Initial results from a phase 1a/b study of OMP-131R10, a first-in-class anti-RSPO3 antibody, in advanced solid tumors and previously treated metastatic colorectal cancer (CRC)

Bendell, J.C.; Eckhardt, Gail; Hochster, H. S.; Morris, Valerie; Strickler, John H.; Kapoun, Ann M.; Wang, M.; Xu, Liang; McGuire, Kathie; Dupont, Jakob; Faoro, Leonardo; Munster, P.N.

doi:10.1016/s0959-8049(16)32668-5

Cited by 23 publications

(14 citation statements)

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“…Anti-FZD1/2/5/7/8 monoclonal antibody (mAb) (vantictumab) ( 100 ), anti-FZD5 mAb (IgG-2919) ( 101 ), anti-RSPO3 mAb (rosmantuzumab) ( 102 ), FZD8-Fc (ipafricept) ( 103 ), PORCN inhibitors (ETC-159, GNF6231, WNT-C59 and WNT974) ( 104 - 107 ) and TNKS inhibitors (AZ1366, G007-LK, NVP-TNKS656 and XAV939) ( 108 - 111 ) are therapeutics targeting upstream regulators of β-catenin ( Fig. 3 ).…”

Section: Therapeutics Targeting β-Catenin For Preventing Organ Fibmentioning

confidence: 99%

Multi‑layered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/β‑catenin signaling activation (Review)

2018

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β-catenin/CTNNB1 is an intracellular scaffold protein that interacts with adhesion molecules (E-cadherin/CDH1, N-cadherin/CDH2, VE-cadherin/CDH5 and α-catenins), transmembrane-type mucins (MUC1/CD227 and MUC16/CA125), signaling regulators (APC, AXIN1, AXIN2 and NHERF1/EBP50) and epigenetic or transcriptional regulators (BCL9, BCL9L, CREBBP/CBP, EP300/p300, FOXM1, MED12, SMARCA4/BRG1 and TCF/LEF). Gain-of-function CTTNB1 mutations are detected in bladder cancer, colorectal cancer, gastric cancer, liver cancer, lung cancer, pancreatic cancer, prostate cancer and uterine cancer, whereas loss-of-function CTNNB1 mutations are also detected in human cancer. ABCB1, ALDH1A1, ASCL2, ATF3, AXIN2, BAMBI, CCND1, CD44, CLDN1, CTLA4, DKK1, EDN1, EOMES, FGF18, FGF20, FZD7, IL10, JAG1, LEF1, LGR5, MITF, MSX1, MYC, NEUROD1, NKD1, NODAL, NOTCH2, NOTUM, NRCAM, OPN, PAX3, PPARD, PTGS2, RNF43, SNAI1, SP5, TCF7, TERT, TNFRSF19, VEGFA and ZNRF3 are representative β-catenin target genes. β-catenin signaling is involved in myofibroblast activation and subsequent pulmonary fibrosis, in addition to other types of fibrosis. β-catenin and NF-κB signaling activation are involved in field cancerization in the stomach associated with Helicobacter pylori (H. pylori) infection and in the liver associated with hepatitis C virus (HCV) infection and other etiologies. β-catenin-targeted therapeutics are functionally classified into β-catenin inhibitors targeting upstream regulators (AZ1366, ETC-159, G007-LK, GNF6231, ipafricept, NVP-TNKS656, rosmantuzumab, vantictumab, WNT-C59, WNT974 and XAV939), β-catenin inhibitors targeting protein-protein interactions (CGP049090, CWP232228, E7386, ICG-001, LF3 and PRI-724), β-catenin inhibitors targeting epigenetic regulators (PKF118-310), β-catenin inhibitors targeting mediator complexes (CCT251545 and cortistatin A) and β-catenin inhibitors targeting transmembrane-type transcriptional outputs, including CD44v6, FZD7 and LGR5. Eradicating H. pylori and HCV is the optimal approach for the first-line prevention of gastric cancer and hepatocellular carcinoma (HCC), respectively. However, β-catenin inhibitors may be applicable for the prevention of organ fibrosis, second-line HCC prevention and treating β-catenin-driven cancer. The multi-layered prevention and treatment strategy of β-catenin-related human diseases is necessary for the practice of personalized medicine and implementation of precision medicine.

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Section: Therapeutics Targeting β-Catenin For Preventing Organ Fibmentioning

confidence: 99%

Multi‑layered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/β‑catenin signaling activation (Review)

2018

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“…A phase Ia/Ib study is ongoing with this agent (NCT02482441; sponsored by Onco Med Pharmaceuticals). 72…”

Section: Targeting the Wnt Signaling Pathwaymentioning

confidence: 99%

Colon cancer stem cells: Potential target for the treatment of colorectal cancer

Gupta

Bhatt

Johnston

et al. 2019

Cancer Biology & Therapy

111

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Despite incessant research, colon cancer still is one of the most common causes of fatalities in both men and women worldwide. Also, nearly 50% of patients with colorectal cancer show tumor recurrence. Recent investigations have highlighted the involvement of colon cancer stem cells (CCSCs) in cancer relapse and chemoresistance. CCSCs deliver a significant protumorigenic niche through persistent overexpression of self-renewal capabilities. Moreover, CSCs cross network with stromal cells, immune infiltrates, and cyotokine-chemokine, which potentiate their aggressive proliferative potential. Targeting CCSCs through small molecule inhibitors, miRNAs, and monoclonal antibodies (mAbs) in in vivo studies has generated compelling evidence for the effectiveness of these various treatments. This review effectively compiles the role of CCSC surface markers and dysregulated and/or upregulated pathways in the pathogenesis of colorectal cancer that can be used to target CCSCs for effective colorectal cancer treatment.

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“…We have discovered that RSPO3-LGR4 pathway can be effectively inhibited by a clinicalgrade anti-RSPO3 monoclonal antibody (rosmantuzumab), which disrupts the RSPO3-LGR4 interaction and abrogates leukemia-initiating capacity of patient-derived LSCs without affecting the healthy stem cell compartment [6]. Rosmantuzumab has proven to be safe and well tolerated in Phase I clinical trials conducted on patients with advanced solid tumors [52]. While the therapeutic efficacy of anti-RSPO3 antibody will need further preclinical validation in a large number of patient-derived xenograft models with different mutational profiles, these findings indicate differential dependence of normal and malignant stem cells on RSPO-LGR4 signaling and underline a therapeutic opportunity for selective targeting of AML LSCs.…”

Section: Therapeutic Targeting Of Lgr4-rspo3 Signalingmentioning

confidence: 99%

Self-Renewal Pathways in Acute Myeloid Leukemia Stem Cells

Yang¹,

Hassan²,

Chen³

et al. 2021

Acute Leukemias

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Acute myeloid leukemia (AML) is a difficult-to-treat blood cancer. A major challenge in treating patients with AML is relapse, which is caused by the persistence of leukemia stem cells (LSCs). Self-renewal is a defining property of LSCs and its deregulation is crucial for re-initiating a new leukemia after chemotherapy. Emerging therapeutic agents inhibiting aberrant self-renewal pathways, such as anti-RSPO3 monoclonal antibody discovered in our recent study, present significant clinical potential that may extend beyond the scope of leukemogenesis. In this chapter, we provide an overview of normal and malignant hematopoietic stem cells, discuss current treatments and limitations, and review key self-renewal pathways and potential therapeutic opportunities in AML.

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Initial results from a phase 1a/b study of OMP-131R10, a first-in-class anti-RSPO3 antibody, in advanced solid tumors and previously treated metastatic colorectal cancer (CRC)

Cited by 23 publications

References 0 publications

Multi‑layered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/β‑catenin signaling activation (Review)

Multi‑layered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/β‑catenin signaling activation (Review)

Colon cancer stem cells: Potential target for the treatment of colorectal cancer

Self-Renewal Pathways in Acute Myeloid Leukemia Stem Cells

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