Browsing by Subject "Human epidermal growth factor receptor 2"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    PI3K-activated MSC proteomes inhibit mammary tumors via Hsp90ab1 and Myh9
    (Elsevier, 2022-08-05) Sun, Xun; Li, Kexin; Aryal, Uma K.; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
    Despite the advance in medications in the past decade, aggressive breast cancer such as triple-negative breast cancer is difficult to treat. Here, we examined a counter-intuitive approach to converting human bone marrow-derived mesenchymal stem cells (MSCs) into induced tumor-suppressing cells by administering YS49, a PI3K/Akt activator. Notably, PI3K-activated MSCs generated tumor-suppressive proteomes, while PI3K-inactivated MSCs tumor-promotive proteomes. In a mouse model, the daily administration of YS49-treated MSC-derived CM decreased the progression of primary mammary tumors as well as the colonization of tumor cells in the lung. In the ex vivo assay, the size of freshly isolated human breast cancer tissues, including estrogen receptor positive and negative as well as human epidermal growth factor receptor 2 (HER2) positive and negative, was decreased by YS49-treated MSC-derived CM. Hsp90ab1 was enriched in CM as an atypical tumor-suppressing protein and immunoprecipitated a non-muscle myosin, Myh9. Extracellular Hsp90ab1 and Myh9 exerted the anti-tumor action and inhibited the maturation of bone-resorbing osteoclasts. Collectively, this study demonstrated that the activation of PI3K generated tumor-suppressive proteomes in MSCs and supported the possibility of using patient-derived MSCs for the treatment of breast cancer and bone metastasis.
  • Thumbnail Image
    Item
    The efficacy and safety of enzalutamide with trastuzumab in patients with HER2+ and androgen receptor-positive metastatic or locally advanced breast cancer
    (Springer, 2021) Wardley, Andrew; Cortes, Javier; Provencher, Louise; Miller, Kathy; Chien, A. Jo; Rugo, Hope S.; Steinberg, Joyce; Sugg, Jennifer; Tudor, Iulia C.; Huizing, Manon; Young, Robyn; Abramson, Vandana; Bose, Ron; Hart, Lowell; Chan, Stephen; Cameron, David; Wright, Gail S.; Graas, Marie‑Pascale; Neven, Patrick; Rocca, Andrea; Russo, Stefania; Krop, Ian E.; Medicine, School of Medicine
    Purpose: Androgen receptor (AR) expression occurs in up to 86% of human epidermal growth factor receptor 2-positive (HER2+) breast cancers. In vitro, AR inhibitors enhance antitumor activity of trastuzumab, an anti-HER2 antibody, in trastuzumab-resistant HER2+ cell lines. This open-label, single-arm, phase II study evaluated the efficacy and safety of enzalutamide, an AR-signaling inhibitor, in patients with advanced HER2+ AR+ breast cancer previously treated with trastuzumab. Methods: Eligible patients had measurable or non-measurable evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Eastern Cooperative Oncology Group status ≤ 1, no history of brain metastases, and previously received ≥ 1 anti-HER2 regimen for advanced disease. Patients received 160 mg oral enzalutamide daily and 6 mg/kg intravenous trastuzumab every 21 days until disease progression or unacceptable toxicity. Primary end point was clinical benefit rate at 24 weeks (CBR24); secondary end points included progression-free survival (PFS) and safety. Results: Overall, 103 women were enrolled [median age 60 years (range 34-83)]; 62% had received ≥ 3 lines of prior anti-HER2 therapy. CBR24, comprising patients with confirmed partial responses (5%) and durable stable disease at 24 weeks (19%), was 24% in the efficacy evaluable set (n = 89). CBR24 did not seem related to AR-expression levels or hormone receptor status. Median PFS was 3.4 months (95% confidence interval 2.0-3.8). Overall, 97 (94%) patients experienced treatment-emergent adverse events (TEAEs), with fatigue most common (34%). Dyspnea (4%) and malignant neoplasm progression (3%) were the only TEAEs grade ≥ 3 reported in ≥ 3 patients. 22 patients (21%) reported serious TEAEs. Four patients (4%) experienced fatal, non-drug-related TEAEs. Conclusions: Enzalutamide plus trastuzumab was well tolerated, and a subset of patients in this heavily pretreated population had durable disease control. Determination of biomarkers is needed to identify patients most likely to benefit from this combination.