tumor activity of these tumor-resistant T cells will be tested clinically in patients with metastatic breast cancer. Our approach has a potentially outstanding pharmaco-economic profile since the clinical the benefits of T cell therapy can be sustained long-term, and should be associated with minimal toxicities. The Center for Cell and Gene Therapy (CAGT), and the Breast Cancer Center at Texas Medical Center are uniquely positioned to translate to the clinic the proposed studies given the knowledge, experience, and specialized infrastructure possessed by these centers.

Core A: National Tissue Resource And Pathology Core

Core Directors:
Carolina Gutierrez, M.D.
Susan G. Hilsenbeck, Ph.D.

Our previous SPORE had separate Cores for tissue collection/curation (old Core A: National Tissue Resource) and for pathologic evaluation (old Core C: Pathology), but in this new application they are combined in one Core, the National Tissue Resource and Pathology Core (NTRPC), since they are highly integrated and work closely with one another. The NTRPC also collaborates closely with Core B (Biostatistics and Data Management), which is responsible for informatics to manage inventory and annotation data.

The objectives of the NTPRC are: (1) To provide centralized support for acquisition, banking, management, and distribution of tissue within the SPORE, and to maintain and update the databases with annotation and follow-up associated with these tissues. We will manage and distribute tissue and data from legacy inventories to qualified researchers, inside and outside our SPORE; collect, quality control, manage, and distribute newly acquired breast cancer materials including clinical trial specimens to qualified researchers; and annotate materials already in the collections from appropriately consented subjects with additional clinical, pathologic and follow-up information. (2) To provide histologic assessment and quality control of these tissues, along with tissue-based studies such as IHC using these clinical specimens as well as mouse tissues from the preclinical experiments. We will quality control and perform accurate pathologic assessment of tumors; and coordinate and manage the pathology support for the SPORE projects, developing new assays as required and working with the investigators to determine the methodologies most appropriate for their needs.

The NTRPC is a continuation of two existing, well-functioning, and absolutely essential Cores. Although the guidelines state that “each SPORE must have a dedicated core for collection and distribution of human cancer specimens”, the NTRPC greatly surpasses this minimum requirement — it is critical not only for the research activities proposed in this SPORE, but it has been and will continue to be an important research resource to other scientists within and outside Baylor College of Medicine who are engaged in translational breast cancer research. In fact, over the past 20 years, 46,880 specimens have been distributed to more than 159 investigators/institutions around the country.

Core B: Biostatistics and Data Management

Core Directors:
Susan G. Hilsenbeck, Ph.D.
Lauren Becnel, Ph.D.

This is a continuation of an existing, well-functioning and absolutely essential Core. During the previous funding period the Core provided extensive biostatistical and data management support to all five projects, to both Core A (National Tissue Resource) and Core C (Pathology), and to several of the Developmental Projects, resulting in a total of 39 coauthored publications, many in high impact journals. All projects in our new SPORE application will require statistical support for a range of preclinical and clinical experiments. All four projects propose clinical trials, and we have a strong track record of electronic clinical trial data management for both small single institution trials and more complex randomized multi-institution trials. We also provide data management support to Core A (National Tissue Resource). Indeed, new informatic development in support of banking and clinical annotation, undertaken and cost shared with several other large projects, will be a major focus in the new funding period. In our experience, centralized biostatistical and informatics support ensures that the biostatisticians and informatics professionals are completely familiar with all aspects of the Projects and Cores. This provides continuity, increases efficiency, and ensures that appropriate methods are applied. The specific aims are to: (1) Provide comprehensive biostatistical and bioinformatics consultation, experimental design, data analysis and reporting; (2) Provide comprehensive support for design, conduct and analysis of clinical trials, including assistance with data quality, interim monitoring and analysis, final analysis, and reporting; (3) Develop and maintain databases, and database and web applications in support of Projects and Cores.

The SPORE benefits greatly from having a dedicated and experienced team with a range of skills. The Core can also draw flexibly on the resources and personnel in the Cancer Center Biostatistics and Informatics Shared Resource to augment expertise, or alter access to resources as needs change. Sample size considerations, experimental designs, and overviews of planned analyses for all projects were prepared in collaboration with the Core. In addition, deep understanding of SPORE data and analysis needs, in turn, drives database and application development, ensuring that informatic solutions meet the broad, as well as project-specific, needs of the SPORE. A hallmark of SPOREs is flexibility to terminate futile studies and pursue new leads. With dedicated Core personnel, we can also help investigators design new studies and test new hypotheses that may arise by cross-fertilization of these related projects.

Core C: Administration

Core Director:
C. Kent Osborne, M.D.

Our Breast SPORE consists of four full research projects as well as developmental projects, career development, and specialized core resources. An Administrative Core is needed to efficiently utilize administrative personnel and to provide common services for these projects and cores. Dr. C. Kent Osborne, as Principal Investigator of the SPORE, will direct this Administrative Core.

The Core will support communication and integration among SPORE members, organize regular SPORE membership meetings as well as conferences and seminars, and assist in coordinating clinical trials management within the SPORE projects. The Core also provides a pool of services which are common to all components of the SPORE, including: financial administration of grant funds and the Director’s discretionary funds, organization of conferences and seminars, administrative processing of review and funding of Developmental Projects, management and review of Developmental Projects, coordination of travel, report preparation, monitoring Human Subjects training, conflict of interest reporting and management, and assurance of compliance with all NIH and institutional grant regulations. The Core will also coordinate the services of our Internal Advisory Board and Advocates Committee, and arrange for the visits of our External Advisory Board members to review our progress and make recommendations.

In summary, consolidation of common support and administrative functions relieves individual projects of many minor but important tasks, and assures quality control in record-keeping, services, and compliance issues. Core personnel are highly experienced, and the Core provides well-organized and cost-effective support to all components of the SPORE

Career Enhancement Program

Program Director:
Gary C. Chamness, Ph.D.

The purpose of this Career Enhancement Program is to support promising investigators who will participate in translational breast cancer research projects. There are one to two awardees at any one time, who may be either MD's or PhD's. Candidates are selected based on their previous accomplishments and their potential and desire to pursue a career in academic breast cancer research. While our primary focus is to support promising young investigators at the junior faculty level, it is possible that more established investigators may also be appropriate for support.
The general outline of each awardee’s research will have been discussed by the applicant and the Selection Committee as a part of the selection process, and a principal mentor from the Program Faculty will be agreed upon. Awardees will receive further guidance from the Executive Committee and the selected mentor in developing their translational research projects throughout the award period. They will also participate in an extensive set of seminars, professional development courses, and clinical opportunities.

The research environment at the Baylor Breast Center is ideal for supporting translational activities. Scientific excellence in breast cancer research continues to be reaffirmed by the award of both individual and collaborative grants, while both national and local programs of clinical investigation are well established at the Baylor Breast Center and can serve to assist in the translation of research findings into clinical practice. This is an excellent setting for enhancing and focusing the careers of outstanding investigators on productive translational research in breast cancer. Indeed, of the 17 young investigators who received partial support from this program in the 21 years of our previous SPORE, most are active in academic research positions in breast cancer, and two have important roles in this new SPORE proposal.

Developmental Research Program

Program Director:
Gary C. Chamness, Ph.D.

To enable SPORE investigators to rapidly develop new research opportunities which could translate into early benefits for breast cancer patients, and to allow for exploration of new techniques which may require substantial efforts but which are nevertheless not ready for full scale multi-year research funding, we have devoted considerable effort and resources to this SPORE Developmental Research Program. The Executive Committee, together with the advocate members and the Internal Advisory Board, selects proposals for funding as Developmental Projects, based on their scientific merit and relevance to SPORE translational goals.

Through the funding of pilot projects, we broaden the scope of research, and allow exploration of high-risk ideas that have the potential for high yields in treatment, prevention, or basic biology of breast cancer. We also attract new investigators with a wide variety of special expertise to apply their expertise to problems and questions in breast cancer research, and we catalyze productive collaborations in which individual skills and approaches combine to create progress that no single investigator could achieve alone. It is important to point out that, although only $50,000 per year is requested from SPORE funds for this program, the Dan L. Duncan Cancer Center is contributing an additional $50,000 per year in recognition of the value of this outreach effort to cancer research in general.

During the 21 years of our previous Breast SPORE, initiated in 1992, we funded 97 developmental projects, contributing to 120 publications and providing essential preliminary data for 77 funded grants plus several still pending (including new Projects 3 and 4 in this new SPORE proposal). This mechanism complements the larger and longer-term regular research projects, offering a degree of flexibility which leads to enhanced productivity for the SPORE as a whole.

INTERNAL ADVISORS

Jeff Rosen, Melissa Bondy, Helen Heslop, Michael Ittmann, Nancy Weigel

EXTERNAL ADVISORS

Myles Brown-Dana Farber; Powel Brown-MDACC, Nancy Davidsonn-U of Pittsburgh, Patrick Hwu-MDACC, Gordon Mills-MDACC, Mark Pegram-Stanford

Advocates

Susan Rafte, Jane Marmion