DLL4 Blockade Inhibits Tumor Growth and Reduces Tumor-Initiating Cell Frequency

Hoey, Timothy; Yen, Wan-Ching; Axelrod, Fumiko; Basi, Jesspreet; Donigian, Lucas; Dylla, Scott J.; Fitch-Bruhns, Maureen; Lazetic, Sasha; Park, Inkyung; Sato, Aaron K.; Satyal, Sanjeev; Wang, Xinhao; Clarke, Michael F.; Lewicki, John; Gurney, Austin

doi:10.1016/j.stem.2009.05.019

Cited by 372 publications

(314 citation statements)

References 42 publications

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“…These models were conducted with minimally passaged human tumors (19,20) (Table S1). OMP-18R5 treatment resulted in inhibition of growth in several types of human tumors, including breast, pancreatic, colon [wild-type adenomatous polyposis coli (APC) and β-catenin] and lung tumors (Fig.…”

Section: Wnt Pathway Blockade Inhibits the Growth Of Human Tumor Xenomentioning

confidence: 99%

Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors

Gurney

Axelrod

Bond

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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504

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The Wnt/β-catenin pathway, which signals through the Frizzled (Fzd) receptor family and several coreceptors, has long been implicated in cancer. Here we demonstrate a therapeutic approach to targeting the Wnt pathway with a monoclonal antibody, OMP-18R5. This antibody, initially identified by binding to Frizzled 7, interacts with five Fzd receptors through a conserved epitope within the extracellular domain and blocks canonical Wnt signaling induced by multiple Wnt family members. In xenograft studies with minimally passaged human tumors, this antibody inhibits the growth of a range of tumor types, reduces tumor-initiating cell frequency, and exhibits synergistic activity with standard-of-care chemotherapeutic agents.differentiation | cancer stem cell | pancreatic | breast | lung

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Section: Wnt Pathway Blockade Inhibits the Growth Of Human Tumor Xenomentioning

confidence: 99%

Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors

Gurney

Axelrod

Bond

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

504

435

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“…4B). This approach has been used to assess TIC targeting of other compounds (24). We conducted the assay in the NSCLC PDX 37622A1, which has heterogeneous expression of 5T4 (Fig.…”

Section: Reduction Of Tic Frequencymentioning

confidence: 99%

Long-term Tumor Regression Induced by an Antibody–Drug Conjugate That Targets 5T4, an Oncofetal Antigen Expressed on Tumor-Initiating Cells

Sapra

Damelin

DiJoseph

et al. 2013

Molecular Cancer Therapeutics

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Antibody-drug conjugates (ADC) represent a promising therapeutic modality for the clinical management of cancer. We sought to develop a novel ADC that targets 5T4, an oncofetal antigen expressed on tumorinitiating cells (TIC), which comprise the most aggressive cell population in the tumor. We optimized an anti-5T4 ADC (A1mcMMAF) by sulfydryl-based conjugation of the humanized A1 antibody to the tubulin inhibitor monomethylauristatin F (MMAF) via a maleimidocaproyl linker. A1mcMMAF exhibited potent in vivo antitumor activity in a variety of tumor models and induced long-term regressions for up to 100 days after the last dose. Strikingly, animals showed pathologic complete response in each model with doses as low as 3 mg antibody/kg dosed every 4 days. In a non-small cell lung cancer patient-derived xenograft model, in which 5T4 is preferentially expressed on the less differentiated tumor cells, A1mcMMAF treatment resulted in sustained tumor regressions and reduced TIC frequency. These results highlight the potential of ADCs that target the most aggressive cell populations within tumors, such as TICs. In exploratory safety studies, A1mcMMAF exhibited no overt toxicities when administered to cynomolgus monkeys at doses up to 10 mg antibody/kg/ cycle Â 2 and displayed a half-life of 5 days. The preclinical efficacy and safety data established a promising therapeutic index that supports clinical testing of A1mcMMAF. Mol Cancer Ther; 12(1); 38-47. Ó2012 AACR.

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“…In addition, other regulators of Notch signaling, including Delta/Notch-like epidermal growth factor-related receptor (DNER) and the Notch ligand Delta-like 4 (DLL4), can also regulate GBM tumor growth (Li et al, 2007;Sun et al, 2009;Jeon et al, 2008). Anti-DLL4 therapies have demonstrated anti-cancer stem cell activity (Hoey et al, 2009) but concern has been raised as chronic DLL4 targeting can induce neoplasia as well (Yan et al, 2010). Further, other signaling regulators such as ID4 (inhibitor of differentiation 4) and CXCR4 also functionally interact with Notch signaling in brain tumors (Jeon et al, 2008;Williams et al, 2008).…”

Section: Notch Signalingmentioning

confidence: 99%

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

et al. 2010

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Glioblastomas (GBMs) are highly lethal primary brain tumors. Despite current therapeutic advances in other solid cancers, the treatment of these malignant gliomas remains essentially palliative. GBMs are extremely resistant to conventional radiation and chemotherapies. We and others have demonstrated that a highly tumorigenic subpopulation of cancer cells called GBM stem cells (GSCs) promotes therapeutic resistance. We also found that GSCs stimulate tumor angiogenesis by expressing elevated levels of VEGF and contribute to tumor growth, which has been translated into a useful therapeutic strategy in the treatment of recurrent or progressive GBMs. Furthermore, stem cell-like cancer cells (cancer stem cells) have been shown to promote metastasis. Although GBMs rarely metastasize beyond the central nervous system, these highly infiltrative cancers often invade into normal brain tissues preventing surgical resection, and GSCs display an aggressive invasive phenotype. These studies suggest that targeting GSCs may effectively reduce tumor recurrence and significantly improve GBM treatment. Recent studies indicate that cancer stem cells share core signaling pathways with normal somatic or embryonic stem cells, but also display critical distinctions that provide important clues into useful therapeutic targets. In this review, we summarize the current understanding and advances in glioma stem cell research, and discuss potential targeting strategies for future development of anti-GSC therapies.

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DLL4 Blockade Inhibits Tumor Growth and Reduces Tumor-Initiating Cell Frequency

Cited by 372 publications

References 42 publications

Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors

Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors

Long-term Tumor Regression Induced by an Antibody–Drug Conjugate That Targets 5T4, an Oncofetal Antigen Expressed on Tumor-Initiating Cells

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

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