The NOTCH1-MYC highway toward T-cell acute lymphoblastic leukemia.

Notch signalling is involved in many aspects of cancer biology, including angiogenesis, tumour immunity and the maintenance of cancer stem-like cells. In addition, Notch can function as an oncogene and a tumour suppressor in different cancers and in different cell populations within the same tumour. Despite promising preclinical results and early-phase clinical trials, the goal of developing safe, effective, tumour-selective Notch-targeting agents for clinical use remains elusive. However, our continually improving understanding of Notch signalling in specific cancers, individual cancer cases and different cell populations, as well as crosstalk between pathways, is aiding the discovery and development of novel investigational Notch-targeted therapeutics.

Targeting Notch in oncology: the path forward.

Notch signaling is a conserved system of communication between adjacent cells, influencing numerous cell fate decisions in the development of multicellular organisms. Aberrant signaling is also imp...

Biophysics of Notch Signaling.

Evolutionarily conserved Notch plays a critical role in embryonic development and cellular self-renewal It has both tumour suppressor and oncogenic activity, the latter of which is widely described Notch-activating mutations are associated with haematological malignancies and several solid tumours including breast, lung and adenoid cystic carcinoma Moreover, upregulation of Notch receptors and ligands and aberrant Notch signalling is frequently observed in cancer It is involved in cancer hallmarks including proliferation, survival, migration, angiogenesis, cancer stem cell renewal, metastasis and drug resistance It is a key component of cell-to-cell interactions between cancer cells and cells of the tumour microenvironment, such as endothelial cells, immune cells and fibroblasts Notch displays diverse crosstalk with many other oncogenic signalling pathways, and may drive acquired resistance to targeted therapies as well as resistance to standard chemo/radiation therapy The past 10 years have seen the emergence of different classes of drugs therapeutically targeting Notch including receptor/ligand antibodies, gamma secretase inhibitors (GSI) and most recently, the development of Notch transcription complex inhibitors It is an exciting time for Notch research with over 70 cancer clinical trials registered and the first-ever Phase III trial of a Notch GSI, nirogacestat, currently at the recruitment stage

https://www.mdpi.com/2073-4409/9/6/1503/pdf

Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives

The purpose of this study was to compare the expression and function of NOTCH1 in chronic lymphocytic leukemia (CLL) patients harboring a wild-type (WT) or mutated NOTCH1 gene. NOTCH1 mRNA and surface protein expression levels were independent of the NOTCH1 gene mutational status, consistent with the requirement for NOTCH1 signaling in this leukemia. However, compared with NOTCH1-WT CLL, mutated cases displayed biochemical and transcriptional evidence of an intense activation of the NOTCH1 pathway. In vivo, expression and activation of NOTCH1 was highest in CLL cells from the lymph nodes as confirmed by immunohistochemistry. In vitro, the NOTCH1 pathway was rapidly downregulated, suggesting that signaling relies upon micro-environmental interactions even in NOTCH1-mutated cases. Accordingly, co-culture of Jagged1+ (the NOTCH1 ligand) nurse-like cells with autologous CLL cells sustained NOTCH1 activity over time and mediated CLL survival and resistance against pro-apoptotic stimuli, both abrogated when NOTCH1 signaling was pharmacologically switched off. Together, these results show that NOTCH1 mutations have stabilizing effects on the NOTCH1 pathway in CLL. Furthermore, micro-environmental interactions appear critical in activating the NOTCH1 pathway both in WT and mutated patients. Finally, NOTCH1 signals may create conditions that favor drug resistance, thus making NOTCH1 a potential molecular target in CLL.

Functional impact of NOTCH1 mutations in chronic lymphocytic leukemia.

Triple negative (ER-, PR- Her2-) breast cancer accounts for 10% of all types of breast cancer and is known to particularly aggressive and refractory to current therapies. Chemotherapeutic agents, such as taxanes, are currently the only treatment option for this type of breast cancer, however, these treatments often result in high rates of local and systemic relapse. It has been suggested that cancer stem cells drive tumor growth and progression and are preferentially resistant to many current therapies. Delta-like 4 ligand (DLL4) is an important component of the Notch signaling pathway which is known to mediate stem cell self-renewal and vascular development. We hypothesized that targeting cancer stem cells and the tumor vasculature by interfering with the DLL4/Notch pathway will improve treatment outcome. We developed anti-DLL4 antibodies that recognize either the human or murine protein and have potent binding and antagonist activities. We have used these antibodies to investigate the role of DLL4 in triple negative breast cancer and to probe the mechanism in tumor and stromal cells in xenograft models derived from primary breast tumors. These studies showed that anti-DLL4 was efficacious as a single agent and in combination with paclitaxel (Taxol) against triple negative breast tumors including a tumor that developed paclitaxel resistance. Gene expression analysis showed that anti-DLL4 affected vascular-related genes in the stroma and Notch target genes in the tumor and stroma. Furthermore, inclusion of anti-DLL4 delayed breast tumor recurrence following termination of paclitaxel treatment. A tumorigenicity study indicated that treatment with anti-DLL4 decreased cancer stem cell frequency as measured by in vivo limiting dilution assay, whereas paclitaxel alone was ineffective. The combination of anti-DLL4 and paclitaxel further decreased cancer stem cell frequency compared to single agents. Our findings provide a rationale for targeting cancer stem cells and tumor vasculature through inhibition of the DLL4/Notch signaling for breast cancer treatment. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5071.

Targeting Cancer Stem Cells and Vasculature by a Novel Anti-Delta-Like 4 Ligand (DLL4) Antibody for Treatment of Triple Negative Breast Cancer.

T-acute lymphoblastic leukemia (T-ALL) is characterized by several genetic alterations and poor prognosis in about 20-25% of patients. Notably, about 60% of T-ALL shows increased Notch1 activity, due to activating NOTCH1 mutations or alterations in the FBW7 gene, which confer to the cell a strong growth advantage. Therapeutic targeting of Notch signaling could be clinically relevant, especially for chemotherapy refractory patients. This study investigated the therapeutic efficacy of a novel anti-Notch1 monoclonal antibody by taking advantage of a collection of pediatric T-ALL engrafted systemically in NOD/SCID mice and genetically characterized with respect to NOTCH1/FBW7 mutations. Anti-Notch1 treatment greatly delayed engraftment of T-ALL cells bearing Notch1 mutations, including samples derived from poor responders or relapsed patients. Notably, the therapeutic efficacy of anti-Notch1 therapy was significantly enhanced in combination with dexamethasone. Anti-Notch1 treatment increased T-ALL cell apoptosis, decreased proliferation and caused strong inhibitory effects on Notch-target genes expression along with complex modulations of gene expression profiles involving cell metabolism. Serial transplantation experiments suggested that anti-Notch1 therapy could compromise leukemia-initiating cell functions. These results show therapeutic efficacy of Notch1 blockade for T-ALL, highlight the potential of combination with dexamethasone and identify surrogate biomarkers of the therapeutic response.

Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts

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Targeting Cancer Stem Cells and Vasculature by a Novel Anti-Delta-Like 4 Ligand (DLL4) Antibody for Treatment of Triple Negative Breast Cancer.

Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts