lde225 and Triple-Negative-Breast-Neoplasms

The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple negative breast cancer (TNBC), Hedgehog ligand produced by neoplastic cells reprograms cancer-associated fibroblasts (CAFs) to provide a supportive niche for the acquisition of a chemo-resistant, cancer stem cell (CSC) phenotype via FGF5 expression and production of fibrillar collagen. Stromal treatment of patient-derived xenografts with smoothened inhibitors (SMOi) downregulates CSC markers expression and sensitizes tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden. In the phase I clinical trial EDALINE, 3 of 12 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonidegib and docetaxel chemotherapy, with one patient experiencing a complete response. These studies identify Hedgehog signaling to CAFs as a novel mediator of CSC plasticity and an exciting new therapeutic target in TNBC.

Topics: Adult; Aged; Anilides; Animals; Antineoplastic Combined Chemotherapy Protocols; Biphenyl Compounds; Cell Line, Tumor; Docetaxel; Drug Resistance, Neoplasm; Female; Humans; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Middle Aged; Neoplastic Stem Cells; Pyridines; Treatment Outcome; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Triple-negative breast cancer (TNBC) and HER2-positive breast cancer are particularly aggressive and associated with unfavorable prognosis. TNBC lacks effective treatments. HER2-positive tumors have treatment options but often acquire resistance to HER2-targeted therapy after initial response. To address these challenges, we determined whether novel combinations of JAK2-STAT3 and SMO-GLI1/tGLI1 inhibitors synergistically target TNBC and HER2 breast cancer since these two pathways are concurrently activated in both tumor types and enriched in metastatic tumors. Herein, we show that novel combinations of JAK2 inhibitors (ruxolitinib and pacritinib) with SMO inhibitors (vismodegib and sonidegib) synergistically inhibited in vitro growth of TNBC and HER2-positive trastuzumab-resistant BT474-TtzmR cells. Synergy was also observed against breast cancer stem cells. To determine if the combination is efficacious in inhibiting metastasis, we treated mice with intracardially inoculated TNBC cells and found the combination to inhibit lung and liver metastases, and prolong host survival without toxicity. The combination inhibited orthotopic growth, VEGF-A expression, and tumor vasculature of both TNBC and HER2-positive trastuzumab-refractory breast cancer. Lung metastasis of orthotopic BT474-TtzmR xenografts was suppressed by the combination. Together, our results indicated that dual targeting of JAK2 and SMO resulted in synergistic suppression of breast cancer growth and metastasis, thereby supporting future clinical testing.

Topics: Alternative Splicing; Anilides; Animals; Antineoplastic Combined Chemotherapy Protocols; Biphenyl Compounds; Bridged-Ring Compounds; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; Janus Kinase 2; Mice; Neoplasm Metastasis; Neoplastic Stem Cells; Nitriles; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor, ErbB-2; Signal Transduction; Smoothened Receptor; STAT3 Transcription Factor; Trastuzumab; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays; Zinc Finger Protein GLI1

Several evidences suggest a marked angiogenic dependency in triple-negative breast cancer (TNBC) tumorigenesis and a potential sensitivity to anti-angiogenic agents. Herein, the putative role of Hedgehog (Hh) pathway in regulating TNBC-dependent angiogenesis was investigated.. Expression and regulation of the Hh pathway transcription factor glioma-associated oncogene homolog1 protein (GLI1) were studied on the endothelial compartment and on TNBC-initiated angiogenesis. To evaluate the translational relevance of our findings, the combination of paclitaxel with the Smo inhibitor NVP-LDE225 was tested in TNBC xenografted mice.. Tissue microarray analysis on 200 TNBC patients showed GLI1 overexpression paired with vascular endothelial growth factor receptor 2 (VEGFR2) expression. In vitro, Hh pathway promotes TNBC progression in an autocrine manner, regulating the VEGF/VEGFR2 loop on cancer cell surface, and in a paracrine manner, orchestrating tumour vascularisation. These effects were counteracted by Smo pharmacological inhibition. In TNBC xenografted mice, scheduling NVP-LDE225 rather than bevacizumab provided a better sustained inhibition of TNBC cells proliferation and endothelial cells organisation.. This study identifies the Hh pathway as one of the main regulators of tumour angiogenesis in TNBC, thus suggesting Hh inhibition as a potential new anti-angiogenic therapeutic option to be clinically investigated in GLI1 overexpressing TNBC patients.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biphenyl Compounds; Cell Proliferation; Coculture Techniques; Endothelial Cells; Female; Gene Silencing; Hedgehog Proteins; Human Umbilical Vein Endothelial Cells; Humans; MCF-7 Cells; Membrane Proteins; Mice; Mice, Nude; Middle Aged; Neoplasm Transplantation; Neovascularization, Pathologic; Paclitaxel; Pyridines; RNA, Messenger; Signal Transduction; Thrombospondin 1; Tissue Array Analysis; Transfection; Triple Negative Breast Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Young Adult; Zinc Finger Protein GLI1