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Last Updated: 08/23/19

SPORE in Breast Cancer

Vanderbilt University Medical Center

Principal Investigators:

Ingrid A. Mayer, MD, MSCI
Ingrid A. Mayer, MD, MSCI
Jennifer A. Pietenpol, PhD
Jennifer A. Pietenpol, PhD

PRINCIPAL INVESTIGATOR CONTACT INFORMATION

Ingrid A. Mayer, MD, MSCI
Ingram Professor of Cancer Research
Professor of Medicine
Co-Leader, VICC Breast Cancer Research Program
Division of Hematology/ Oncology
Vanderbilt University Medical Center/
Vanderbilt-Ingram Cancer Center
2220 Pierce Ave. 777 PRB
Nashville, TN 37232
phone: 615-936-2033
fax: 615-343-7602

Jennifer A. Pietenpol, PhD (contact PI)
Benjamin F. Byrd Jr. Professor of Oncology
Professor of Biochemistry and Otolaryngology
Director, Vanderbilt-Ingram Cancer Center
Executive Vice President for Research
Vanderbilt University Medical Center/
Vanderbilt-Ingram Cancer Center
2220 Pierce Ave. 698 PRB
Nashville, TN 37232
phone: 615-936-1374
fax: 615-936-1790

OVERVIEW

This is the third competing renewal application of the Vanderbilt-Ingram Cancer Center (VICC) SPORE in Breast Cancer, thanks to a very active and strong multidisciplinary VICC Breast Cancer Program that is robustly supported by the SPORE mechanism. Our overall goal remains the same: To conduct collaborative, multidisciplinary and mechanism-based translational research that will have the highest possible impact for women and men with or at risk for breast cancer. After internal and external planning and evaluation, we present four bi-directional translational projects addressing basic and clinical research questions of importance in human breast cancer: Projects 1 and 2 are continuation projects; Projects 3 and 4 are new projects that have evolved from two CEP awards in the current funding cycle. Our new Immunophenotyping Core (IPC), which includes innovative Immuno-PET imaging, along with the highly used Pathology and Tissue Informatics (PTIC), Biostatistics and Bioinformatics (BBC) and Administrative and Engagement Cores (AEC) give key support to SPORE investigators (Fig. 1). Six interventional therapeutic clinical trials are associated with the highly translational projects in this proposal, all based on extensive collaboration between world-class basic and clinical investigators.

Figure 1

PROJECTS

Project 1: Mechanisms of Resistance to Endocrine Therapy in ER+ Breast Cancer

Project Co-leaders:
Brent Rexer, MD, PhD (clinical);
Carlos L. Arteaga, MD (basic)

Co-investigators:
Ariella Hanker, PhD;
Ingrid A. Mayer, MD, MSCI;
Janet Piper (patient advocate)

Specific Aims:

Aim 1: To elucidate the mechanisms by which FGFR1 amplification confers resistance to the combination of fulvestrant and CDK4/6 inhibitors in ER+/FGFR amplified breast cancers

Aim 2: To conduct a randomized phase II trial of the ER downregulator fulvestrant plus palbociclib ± the pan-FGFR inhibitor erdafitinib in patients with ER+/FGFR-amplified metastatic breast cancer

Aim 3: To discover mechanisms of resistance to fulvestrant/palbociclib ± erdafitinib in organoids derived from tumors progressing in the clinical trial proposed in Aim 2

Figure 2

The Project 1 team profiled 155 HR+/HER2- early breast cancers from 143 patients treated with the aromatase inhibitor letrozole for 7-21 days before surgery (Science Translational Medicine 2017 PMC5723145). Whole-exome sequencing (WES) revealed a correlation between 8p11-12 and 11q13 gene amplifications, including FGFR1 and CCND1, respectively, and high on-treatment Ki67. Of note, FGFR1 is amplified in ~15% of early ER+ breast cancers where it is associated with early relapse following adjuvant tamoxifen therapy and poor patient outcome. Additionally, ctDNA data from patients enrolled in MONALEESA-2, the registration trial of ribociclib, a CDK4/6 inhibitor, showed that patients with FGFR1 amplification in ctDNA exhibited a progression-free survival of 10.6 months vs. 24.8 months in patients with wild-type FGFR1. Subsequent to these findings, Project 1 revealed that co-amplification of FGFR1 and CCND1 were associated with endocrine therapy and CDK4/6 inhibitor resistance, that could be reversed by treatment with FGFR1 and CDK4/6 inhibitors (Clin Cancer Res, 2017 PMID 29284706), and reported marked HR+/FGFR1-amplified patient-derived xenografts tumor regressions with fulvestrant, palbociclib (a CDK4/6 inhibitor) and erdafitinib (a pan-FGFR tyrosine kinase inhibitor) (Nat Commun, 2019 PMID 30914635). Based on the above preclinical data, in 2016, Dr. Mayer successfully competed for funding of a three-year Pfizer ASPIRE Breast Cancer Research Award entitled “Phase Ib trial of fulvestrant, palbociclib and erdafitinib in HR+/HER2-/FGFR-amplified metastatic breast cancer,” which now funds one of the highly translational, multi-institutional trials that will test the hypothesis that FGFR inhibitors should be tested in combination with ER antagonists and CDK4/6 inhibitors in patients with HR+/FGFR amplified breast cancer.

Project 2: Strategies to Improve Outcomes for Triple-Negative Breast Cancer Patients Integrating Subtype-Specific Genomic and Immune-Based Discoveries

Project Co-leaders:
Vandana G. Abramson, MD (clinical);
Jennifer A. Pietenpol, PhD (basic)

Co-investigators:
Brian Lehmann, PhD;
Alissa Weaver, MD, PhD;
Patricia “Patty” Lee (patient advocate)

Specific Aims:

Aim 1: To determine mechanisms by which standard chemotherapies modulate tumor immune response in combination with checkpoint immunotherapy

Aim 2: To determine mechanisms of immune-modulation in metastatic TNBC subtypes

Aim 3: To evaluate the feasibility of targeting the tumor microenvironment myeloid-derived cells

Figure 3

The Project 2 team is using the discovery framework of preclinical models, genomic tools and TNBC patient tumor biospecimens to achieve improved outcomes for TNBC patients through use of subtype-informed combination immunotherapy. In the prior trial “Randomized phase II neoadjuvant study of cisplatin and paclitaxel with or without everolimus in patients with TNBC” (NCT00930930; Clin Cancer Res, 2017 PMC5540799), they revealed that cisplatin caused increases in TILs in M subtype tumors, as 40.6% of tumors treated with cisplatin had increased PD-L1 expression. The increased PD-L1 expression provided the rationale for the initiation of a phase II clinical trial (NCT03206203) investigating the combination of carboplatin with the anti-PD-L1 antibody atezolizumab with intent to identify biomarkers of response, led by Dr. Abramson (BC). The collection and comprehensive analysis of the biospecimens relative to clinical response enables this project to test the hypothesis that patients receiving carboplatin in combination with atezolizumab will have a better response to PD-L1 treatment. If proven, would suggest carboplatin treatment inhibits MDSC- and Treg-mediated suppression of TIL infiltration.

Project 3: Targeting the DNA Damage Response in Breast Cancer

Project Co-leaders:
Vandana Abramson, MD (clinical);
David Cortez, PhD (basic)

Co-investigators:
Violeta Serra, PhD;
Kimberly Dahlman, PhD;
Deborah Lannigan, PhD;
Mark O’Connor, PhD;
Lynn Cargen (patient advocate)

Specific Aims:

Aim 1. Examine mechanisms of sensitivity/resistance to PARP inhibitors in breast cancer patients

Aim 2: Define basic mechanisms that regulate anti-DDR drug responses

Figure 4

A specific example of how BC translates important clinical problems to the lab and back to the bedside is highlighted here. Although PARP inhibitors are now approved for germline mutated BRCA1 and 2 metastatic disease, resistance to these drugs still occurs. David Cortez found that DNA replication fork protection is an important determinant of drug sensitivity and suggested that changes in RADX expression may be a mechanism driving drug resistance in patients treated with PARP inhibitors (Mol Cell, 2015 PMC4575883; Mol Cell, 2017 PMC5548441;). Based on these data, Vandana Abramson is co-leading a Breast SPORE project with Dr. Cortez to improve patient outcomes by defining the mechanisms by which homology-directed repair (HDR) proteins (such as BRCA1 and BRCA 2) regulate replication fork dynamics, understanding the contribution of replication fork dynamics to PARP inhibitor sensitivity, and identifying drug combinations that can be used to overcome PARP inhibitor resistance in vitro and in vivo. In a randomized clinical trial led by Dr. Abramson (BC), PARP inhibitor-resistant metastatic breast cancer patients will be treated with combinations of the PARP inhibitor olaparib and ATR or WEE1 inhibitors to directly test this hypothesis.

Project 4: Targeting Antigen Presentation to Improve Immunotherapy Responses in Breast Cancer

Project Co-leaders:
Ingrid A. Mayer, MD, MSCI (clinical);
Justin M. Balko, PharmD, PhD (basic)

Co-investigators:
Brent Ferrell, MD; Linda Horton (patient advocate)

Specific Aims:

Aim 1: Determine if MEKi-mediated antigen presentation upregulation predicts immunotherapy outcome in breast cancer patient tumors

Aim 2: Determine the mechanism whereby MEK suppresses anti-tumor immunity

Figure 5

The Project 4 team showed that MEK activation suppresses tumor cell surface MHC class I and II and PD-L1 expression in breast cancer. Conversely, inhibition of MEK enhanced these factors, blocked naïve CD8+ T cell priming, and protected CD8+TIL cytotoxicity by preventing apoptosis driven by chronic TCR stimulation (Clin Cancer Res, 2015 PMC4794351). In luminal-like breast cancer models (MMTV-neu and MMTV-PyVmT), a combination of MEK inhibition and PD-1/PD-L1 inhibitors induced profound anti-tumor effects . Based on these preliminary data, in 2016, Drs. Mayer and Hope Rugo, MD (UCSF) successfully competed for funding of a three-year Breast Cancer Research Fund (BCRF)-Pfizer award entitled “Immunotherapy combination strategies to treat TNBC: a multicenter, multi-arm Translational Breast Cancer Research Consortium (TBCRC) study”. This is a multicenter, open-label, four-arm phase II trial that will evaluate the anti-tumor effect of a PD-L1 inhibitor alone or in combination with either a MEK inhibitor, an OX40 agonist or a 41BB agonist in patients with metastatic TNBC. In 2017, Drs. Mayer and Balko were awarded a three-year Stand Up to Cancer (SU2C)-American Association for Cancer Research (AACR) Catalyst Research Grant titled “Immunotherapy Combination Strategies in ER+ Metastatic Breast Cancer.” This is a multicenter, open-label, two-arm phase Ib/II trial that will evaluate the safety and anti-tumor effect of a PD-L1 inhibitor in combination with a MEK inhibitor in patients with endocrine therapy-refractory TP53-mutated ER+ metastatic BC, and a PD-L1 inhibitor in combination with an MDM2 antagonist in patients with endocrine therapy-refractory TP53-wildtype ER+ metastatic BC (VICCBRE17017/ NCT03566485). These trials will test for synergy between MEK inhibition and anti-PD-L1 therapy, identify predictive biomarkers, as well as validate the clinical utility of new therapeutic combinations that promote anti-tumor immunity through enhancement of antigen presentation.

CORES

Administration and Engagement Core

Core Directors:
Jennifer Pietenpol, PhD;
Ingrid Mayer, MD, MSCI

Specific objectives: Management of SPORE resources, provision of quality control, and active communication and engagement, including fostering interaction amongst SPORE components and collaborators, other SPOREs, the patient and advocate community and the National Cancer Institute (NCI).

Biostatistics and Bioinformatics Core

Core Director:
Yu Shyr, PhD

Specific objectives: Development of experimental designs, power analysis and sample size estimation, data quality control, statistical/bioinformatics analysis and interpretation of findings, and collaboration on presentation of results.

Pathology and Tissue Informatics Core

Core Directors:
Melinda Sanders, MD;
Ben Park, MD, PhD

Pathology and Tissue Informatics Core

Specific objectives: Clinical trial-related tissue collection, procurement for the Vanderbilt Breast Tissue and Body Fluids Repository, provision of specialized technical and diagnostic histopathology services, informatics support (de-identification, histopathological and clinical annotation, tracking and distribution of breast tissues) for translational research by SPORE investigators, linking specimen-specific information to immunohistochemistry (IHC), and Next Generation Sequencing (NGS) data permitting queries to inform future investigations. Pathology assessments will be made by research and licensed clinical pathologists of the PTIC for clinical/correlative studies within all SPORE clinical trials. The PTIC will also manage the Breast SPORE TNBC Collaborative Atlas.

 

Immunophenotyping Core

Core Directors:
Young Kim, MD, PhD;
Jeffrey Rathmell, PhD

Immunophenotyping Core

Specific objectives: Provide state-of-the-art comprehensive assays that range from validated single cell sequencing of T cells for both α and β chain of TCR and validated Mass Cytometry by Time of Flight (CyTOF) assays; provide established immunological assays — ELISPOT, immunohistochemistry/immunofluorescence with digital quantitation, flow cytometry, Luminex-based cytokine profiling assays, and NGS; provide both immune-cellular phenotyping and immune-genomic phenotyping; support murine model preclinical studies that require immune-cellular phenotyping.

 

 

DEVELOPMENTAL RESEARCH PROGRAM

Directors:
Ingrid A. Mayer, MD, MSCI;
Jennifer A. Pietenpol, PhD;
Scott Hiebert, PhD;
Ben Ho Park, MD, PhD

During the current project period, the SPORE Developmental Research Program awarded 15 pilot projects to 14 investigators, of which four were junior faculty at the time of award. All are from nine primary departments in the School of Medicine (Department of Medicine, Biochemistry, Biostatistics, Chemistry, Biomedical Informatics, Cell and Developmental Biology; Pathology, Microbiology & Immunology, Pediatrics, Pharmacology) and six of the eight research programs at VICC (Signal Transduction & Chemical Biology, Host-Tumor Interactions, Genome Maintenance, Translational Research and Interventional Oncology, Breast Cancer, and Cancer Health Outcomes and Control). Although eight of the 15 projects were awarded at or after April 2016 and the PI of a ninth project was recruited to the University of Texas Health Science Center, three of the remaining awardees have obtained R01 or R01-equivalent grants for a combined amount of $2.5M (direct costs), $3.6M (total costs). This return in extramural grant dollars is impressive given the $667,149 overall investment made in the DRP. There are at least 27 published manuscripts supported by this research. Finally, all awardees have presented their research at SPORE monthly meetings or the VICC Breast Cancer Program and SPORE Monthly Series.

CAREER ENHANCEMENT PROGRAM

Directors:
Ingrid A. Mayer, MD, MSCI;
Jennifer A. Pietenpol, PhD;
W. Kimryn Rathmell, MD, PhD

During the current project period, the SPORE CEP supported 11 investigators (13 total awards): three physician-scientists and eight basic scientists from three Departments in the School of Medicine at Vanderbilt (Radiology and Radiological Sciences, Medicine, and Biochemistry), the Department of Biochemistry and Cancer Biology at Meharry Medical College and four research programs at VICC (Genome Maintenance, Translational Research and Interventional Oncology, Host-Tumor Interactions and Breast Cancer). Thirty publications have resulted from CEP awardees. Six of the awardees have obtained extramural grants for a total combined budget of over $6.8M (direct costs), $9.2M (total costs). This return in extramural grant dollars far surpasses the investment made in the CEP. In addition, two awardees are co-leaders in two of the translational projects in the proposed SPORE, two other awardees (Drs. Hanker and Lehmann) are working with project leaders as basic co-investigators and one awardee (Dr. Houghton) is working with core directors as a co-investigator.