Collaborative Research Efforts in Breast Cancer: The Fuqua Baylor College of Medicine and Beyond

Breast cancer remains a significant health challenge for women worldwide. It is the most commonly diagnosed cancer and the second leading cause of cancer-related death in women. Approximately 155,000 women in the United States have metastatic breast cancer (mBCa), and the median overall survival in this setting is three years. A critical need exists for targeting additional mechanisms alone or in combination with antiestrogens to enhance therapeutic response and provide these patients with better outcomes. To tackle this challenge, collaborative research efforts are crucial. This article explores the collaborative research efforts, particularly focusing on Context Therapeutics' strategic research collaborations, including the work being done at Baylor College of Medicine with Dr. Suzanne Fuqua, and other institutions, to advance the understanding and treatment of breast cancer.

Context Therapeutics' Strategic Research Collaborations

Context Therapeutics, a clinical-stage biopharmaceutical company, is dedicated to creating new medicines to treat hormone-responsive cancers. Recognizing the importance of understanding the role of progesterone receptor (PR) signaling in overcoming resistance mechanisms underlying metastatic breast cancer (mBCa), Context Therapeutics has signed multiple research collaborations with key leaders in the progesterone and breast cancer fields. These collaborations include Dr. Carol Lange, PhD at University of Minnesota and Dr. Suzanne Fuqua, PhD at Baylor College of Medicine, both of whom also serve as Scientific Advisory Board members at Context. Additional academic collaborations include the laboratories of Dr. Sarat Chandarlapaty, MD, PhD at Memorial Sloan Kettering Cancer Center, Dr. Geoffrey Greene, PhD at University of Chicago and Dr. Seema Khan, MD at Northwestern University.

Apristor: A Novel Approach to Breast Cancer Treatment

Context Therapeutics is pursuing an innovative approach to the treatment of advanced breast cancer by blocking both ER and PR, the primary drivers of HR+ mBCa disease progression, through the combination of Apristor, a unique PR full antagonist, with the antiestrogen Falsodex® (fulvestrant). Up to 60% of breast cancer patients are believed to be PR+. Apristor is an investigational medicine that has completed Phase 1 development and will be further evaluated in an upcoming randomized, placebo-controlled Phase 2 trial in second-line metastatic breast cancer patients who are PR+ and have failed prior antiestrogen therapeutic with or without the addition of a Cdk4/6 inhibitor. Apristor has established efficacy as an antitumor agent in this setting, as well as in multiple preclinical breast cancer models and exhibits additive/synergistic effects with antiestrogens, providing a strong rationale for this combination.

A Phase 2 clinical trial in advanced breast cancer patients with Apristor in combination with Fulvestrant in 2L therapy is planned. The randomized, double-blind, placebo-controlled study will be powered to show efficacy with Apristor added to the standard of care (Fulvestrant) versus the standard of care alone.

Focus of Collaborative Research

The research at the above academic centers will focus on expanding the understanding of mechanisms underlying resistance in breast cancer and novel therapeutic combinations that could be useful in treating advanced breast cancer with Apristor. Under the terms of the collaborations, Context will provide Apristor and collaborate with the research groups. While it is well known that Apristor is a unique PR antagonist that inhibits both ligand-dependent and growth factor induced PR activities, access to the drug for basic research purposes has been historically limited. Context is providing the compound to key interested academic partners with the aim of advancing breast cancer research and understanding the role of PR signaling in mammary tumors and other indications.

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Dr. Suzanne Fuqua's Research at Baylor College of Medicine

Dr. Suzanne Fuqua, a Professor of Medicine and Molecular and Cellular Biology at Baylor College of Medicine, is a key collaborator in Context Therapeutics' research efforts. Her research focuses on overcoming resistance to therapies to prevent metastasis of estrogen receptor-positive breast cancer. When breast cancer spreads to other tissues, it often loses its sensitivity to anti-cancer drugs. For the most common type of breast cancer, estrogen receptor (ER)-positive, mutations in the ESR1 gene are a cause of resistance to anti-estrogen therapies called aromatase inhibitors (AI) and promote metastasis.

Addressing ESR1 Mutations and Drug Resistance

Dr. Fuqua’s research is focused on finding ways to counter the effect of mutated ESR1 to improve treatment and prevention strategies for metastatic breast cancer (MBC). Her work could lead to new, more effective ways of managing ER-positive MBC. Dr. Fuqua and her team previously discovered that mutations in the ESR1 gene are the major drivers in the development of drug resistance leading to metastasis. Their research has also uncovered a key weakness in these cancers: they are highly sensitive to drugs that target DNA repair, like FDA-approved PARP inhibitors. When combined with standard hormone therapy in laboratory models, these treatments significantly reduce tumor growth and results suggest they may prevent further spread. This promising approach could give women with ESR1 mutations more effective options to extend and improve their lives.

Future Directions

Dr. Fuqua and her team are now using cutting-edge technology to further understand why these treatments work so well and how to make them even more powerful. By analyzing how tumors evolve from their original form to metastatic disease, they have discovered that certain genes become abnormally active, helping cancer spread. They are testing new therapies that can shut down these genes using both gene-silencing techniques and small molecule drugs. These next steps may help identify precise, personalized treatments to stop ESR1 mutant breast cancer from progressing. The main goal of her research is to determine the role of specific somatic mutations in estrogen receptor alpha, called K303R and Y537N, in the clinical problem of hormone resistance. Dr. Fuqua was the first to discover alternatively spliced transcriptional isoforms and somatic mutations in breast tumors. She has determined that the K303R mutation alters many aspects of hormone action, including binding to co-regulatory proteins, enhanced stability, estrogen hypersensitivity, response to tamoxifen, and resistance to the aromatase inhibitor anastrozole. Her team discovered the Y537N mutation, a constitutionally active receptor in metastatic tumors. A major goal of her laboratory is to develop novel therapeutics to target these alterations in ER alpha to restore hormone sensitivity, as well as to identify other novel mechanisms of resistance.

Baylor College of Medicine's Breast Cancer SPORE

Baylor College of Medicine is also home to a Specialized Programs of Research Excellence (SPORE) grant focused on breast cancer research. Lack of progress in curing metastatic breast cancer is due to a number of fundamental treatment barriers. These include insufficient knowledge of therapeutic vulnerabilities, lack of reliable predictive biomarkers, inability to target common tumor suppressor gene loss, inability to target oncogenes that are not protein kinases or ligand- dependent transcription factors, resistance due to clonal evolution and tumor heterogeneity, and failure to mount an immune response against the tumor. This Specialized Programs of Research Excellence (SPORE) renewal focuses on these obstacles by articulating cross-cutting objectives and aligned approaches that increase the efficiency of core utilization and promote inter-project collaboration.

The SPORE program at Baylor includes multiple projects aimed at overcoming these barriers. The three full Projects include studies on how to target the de-repressed kinases consequent upon loss of the PTPN12 or the NF1 tumor suppressors in breast cancer, as well as the development of a promising new therapeutic approach for MYC-positive breast cancer. During the execution of these Projects we will:deploy proteogenomic approaches for monitoring kinase targets and resistance pathways;establish high-quality biomarkers for clinical trial eligibility and stratification;investigate disease-monitoring approaches with circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA);incorporate immunological approaches into treatment regimens by increasing the quality and quantity of tumor infiltrating lymphocytes;embed our SPORE biomarker program into early phase clinical trials to inform the design of Phase 3 trials; andpromote collaborative research between Academia, NCI-Supported Cooperative Groups, Industry, and Advocacy Groups.

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Projects within the SPORE Program

Several projects are ongoing within the SPORE program at Baylor, including:

Project 1: Co-Targeting ER and Kinome Deregulation in Breast Cancers with Neurofibromin Deficiency: This project investigates the hypothesis that NF1-deficient ER+ breast tumors should be treated by a SERD combined with inhibitors that block the Ras-Raf pathway.
Project 3: Targeting Endoplasmic Reticulum Stress Sensor IRE1 to Enhance Chemotherapy Sensitivity in MYC-driven breast cancer: This project aims to design and open a phase 2 clinical trial in MYC-positive metastatic breast cancer.
Project 4: Advancing Toward TRAILBLASER: A Trial of TRAIL-R2/HER2 CART for Metastatic Breast Cancer: Our overarching hypothesis is that co-expressing T2B, IL15, and iC9 in HER2 CART cells (H2.T2B.15 CART) will result in a safe and effective treatment for stage IV HER2-expressing BC.

Core Facilities Supporting the SPORE

These objectives are served by three reformatted Cores. We are adding a dedicated and highly-qualified molecular research pathologist for the Pathology and Biobanking Core, deeper bioinformatics expertise to the Informatics and Biostatistics Core, and a new SPORE director. We are also providing additional advocates and advisory board members for the Administration Core. The Career Enhancement and Developmental Research Programs will be guided by highly experienced leadership and, as before, they will cement the future of our SPORE. With this powerful enhanced program, we will advocate nationally for progress in the treatment of advanced breast cancer, with the conviction that a cure is a near-term possibility.

Administrative Core: The Administrative Core is charged with facilitating communication and sustaining integration among the SPORE members and projects, as well as providing efficient support services for all the SPORE components, in order to maximize synergy in achieving our translational research goals.
Informatics and Statistics Core: The Informatics and Statistics Core (ISC) will provide three broad types of services:Comprehensive biostatistical consultation, experimental design, data analysis and reporting;Integrative proteome-genomic bioinformatic consultation, experimental design, data analysis and reporting;Development, customization, integration, and maintenance of databases and data management systems to support data management needs of SPORE projects and cores.
Pathology and Biobanking Core: The Pathology and Biobanking Core will provide the following services to projects and integration with other cores in this proposal:A centralized resource to acquire, store, and utilize human biospecimens for cancer research;To coordinate and manage the pathology activities of this SPORE project, and ensure that Project Investigators have ready access to specialized pathology expertise and interpretation; andTo design and validate biomarker-based tests (genomic and/or proteomic) that support all project stages, including clinically-validated and reported assays for SPORE-based clinical trials.
Developmental Research Program: In order 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.
Career Enhancement Program: Awardees 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.

ER-β Expression and Tamoxifen Response

Research has also focused on the role of estrogen receptor beta (ER-β) in breast cancer. For more than 30 years, the classical estrogen receptor, called ER-α, has been extensively studied as a prognostic and predictive marker in clinical breast cancer, making this nuclear receptor the most valuable target for the treatment of human breast cancer with selective estrogen receptor modulators or the newer generation aromatase inhibitors. Patients with ER-α-positive tumors have a significantly prolonged overall and recurrence-free survival with selective estrogen receptor modulators (1) and aromatase inhibitor therapy (2). Our understanding of ER in breast cancer became less clear with the identification of a second related ER isoform called ER-β (3, 4).

ER-β as a Predictor of Tamoxifen Response

A study involving 305 patients with axillary node-positive tumors examined the association between ER-β expression and clinical outcome. The study found that high levels of ER-β predicted an improved disease-free and overall survival in patients treated with adjuvant tamoxifen therapy. These findings provide evidence that ER-β may be an independent predictor of response to tamoxifen in breast cancer.

Methods Used in ER-β Research

To assess whether ER-β expression is associated with clinical outcome, protein levels were measured by immunoblot analysis of a retrospective bank of tumor cell lysates from 305 axillary node-positive patients. A total of 119 received no adjuvant therapy, and 186 were treated with tamoxifen only. The median follow-up time was 65 months. Univariate and multivariate Cox regression modeling was done to assess the prognostic and predictive significance of ER-β expression. A cohort of frozen primary breast tumor specimens from 305 axillary lymph node-positive patients was selected from the tumor bank of The Breast Center, Baylor College of Medicine, for use in the immunoblot study. This study was approved by the Baylor College of Medicine Institutional Review Board. This patient cohort has previously been evaluated for expression of other clinical variables (19, 20). Proteins were extracted from the tumors as described previously (21). Briefly, 30 mg of pulverized tumor powder were solubilized in 300 μL of 5% SDS at 90°C for 5 minutes and centrifuged at 13,000 × g for 5 minutes. Protein concentrations of the supernatants were determined using the bicinchoninic acid method (Pierce, Rockford, IL). Typical protein yields were 2 to 5 μg/μL. We have previously shown that MCF-7 human breast cancer cells express full-length ER-β protein corresponding to the 530 amino acid isoform (22). Thus, MCF-7 extracts (also stored at −70°C) were used as a standard on each gel to correct for gel to gel variations. MCF-7 cell lysates were prepared the same as the patient tumor samples. ER-β expression levels were measured by an investigator that was blinded to all of the clinical information. The extracted proteins were solubilized in sample buffer [0.05 mol/L Tris (pH 6.8) containing 2% SDS, 2.5% β-mercaptoethanol, 10% glycerol, and 0.1% bromphenol blue as tracking dye] and placed in boiling water for 2 minutes, cooled to room temperature, and centrifuged at 13,000 × g for 1 minute. For immunoblotting, SDS-PAGE was done with precast 8% Tricine-Glycine polyacrylamide gels (Invitrogen, Carlsbad, CA) with 20 μg of extracted protein from the tumor lysates and 10 μg of protein from the MCF-7 standard extract per gel, and then the proteins were transferred onto nitrocellulose (Schleicher and Schuell, Keene, NH) at 4°C overnight at 20 mA. The immunoblots were blocked with 5% nonfat dry milk in TBST [Tris-buffered saline, 100 mmol/L Tris (pH 7.5), 0.9% NaCl, and 0.1% Tween 20] and then incubated for 1 hour with the primary ER-β-specific antibody (1:200 mouse clone anti-14C8, GeneTex, San Antonio, TX), which does not recognize ER-α protein (11), followed by washing three times in TBST, and then incubated for 1 hour with horseradish peroxidase-labeled antimouse IgG (1:2000; Amersham Pharmacia Biotech, Piscataway, NJ). After extensive washing in TBST, ER-β protein was then visualized on a FluorChem digital imaging system (α Innotech, San Leandro, CA) with an enhanced chemiluminescence detection system. Total ER and PR levels were measured by ligand-binding assay as described elsewhere (23). Briefly, cytosolic proteins were extracted from tumor tissues that had been pulverized in liquid nitrogen. Iodine-125-labeled estradiol and tritiated-ORG 2058 (Amersham Pharmacia Biotech) addition allowed for the simultaneous determination of both ER and progesterone receptor (PgR) levels in a standard multipoint dextran-coated charcoal assay. Tumors with an ER content of at least 3 fmol/mg protein and with a PgR content of at least 10 fmol/mg protein were considered positive for ER and PgR, respectively.

Correlation of ER-β with Clinical Variables

Expression of ER-β protein did not correlate significantly with any other clinical variables, including ER and progesterone levels (as measured ligand binding assay), tumor size, age, or axillary nodal status. In the untreated population, those patients whose tumors who expressed both receptor isoforms exhibited the most favorable outcome as compared with those patients who had lost ER-α expression. However, there was no association between ER-β levels alone and either disease-free or overall survival in the untreated patient population.

The Broader Landscape of Breast Cancer Research

Beyond the specific collaborations and research efforts highlighted above, numerous other institutions and researchers are dedicated to advancing breast cancer research. These efforts span a wide range of areas, including:

Identifying new drug targets: Researchers are constantly seeking to identify new molecules and pathways that can be targeted to disrupt cancer cell growth and survival.
Developing novel therapies: This includes the development of new drugs, immunotherapies, and other treatment modalities.
Improving early detection methods: Early detection is crucial for improving outcomes, and researchers are working to develop more sensitive and accurate screening methods.
Understanding the genetic and environmental risk factors for breast cancer: Identifying these factors can help to develop strategies for prevention and risk reduction.

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