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Targeted Therapy for Cancer Stem Cells
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Rama Krishna Nimmakayala, Saswati Karmakar, Garima Kaushik, Sanchita Rauth, Srikanth Barkeer, Saravanakumar Marimuthu, Moorthy P. Ponnusamy
Notch signaling played a role in cell-cell communication and was found to be essential for cell proliferation and apoptosis during embryonic development. Several pathways such as nuclear factor-xB (NF-xB), HH, mammalian target of rapamycin (mTOR), Wnt, and epidermal growth factor have been shown to cross-talk with notch pathway, and thus, play significant functions in CSCs and tumor growth [69–71]. Therefore, Notch can be an attractive therapeutic target for CSCs treatment. Therapeutics aiming Notch signaling mainly consist of anti-Delta-like ligand 4 (DLL4) antibodies and g-secretase inhibitors. The main function of monoclonal antibodies against DLL4 is to block the binding of a ligand. Encticumab (REN421) is a DLL4 targeting antibody and has been used to treat advanced ovarian solid tumors overexpressing DLL4 [72]. Demcizumab is another anti-DLL4 antibody developed by OncoMed Pharmaceuticals and Celgene, and has completed the phase I clinical trial. In addition to inhibitors against DLL4, various g-secretase inhibitors such as RO4929097 and LY900009 have been undergoing phase I trial. RO4929097 suppresses Notch signaling genes, such as Hey1, Hey L and Hes1, thus blocking activation of self-renewal genes [10].
The role of the Notch pathway in the pathogenesis of systemic sclerosis: clinical implications
Published in Expert Review of Clinical Immunology, 2021
Filipe Seguro Paula, José Delgado Alves
mAbs directed against Notch ligands have also been developed with the most studies to date being directed against Dll-4 due to its role in angiogenesis. Inhibition of Dll-4 induces a endothelium-specific defect in Notch signaling, that will lead to a highly ramified vascular network, which is paradoxically dysfunctional – many capillaries lack a lumen and have serious defects in pericyte covering, leading to hemorrhages and hypoxia [92]. This effect was beneficial in tumors, halting their growth and in some cases inducing regression of the tumor mass. However, a serious adverse consequence of these changes in the microcirculation seen with the anti-Dll4 mAbs demcizumab and enoticumab was the development of pulmonary hypertension [93] which prohibits its use in SSc, as it is one of the most serious manifestations of the disease. A mAb against the ligand Jagged-1 could have an excellent applicability in SSc due to its central role in myofibroblast activation and endothelial cell-perivascular cell interactions. Even though it has only been tested in preclinical trials and despite being developed for oncologic applications, it showed a very interesting safety profile [94,95].
PD-L1 and Notch as novel biomarkers in pancreatic sarcomatoid carcinoma: a pilot study
Published in Expert Opinion on Therapeutic Targets, 2021
Nicola Silvestris, Antonella Argentiero, Oronzo Brunetti, Margherita Sonnessa, Fulvia Colonna, Sabina Delcuratolo, Claudio Luchini, Aldo Scarpa, Sara Lonardi, Floriana Nappo, Matteo Fassan, Antonio Giovanni Solimando, Livia Fucci, Concetta Saponaro
On the other hand, preliminary preclinical and clinical studies revealed potential antitumor activity of anti-Notch antibodies in pancreatic cancer, either as a single agent or in combination with chemotherapy [16,56,57]. In a phase Ib trial tarextumab, targeting Notch2 and Notch3 receptors showed a favorable PFS and OS results with a tolerable safety profile in PDAC patients. Nevertheless, a randomized phase II study evaluating tarextumab or placebo combined with nab-paclitaxel and gemcitabine observed no improvement in outcome compared to standard chemotherapy [58]. Similar results were reported from another phase II trial assessing the efficacy of demcizumab, an anti-Delta-like ligand 4 inhibiting the Notch pathway [59].
The shifting paradigm of colorectal cancer treatment: a look into emerging cancer stem cell-directed therapeutics to lead the charge toward complete remission
Published in Expert Opinion on Biological Therapy, 2021
Jessica Kopenhaver, Madison Crutcher, Scott A. Waldman, Adam E. Snook
Current CRC treatment has gradually moved toward addressing this dilemma by targeting CSCs directly, as well as combining traditional therapies with anti-CSC agents. These drugs are commonly directed toward either increasing the susceptibility of CSCs to chemotherapeutics, or blocking stemness-related pathways like Wnt, Hedgehog, JAK/STAT, or Notch [84]. In an animal model of CRC, the polyclonal antibody demcizumab was implemented to target the Notch pathway by inhibiting DLL4, consequently reducing tumor cell count and growth kinetics [85]. Additionally, treatment against IL-6, which stimulates stemness of CRC-SCs through Notch-3 signaling, reduced expression of stemness-related proteins and induced chemosensitivity [86]. In vitro studies have shown promise for treatment with Wnt/β-catenin pathway-targeting proteins like PER3, which can attenuate chemoresistance and sensitize cells to 5-fluorouracil by inhibiting β-catenin expression [84,87]. Currently in a Phase II clinical trial, an orally administered anti-stemness drug BBI608 (NCT01776307) is being tested in conjunction with established neoplastic agents cetuximab, panitumumab, or capecitabine in patients with advanced CRC. Differentiation therapy may also be a possible method for eliminating CRC-SCs. BMP, a glycoprotein belonging to the TGF-β superfamily, functions as both a suppressor of Wnt/β-catenin signaling and a cell fate determinant by inducing differentiation [88]. Treatment of xenograft tumors derived from CRC-SCs with BMP4, along with oxaliplatin and 5-flouroucil, has resulted in complete tumor remission [89]. Another study on glioma CSCs demonstrated that a variant type of BMP7 decreases tumor growth, angiogenesis, and invasion by inducing CSC differentiation [90].