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  1. Article ; Online: Unique macrophage phenotypes activated by BMP signaling in breast cancer bone metastases.

    Ihle, Claire L / Straign, Desiree M / Canari, Johana A / Torkko, Kathleen C / Zolman, Kathryn L / Smith, Elizabeth E / Owens, Philip

    JCI insight

    2024  Volume 9, Issue 1

    Abstract: Metastatic breast cancer (mBC) tissue in bone was systematically profiled to define the composition of the tumor microenvironment. Gene expression identified a high myeloid signature of patients with improved survival outcomes. Bone metastases were ... ...

    Abstract Metastatic breast cancer (mBC) tissue in bone was systematically profiled to define the composition of the tumor microenvironment. Gene expression identified a high myeloid signature of patients with improved survival outcomes. Bone metastases were profiled by spatial proteomics to examine myeloid populations within the stroma that correlated with macrophage functions. Single-cell spatial analysis uncovered macrophage activation in the stroma of mBC bone lesions. Matched BC patient samples of primary breast tumor and bone metastasis tissues were compared for gene expression in the bone, where bone morphogenetic protein 2 (BMP2) was most significantly upregulated. Immune cell changes from breast to bone demonstrated a loss of lymphoid cells but a consistent population of macrophages. BMP-activated macrophages were increased uniquely in bone. Bone marrow-derived macrophage activation coupled with BMP inhibition increased inflammatory responses. Using experimental mouse models of mBC bone metastasis and trained immunity, we found that BMP inhibition restricts progression of metastases early in the macrophage activation state but not after tumors were established in the bone. This study revealed unique myeloid BMP activation states that are distinctly integrated with bone metastases.
    MeSH term(s) Animals ; Female ; Humans ; Mice ; Bone and Bones ; Bone Neoplasms/secondary ; Breast Neoplasms/pathology ; Macrophages ; Phenotype ; Tumor Microenvironment ; Bone Morphogenetic Proteins/metabolism
    Chemical Substances Bone Morphogenetic Proteins
    Language English
    Publishing date 2024-01-09
    Publishing country United States
    Document type Journal Article
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.168517
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Phase II trial of fulvestrant plus enzalutamide in ER+/HER2- advanced breast cancer.

    Elias, Anthony D / Spoelstra, Nicole S / Staley, Alyse W / Sams, Sharon / Crump, Lyndsey S / Vidal, Gregory A / Borges, Virginia F / Kabos, Peter / Diamond, Jennifer R / Shagisultanova, Elena / Afghahi, Anosheh / Mayordomo, Jose / McSpadden, Tessa / Crawford, Gloria / D'Alessandro, Angelo / Zolman, Kathryn L / van Bokhoven, Adrie / Zhuang, Yonghua / Gallagher, Rosa I /
    Wulfkuhle, Julia D / Petricoin Iii, Emanuel F / Gao, Dexiang / Richer, Jennifer K

    NPJ breast cancer

    2023  Volume 9, Issue 1, Page(s) 41

    Abstract: This clinical trial combined fulvestrant with the anti-androgen enzalutamide in women with metastatic ER+/HER2- breast cancer (BC). Eligible patients were women with ECOG 0-2, ER+/HER2- measurable or evaluable metastatic BC. Prior fulvestrant was allowed. ...

    Abstract This clinical trial combined fulvestrant with the anti-androgen enzalutamide in women with metastatic ER+/HER2- breast cancer (BC). Eligible patients were women with ECOG 0-2, ER+/HER2- measurable or evaluable metastatic BC. Prior fulvestrant was allowed. Fulvestrant was administered at 500 mg IM on days 1, 15, 29, and every 4 weeks thereafter. Enzalutamide was given at 160 mg po daily. Fresh tumor biopsies were required at study entry and after 4 weeks of treatment. The primary efficacy endpoint of the trial was the clinical benefit rate at 24 weeks (CBR24). The median age was 61 years (46-87); PS 1 (0-1); median of 4 prior non-hormonal and 3 prior hormonal therapies for metastatic disease. Twelve had prior fulvestrant, and 91% had visceral disease. CBR24 was 25% (7/28 evaluable). Median progression-free survival (PFS) was 8 weeks (95% CI: 2-52). Adverse events were as expected for hormonal therapy. Significant (p < 0.1) univariate relationships existed between PFS and ER%, AR%, and PIK3CA and/or PTEN mutations. Baseline levels of phospho-proteins in the mTOR pathway were more highly expressed in biopsies of patients with shorter PFS. Fulvestrant plus enzalutamide had manageable side effects. The primary endpoint of CBR24 was 25% in heavily pretreated metastatic ER+/HER2- BC. Short PFS was associated with activation of the mTOR pathway, and PIK3CA and/or PTEN mutations were associated with an increased hazard of progression. Thus, a combination of fulvestrant or other SERD plus AKT/PI3K/mTOR inhibitor with or without AR inhibition warrants investigation in second-line endocrine therapy of metastatic ER+ BC.
    Language English
    Publishing date 2023-05-20
    Publishing country United States
    Document type Journal Article
    ISSN 2374-4677
    ISSN 2374-4677
    DOI 10.1038/s41523-023-00544-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Induction of ADAM10 by Radiation Therapy Drives Fibrosis, Resistance, and Epithelial-to-Mesenchyal Transition in Pancreatic Cancer.

    Mueller, Adam C / Piper, Miles / Goodspeed, Andrew / Bhuvane, Shiv / Williams, Jason S / Bhatia, Shilpa / Phan, Andy V / Van Court, Benjamin / Zolman, Kathryn L / Peña, Brisa / Oweida, Ayman J / Zakem, Sara / Meguid, Cheryl / Knitz, Michael W / Darragh, Laurel / Bickett, Thomas E / Gadwa, Jacob / Mestroni, Luisa / Taylor, Matthew R G /
    Jordan, Kimberly R / Dempsey, Peter / Lucia, M Scott / McCarter, Martin D / Del Chiaro, Marco / Messersmith, Wells A / Schulick, Richard D / Goodman, Karyn A / Gough, Michael J / Greene, Casey S / Costello, James C / Neto, Antonio Galveo / Lagares, David / Hansen, Kirk C / Van Bokhoven, Adrie / Karam, Sana D

    Cancer research

    2021  Volume 81, Issue 12, Page(s) 3255–3269

    Abstract: Stromal fibrosis activates prosurvival and proepithelial-to-mesenchymal transition (EMT) pathways in pancreatic ductal adenocarcinoma (PDAC). In patient tumors treated with neoadjuvant stereotactic body radiation therapy (SBRT), we found upregulation of ... ...

    Abstract Stromal fibrosis activates prosurvival and proepithelial-to-mesenchymal transition (EMT) pathways in pancreatic ductal adenocarcinoma (PDAC). In patient tumors treated with neoadjuvant stereotactic body radiation therapy (SBRT), we found upregulation of fibrosis, extracellular matrix (ECM), and EMT gene signatures, which can drive therapeutic resistance and tumor invasion. Molecular, functional, and translational analysis identified two cell-surface proteins, a disintegrin and metalloprotease 10 (ADAM10) and ephrinB2, as drivers of fibrosis and tumor progression after radiation therapy (RT). RT resulted in increased ADAM10 expression in tumor cells, leading to cleavage of ephrinB2, which was also detected in plasma. Pharmacologic or genetic targeting of ADAM10 decreased RT-induced fibrosis and tissue tension, tumor cell migration, and invasion, sensitizing orthotopic tumors to radiation killing and prolonging mouse survival. Inhibition of ADAM10 and genetic ablation of ephrinB2 in fibroblasts reduced the metastatic potential of tumor cells after RT. Stimulation of tumor cells with ephrinB2 FC protein reversed the reduction in tumor cell invasion with ADAM10 ablation. These findings represent a model of PDAC adaptation that explains resistance and metastasis after RT and identifies a targetable pathway to enhance RT efficacy. SIGNIFICANCE: Targeting a previously unidentified adaptive resistance mechanism to radiation therapy in PDAC tumors in combination with radiation therapy could increase survival of the 40% of PDAC patients with locally advanced disease.
    MeSH term(s) ADAM10 Protein/antagonists & inhibitors ; ADAM10 Protein/genetics ; ADAM10 Protein/metabolism ; Amyloid Precursor Protein Secretases/antagonists & inhibitors ; Amyloid Precursor Protein Secretases/genetics ; Amyloid Precursor Protein Secretases/metabolism ; Animals ; Antifibrotic Agents/therapeutic use ; Apoptosis ; Carcinoma, Pancreatic Ductal/pathology ; Carcinoma, Pancreatic Ductal/radiotherapy ; Cell Movement ; Cell Proliferation ; Ephrin-B2/blood ; Epithelial-Mesenchymal Transition ; Female ; Fibrosis/drug therapy ; Fibrosis/etiology ; Fibrosis/metabolism ; Fibrosis/pathology ; Gamma Rays/adverse effects ; Humans ; Membrane Proteins/antagonists & inhibitors ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Pancreatic Neoplasms/pathology ; Pancreatic Neoplasms/radiotherapy ; Prognosis ; Radiation Injuries/drug therapy ; Radiation Injuries/etiology ; Radiation Injuries/metabolism ; Radiation Injuries/pathology ; Survival Rate ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
    Chemical Substances Antifibrotic Agents ; EFNB2 protein, human ; Ephrin-B2 ; Membrane Proteins ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; ADAM10 Protein (EC 3.4.24.81) ; ADAM10 protein, human (EC 3.4.24.81)
    Language English
    Publishing date 2021-02-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-20-3892
    Database MEDical Literature Analysis and Retrieval System OnLINE

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