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BIOMARKER:

ROR1 expression

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Other names: ROR1, Receptor Tyrosine Kinase Like Orphan Receptor 1, Inactive Tyrosine-Protein Kinase Transmembrane Receptor ROR1, Neurotrophic Tyrosine Kinase, Receptor-Related 1, NTRKR1, DJ537F10.1, ROR1
Entrez ID:
Related biomarkers:
7d
Role of the Ror family receptors in Wnt5a signaling. (PubMed, In Vitro Cell Dev Biol Anim)
Therefore, Ror1 and Ror2 have been proposed as potential targets for the treatment of the malignancies. In this review, we provide an overview of the regulatory mechanisms of Ror1/Ror2 expression and discuss how Wnt5a-Ror1/Ror2 signaling is mediated and regulated by their interacting proteins.
Review • Journal
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ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • ROR2 (Receptor Tyrosine Kinase Like Orphan Receptor 2)
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ROR1 expression
20d
Role of Wnt5b-Ror1 signaling in the proliferation of pancreatic ductal adenocarcinoma cells. (PubMed, Genes Cells)
Furthermore, we show that Wnt5b-Ror1 signaling in PANC-1 cells promotes their proliferation in a cell-autonomous manner by modulating our experimental setting in vitro. Collectively, these findings indicate that Wnt5b-Ror1 signaling might play an important role in the progression of some if not all of PDAC by promoting proliferation.
Journal
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ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • ROR2 (Receptor Tyrosine Kinase Like Orphan Receptor 2) • WNT5B (Wnt Family Member 5B)
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ROR1 expression • WNT5B expression
3ms
ROR1 expression in mature B lymphoid neoplasms by flow cytometry. (PubMed, Cytometry B Clin Cytom)
The CD5+/CD10- group had a significantly higher proportion of ROR1 positive samples (89.9%) and more brightly expressed ROR1 than the other groups. Our results highlight the importance of evaluating ROR1 expression in the diagnosis of MBLN to contribute to the differential diagnosis, and possibly therapy of mainly CLL, and indicate that this marker could be considered as a useful addition to immunophenotypic panels, particularly for more challenging cases.
Journal
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ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • CD5 (CD5 Molecule) • MME (Membrane Metalloendopeptidase)
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ROR1 expression • ROR1 positive
3ms
Receptor tyrosine kinase-like orphan receptor 1 inhibitor strictinin exhibits anti-cancer properties against highly aggressive androgen-independent prostate cancer. (PubMed, Explor Target Antitumor Ther)
Strictinin was further identified as synergistic with docetaxel [combination index (CI) = 0.311] and the combination therapy was found to reduce the IC of strictinin to 38.71 µmol/L in PC3 cells. ROR1 is an emerging molecular target that can be utilized for treating prostate cancer. The data from this study establishes strictinin as a potential therapeutic agent that targets AR-AI prostate cancer with elevated ROR1 expression to reduce the migration, invasion, cell cycle progression, and survival of prostate cancer.
Journal
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AR (Androgen receptor) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • CASP3 (Caspase 3) • CASP7 (Caspase 7) • ANXA5 (Annexin A5) • PI3K (Phosphoinositide 3-kinases)
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ROR1 expression • AR negative
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docetaxel
4ms
Exploration of macrocyclic peptide binders to the extracellular CRD domain of human receptor tyrosine kinase-like orphan receptor 1 (ROR1). (PubMed, Bioorg Med Chem Lett)
The parent macrocyclic peptides represented by Compound 1 and Compound 14 displayed nanomolar cell-based binding to ROR1 and relatively good internalization in 786-O and MDA-MB-231 tumor cell lines. However, these peptides were not observed to induce apoptosis in Mia PaCa-2 cells, a model pancreatic tumor cell line with a relatively low level of cell surface expression of ROR1.
Journal
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ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1)
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ROR1 expression
4ms
Canonical Wnt signaling pathway (WSP) alterations in metastatic prostate cancer. (ASCO-GU 2024)
WSP-act prostate cancer demonstrated a pronounced upregulation of ROR1 gene expression, underscoring its potential involvement in the crosstalk between the canonical and non-canonical Wnt signaling pathways. Additionally, the augmented levels of M2 macrophages in WSP-act tumors, combined with the reported role of ROR1 in tumor immunosuppression, suggests that ROR1 may contribute to immune evasion in WSP-act mPCa. Our findings may provide rationale for developing novel therapeutic strategies targeting Wnt-activated prostate cancers.
MSi-H Biomarker • Metastases
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RNF43 (Ring Finger Protein 43) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • SPOP (Speckle Type BTB/POZ Protein) • RSPO2 (R-Spondin 2)
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MSI-H/dMMR • ROR1 expression • RNF43 mutation • SPOP mutation • RNF43 G659fs • CTNNB1 expression
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MI Tumor Seek™
4ms
IL15 (N-803) and IL21 (oHSV-21) Significantly Enhance ROR1 CAR NK Cells Against Pediatric Neuroblastoma (TCT-ASTCT-CIBMTR 2024)
The N-803 combined with dinutuximab and exPBNK cells significantly extended the survival of NB xenografts (Chu/Cairo, et al, JITC...C021 was generated by modifying C134 to express human IL21 gene... Our data demonstrated IL15 or IL21 based novel cytokine therapy (N-803 or C021) significantly enhanced the anti-tumor efficacy of ROR1 CAR NK targeting NB in vitro and in vivo
Clinical
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MYCN (MYCN Proto-Oncogene BHLH Transcription Factor) • IFNG (Interferon, gamma) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • GZMB (Granzyme B) • GZMA (Granzyme A) • IL15 (Interleukin 15) • IL21 (Interleukin 21)
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MYCN amplification • ROR1 expression • ROR1 overexpression
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Anktiva (inbakicept) • Unituxin (dinutuximab)
4ms
Therapeutic targeting of tumor spheroids in a 3D microphysiological renal cell carcinoma-on-a-chip system. (PubMed, Neoplasia)
We next used bortezomib as a cytotoxin to develop automated quantification of dose-dependent tumor spheroid killing...Finally, we demonstrate the RCC-on-a-chip as a platform to model the trafficking of tumor-reactive T cells into the ECM and observed antigen-specific A498 spheroid killing by engineered human CD8 T cells expressing an ROR1-specific chimeric antigen receptor. In summary, the phenotypic differences between the 3D versus 2D environments, rapid imaging-based readout, and the ability to carefully study the impact of individual variables with quantitative rigor will encourage adoption of the RCC-on-a-chip system for testing a wide range of emerging therapies for RCC.
Journal
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CD8 (cluster of differentiation 8) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1)
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ROR1 expression • CD8 expression
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bortezomib
5ms
Targeting B-Cell Malignancies with Anti-ROR1 CAR T-Cell Therapy (ASH 2023)
We found that incorporationof the CD28 hinge and transmembrane domain in the CAR construct dramatically enhanced thein vitro lysis efficiency of anti-ROR1 CAR-T cells. In conclusion, we developed a novel andpotent anti-ROR1 CAR T-cell therapy product that may be used for treatment of various B-cellmalignancies and ROR1-expressing solid tumors.
CAR T-Cell Therapy • IO biomarker
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ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1)
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ROR1 expression
5ms
Development and Testing of a Glycoengineered Anti-ROR1 Antibody with Enhanced Capacity for Directing Antibody-Dependent Cellular Cytotoxicity (ADCC) of Chronic Lymphocytic Leukemia Cells (ASH 2023)
Co-culture of Jurkat-Lucia cells for 6 hours with the anti-CD20 mAb rituximab and MEC1 or MEC1-ROR1 cells induced Jurkat-Lucia cells to express a luciferase reporter gene under the control of an ISG54 minimal promoter fused to six NFAT response elements; this endowed the Jurkat-Lucia cells with high luminescence activity that was not observed in co-cultures of EC and TC without added mAb. ROR1 + CLL cells harboring del(17p) or mutations in TP53 (del(17p)/m TP53) and/or that were resistant to targeted therapies (e. g. , inhibitors of BTK or BCL2), were as susceptible to GE-zilovertamab-directed ADCC as were CLL cells without del(17p)/m TP53 from patients who had not had prior therapy. These data demonstrate that GE-zilovertamab can direct high-level ADCC lysis of ROR1-expressing neoplastic cells with greater activity than zilovertamab, encouraging development of clinical studies to evaluate GE-zilovertamab for therapy of patients with CLL or other ROR1-positive cancers.
IO biomarker
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TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • ADAM17 (ADAM Metallopeptidase Domain 17) • FCGR3A (Fc Fragment Of IgG Receptor IIIa)
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TP53 mutation • ROR1 expression • CD20 expression • ROR1 positive
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Rituxan (rituximab) • zilovertamab (UC-961)
6ms
Trial-in-Progress: A Phase 1/2 Multi-Center Study of Onct-808, a ROR1-Specific CAR T, in Adult Patients with Relapsed/Refractory Aggressive B Cell Lymphoma (ASH 2023)
Zilovertamab vedotin showed preliminary evidence of efficacy and no evidence of on-target off-tumor toxicity in patients with advanced B cell malignancies (Wang 2022)...Subjects will receive a conditioning regimen of intravenous (IV) cyclophosphamide and fludarabine, followed by ONCT-808 IV infusion...The trial is currently active and patients have been treated in the phase 1 dose escalation. Clinical Trial Identifier: NCT05588440
Clinical • P1/2 data • IO biomarker
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ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1)
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ROR1 expression • ROR1 positive
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cyclophosphamide • fludarabine IV • zilovertamab vedotin (MK-2140) • ONCT-808
6ms
Dual Targeting of ROR1 and BTK Augments the Anti-Lymphoma Activity in Mantle Cell Lymphoma (ASH 2023)
In addition, a patient-derived xenograft (PDX) mouse model was also used for evaluating single agent and combination efficacy of BTKis and zilovertamab (Zilo)...Treatment with single BTKi at 2-10 µM (Ibrutinib, zanubrutinib, acalabrutinib or pirtobrutinib) significantly induced cytotoxicity in the TP53Mut MCL cells, and the cell death was remarkedly increased when BTKi was combined with Zilo at 25-50 µg/ml...Conclusion Dual targeting of BTK and ROR1 signaling pathways augmented efficacy selectively in preclinical MCL models with TP53Mut. These data provide insights to develop tailored therapeutics to improve patient outcome for patients with TP53 mutation.
IO biomarker
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1)
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TP53 mutation • TP53 wild-type • ROR1 expression
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Imbruvica (ibrutinib) • Brukinsa (zanubrutinib) • Calquence (acalabrutinib) • Jaypirca (pirtobrutinib) • zilovertamab (UC-961)
6ms
Outsmart™ IL-2/15, a Novel Cytokine Designed to Enhance ROR1-Specific CAR T Anti-Tumor Activity While Minimizing Treg Activation and Systemic Cytokine Exposure (ASH 2023)
In summary, OutSmart™ IL-2/15 is a genetic module that produces CD8-IL-2/15 in response to T cell activation, promoting robust CAR-T expansion and enhanced anti-tumor efficacy. Furthermore, local production of a CD8-IL-2/15 enhances the effector function of bystander CD8+ T cells and NK cells, but only minimally activates Treg cells due to removing the IL-2Rα binding interface. Inducible production of CD8-IL-2/15 dramatically improves the potency of a ROR1 CAR for treating ROR1+ solid and liquid cancers.
IO biomarker
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CD8 (cluster of differentiation 8) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • CD4 (CD4 Molecule) • IL2 (Interleukin 2) • FOXP3 (Forkhead Box P3)
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ROR1 expression • CD8 expression • IL2 expression
6ms
Clinico-Pathological and Prognostic Significance of a Combination of Tumor Biomarkers in Iranian Patients With Breast Cancer. (PubMed, Clin Breast Cancer)
ROR1 and HER3 displayed significant association with different clinic-pathological features and in addition to the other tumor biomarkers could be considered as diagnostic and prognostic biomarkers in breast cancer patients.
Journal
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HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • PGR (Progesterone receptor) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1)
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HER-2 expression • ERBB3 expression • ROR1 expression • TP53 expression
7ms
ROR1-AS1 might promote in vivo and in vitro proliferation and invasion of cholangiocarcinoma cells. (PubMed, BMC Cancer)
siRNA-mediated KD of ROR1-AS1 significantly reduced cell proliferation and inhibited the migration of CCA cells. In addition, ROR1-AS1 KD HuCCT-1 cells injected into nude mice grew slower than normal CCA cells.In summary, our results show that ROR1-AS1 can promote CCA progression and might serve as a new target for diagnosis and treatment of CCA.
Preclinical • Journal
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ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1)
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ROR1 expression
7ms
ROR-1 CAR-T cells with CRISPR/Cas9-mediated glucocorticoid receptor knockout exert potent antitumor efficacy in advanced adrenocortical carcinoma (DGHO 2023)
Considering that ACC is well-known for its GC enriched inhibitory TME, we recapitulated these circumstances in vitro using exogenous supplementation of dexamethasone and 3D cell culture and observed a considerable decrease in antitumor efficacy elicited by ROR-1-CART... Our data show that ROR-1 is commonly and homogenously overexpressed in human ACC specimen. ROR-1 CART exert potent antitumor efficacy, which can be maintained by hGR KO in the presence of glucocorticoid excess in vitro .
Clinical • CAR T-Cell Therapy • IO biomarker • Metastases
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ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1)
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ROR1 expression
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dexamethasone
7ms
Characterization of the surface marker ROR1 as a potential target of CAR-T cell therapy in anaplastic thyroid carcinoma. (DGHO 2023)
ROR1 is a promising and specific CART target for ATC, but in vivo efficiency requires combination of CARTs with VEGF receptor blocking kinase inhibitors like lenvatinib. Our results are the basis for a phase I/II clinical trial for lenvatinib + ROR1-CARTs in ATC.
CAR T-Cell Therapy • IO biomarker
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BRAF (B-raf proto-oncogene) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1)
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RAS mutation • ROR1 expression
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Lenvima (lenvatinib)
7ms
Phase 1 trial of LYL797, a ROR1-targeted CAR T-cell therapy enhanced with genetic and epigenetic reprogramming, in advanced triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) (SITC 2023)
After successful LYL797 manufacturing, pts receive fludarabine and cyclophosphamide followed by a single infusion of LYL797 at the protocol-assigned dose level. Study objectives include assessment of safety and tolerability (primary), as well as anti-tumor activity and pharmacokinetics (secondary) of LYL797. Additional exploratory objectives include evaluation of the effects of Lyell’s genetic and epigenetic reprogramming technologies on T-cell phenotype and activity, as well as evaluation of the relationship between ROR1 expression and LYL797 activity.
P1 data • CAR T-Cell Therapy • Metastases
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ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • JUN (Jun proto-oncogene)
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ROR1 expression
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cyclophosphamide • fludarabine IV • LYL797
7ms
Preclinical development of LYL119, a ROR1-targeted CAR T-cell product incorporating four novel T-cell reprogramming technologies to overcome barriers to effective cell therapy for solid tumors (SITC 2023)
1x106 CAR T cells (figure 2). Conclusions These data suggest that LYL119, which combines c-Jun overexpression, NR4A3 KO, Epi-R protocol, and Stim-R technology, can limit exhaustion, maintain stem-like features, and has potential to provide effective and durable CAR T-cell antitumor activity in patients with ROR1+ solid tumors.
Preclinical • CAR T-Cell Therapy
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EGFR (Epidermal growth factor receptor) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • IL2RA (Interleukin 2 receptor, alpha) • IL7R (Interleukin 7 Receptor) • NR4A3 (Nuclear receptor subfamily 4 group A member 3) • JUN (Jun proto-oncogene)
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ROR1 expression • IL2RA expression • EGFR H1975 • IL7R expression
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LYL119
7ms
ONCT-808 ROR1 CAR T cells induce significant cancer cell death in mantle cell lymphoma cell line-derived CDX models and in vitro killing assays (SITC 2023)
Oncternal’s ONCT-808 autologous CAR T cells are genetically modified via ex vivo transduction with a self-inactivating lentivirus vector to express a ROR1-directed CAR containing single chain variable fragment derived from Oncternal’s clinical stage anti-ROR1 zilovertamab. In cancer therapy efficacy studies using CDX models, treatment with ONCT-808 cells resulted in complete tumor remission in ROR1 Jeko-1 cell-derived CDX mice, and controlled tumor growth in Raji cell-derived CDX mice, reflecting the specificity of the ONCT-808 cells to the ROR1 target. Conclusions ONCT-808 demonstrated high efficacy in inducing ROR1 specific cancer cell death in both in vivo and in vitro studies, suggesting its potential in treating human cancer patients.
Preclinical • CAR T-Cell Therapy • IO biomarker
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IFNG (Interferon, gamma) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • TNFA (Tumor Necrosis Factor-Alpha)
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ROR1 expression • ROR1 positive
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zilovertamab (UC-961) • ONCT-808
7ms
Rho family small GTPase Rif regulates Wnt5a-Ror1-Dvl2 signaling and promotes lung adenocarcinoma progression. (PubMed, J Biol Chem)
Furthermore, we found that Rif was required to activate Wnt5a-Ror1 signaling at the cell surface leading to phosphorylation of the Wnt signaling pathway hub protein Dvl2, which was further promoted by culturing the cells on Matrigel. Our findings reveal a novel function of Rif in mediating Wnt5a-Ror1-Dvl2 signaling, which is associated with the formation of polarized filopodia on three-dimensional matrices in lung adenocarcinoma cells.
Journal
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ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1)
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ROR1 expression
8ms
Prognostic Value of the Expression of Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR-1) in Chronic Lymphocytic Leukemia. (PubMed, Int J Hematol Oncol Stem Cell Res)
The poor prognostic parameters such as splenomegaly, anemia, higher beta-2 microglobulin levels, intermediate/advanced RAİ stage disease, and need for first-line treatment had associated high-level ROR 1 expression of our CLL patients. It needs to be investigated for its effect on predicting disease burden and aggressiveness with more comprehensive studies on ROR1 expression levels in CLL cases.
Journal
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ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • B2M (Beta-2-microglobulin) • CD5 (CD5 Molecule)
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CD19 positive • ROR1 expression
8ms
Evaluation of the prognostic significance of receptor tyrosine kinase-like orphan receptor 1 (ROR1) in lung carcinoma and its relation to lymphangiogenesis and epithelial mesenchymal transition. (PubMed, Pathol Res Pract)
High ROR1 expression, high LVD, large tumor size, and adenocarcinoma histopathological type were independent risk factors for OS in lung carcinoma patients. High ROR1 expression is associated with poor prognostic parameters in lung carcinoma patients including higher grade, advanced stages, high LVD, epithelial mesenchymal transition, as well as decreased PFS and OS.
Journal
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ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • CDH1 (Cadherin 1)
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ROR1 expression • CDH1 expression
8ms
Generation and preclinical evaluation of a novel ROR1-specific CAR T-cells against chronic lymphocytic leukemia (IWCLL 2023)
We utilized the humanized scFv binding domain of zilovertamab (formerly UC-961 and then cirmtuzumab), which showed high affinity and specificity for human ROR1 and a highly favorable safety profile in Phase-1 clinical evaluation [1]...We conclude that lentivirus encoding this anti-ROR1 CAR construct can generate anti-ROR1 CAR T cells using T cells of healthy donors or patients with CLL that are highly effective in killing ROR1-expressing leukemia cells in vitro or in vivo. Moreover, the anti-ROR1 CAR T cells generated using this construct may provide for selective killing of CLL cells without affecting normal CD19/CD20-expressing B cells of patients with CLL, thereby mitigating the risk for further enhancing immune deficiency, such as observed in patients treated with anti-CD19 CAR T cell therapy.
Preclinical • CAR T-Cell Therapy • IO biomarker
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TP53 (Tumor protein P53) • CD20 (Membrane Spanning 4-Domains A1) • CD19 (CD19 Molecule) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • TNFRSF9 (TNF Receptor Superfamily Member 9)
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TP53 mutation • ROR1 expression • CD20 expression • CD19 expression
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zilovertamab (UC-961)
9ms
YAP/BRD4-controlled ROR1 promotes tumor-initiating cells and hyperproliferation in pancreatic cancer. (PubMed, EMBO J)
Furthermore, epigenomic analyses reveal that ROR1 is transcriptionally dependent on YAP/BRD4 binding at the enhancer region, and targeting this pathway reduces ROR1 expression and prevents PDAC growth. Collectively, our findings reveal a critical role for ROR1high cells as tumor-initiating cells and the functional importance of ROR1 in PDAC progression, thereby highlighting its therapeutic targetability.
Journal
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MYC (V-myc avian myelocytomatosis viral oncogene homolog) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • AURKB (Aurora Kinase B) • BRD4 (Bromodomain Containing 4)
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ROR1 expression
10ms
ROR1-STAT3 signaling contributes to ovarian cancer intra-tumor heterogeneity. (PubMed, Cell Death Discov)
Our results show that ROR1 and its downstream STAT3 are co-expressed in epithelial as well as stromal cells of OC tumors, including cancer-associated fibroblasts or CAFs. Our data provides the framework to expand the clinical utility of ROR1 as a therapeutic target to overcome OC progression.
Journal
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ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • STAT3 (Signal Transducer And Activator Of Transcription 3)
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ROR1 expression • STAT3 expression
11ms
The Role of ROR1 in Chemoresistance and EMT in Endometrial Cancer Cells. (PubMed, Medicina (Kaunas))
Additionally, chemoresistance was examined by identifying MDR1 expression and IC50 level of paclitaxel... These in vitro experiments showed that ROR1 is responsible for EMT and chemoresistance in endometrial cancer cell lines. Targeting ROR1 can inhibit cancer metastasis and may be a potential treatment method for patients with endometrial cancer who exhibit chemoresistance.
Journal
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ABCB1 (ATP Binding Cassette Subfamily B Member 1) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • CDH1 (Cadherin 1) • SNAI1 (Snail Family Transcriptional Repressor 1)
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ROR1 expression • CDH1 expression
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paclitaxel
11ms
Targeting ROR1 Inhibits Glucocorticoid-induced Gastric Cancer Metastasis. (PubMed, Steroids)
Collectively, our study indicated that dexamethasone up-regulated ROR1 levels on gastric cancer cells. ROR1 participated in and mediated the role of dexamethasone in promoting gastric tumor growth, and blocking ROR1 can prevent the tumor growth.
Journal
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ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1)
|
ROR1 expression
|
dexamethasone
11ms
CLL Targets Beyond BTKi and Bcl2i (ICLLM 2023)
1, 2 Treatment of CLL cells with entospletinib, but not other BCR-signaling inhibitors, led to a disruption of BAFF-BCR cross-talk and downmodulation of MCL1 mRNA and protein, thus implicating SYK in transduction of multiple pro-survival signals emanating from the tumor microenvironment.1 Entospletinib has shown promising clinical activity in CLL, alone or in combination with obinutuzumab, including in patients with high-risk disease such as TP53 aberrant.3, 4 The drug is very well tolerated, however its development in CLL has been halted. Meanwhile, we have shown that luxeptinib, a dual SYK/BTK kinase inhibitor, has activity in BTK inhibitor-resistant lymphoid models in vitro.5 Luxeptinib is now being investigated in lcinical trials in hematologic malignancies...The early results of MS-553, a selective PKC-β inhibitor, indicates that this agent is tolerable and effective both as single agent and in combination with venetoclax.8 Proteolysis-targeting chimeras (PROTACs) are a new class of small molecules with two covalently-linked ligands recruiting target protein and E3 ubiquitin ligase together to trigger and enable proteasomal degradation of the target protein.9 “BTK degraders”, such as NRX- 2127 (Nurix Therapeutics) and BGB-16673 (Beigene), have entered clinical trials in patients with lymphoid malignancies...Additionally, NX-2127 has shown preclinical activity similar to immunomodulatory drugs (IMiDs) by catalyzing the ubiquitination of Ikaros (IKZF1) and Aiolos (IKZF3), resulting in increased T-cell activation.10 Early results of an ongoing clinical trial of NX-2127 demonstrate an ORR of 33% in heavily pre-treated patients with CLL, and overall good tolerability 11...The preclinical activity of AZD5991 has shown that selective targeting of MCL1 induced metabolic dysfunction and abrogated survival of diffuse large B cell lymphoma and ibrutinib-resistant mantle cell lymphoma cell lines in vivo and in vitro.13 Other BH3-mimetics targeting MCL1 include AMG176 and S63845.14-16 In an experimental design testing the effects of AMG-176 on CLL and normal hematopoietic cell death it was demonstrated that AMG-176 is an active agent in inducing CLL cell death while sparing normal blood cells...Anti-CD20 monoclonal antibodies – rituximab, obinutuzumab and ofatumumab – have significantly improved the survival outcomes. The B cell activating factor receptor (BAFF-R) is one of the main pro-survival receptors in B cells.18 In a preclinical study, ianalumab (VAY-736), a humanized defucosylated engineered antibody directed against BAFF-R, antagonized pro-survival effects of BAFF in CLL cells and showed promising activity both as a single agent and in combination with ibrutinib.19 A phase 1 study of dose escalation and dose expansion investigated the combination of ianalumab with ibrutinib in 32 patients with CLL with median one prior line of therapy (range, 0-4)...This study showed promising results not expected with ibrutinib alone.20 Tafasitamab – a Fc-enhanced, humanized, monoclonal antibody to CD19 – in combination with idelalisib or venetoclax in 24 patients has been associated with an ORR of 77% and 91%, respectively...In a phase 1 study involving 26 patients with R/R CLL, cirmtuzumab administered at four biweekly infusions was shown to have a long plasma half-life and did not have dose-limiting toxicity, potentially providing another treatment opportunity for patients with CLL.22 Immune Cell Enabling Therapies...A recent report of a phase 1/2 study of lisocabtagene maraleucel, an autologous CD19-directed CAR T-cell therapy (TRANSCEND CLL 004), confirmed efficacy in patients with R/R CLL.23 In this study, 23 patients with median 4 prior lines of therapy (range 2-11) were enrolled, 10 of whom were considered double exposed/refractory...In total, 65% of patients required administration of tocilizumab and/or corticosteroids.23 In addition to the ongoing phase 2 portion of this study, efforts now focus on innovative CAR T-cell designs as well as combination strategies...A phase 1b/2 ongoing trial is currently examining the safety and tolerability of the product in patients with R/R CLL. The early results suggest that epcoritamab administered subcutaneously is well tolerated in a heavily pretreated patient population with multiple high-risk features and shows clinical activity.25 Furthermore, an ongoing study is demonstrating preliminary efficacy of epcoritamab in patients with Richters transformation, a notoriously difficult-to-treat complication of CLL.26
IO biomarker
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TP53 (Tumor protein P53) • CD19 (CD19 Molecule) • CD8 (cluster of differentiation 8) • IGH (Immunoglobulin Heavy Locus) • IKZF1 (IKAROS Family Zinc Finger 1) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • CD4 (CD4 Molecule) • IKZF3 (IKAROS Family Zinc Finger 3) • SYK (Spleen tyrosine kinase) • PRKCB (Protein Kinase C Beta)
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TP53 mutation • ROR1 expression • CD20 expression • CD19 expression • BTK C481 • BTK overexpression
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Venclexta (venetoclax) • Imbruvica (ibrutinib) • Rituxan (rituximab) • Gazyva (obinutuzumab) • Zydelig (idelalisib) • Breyanzi (lisocabtagene maraleucel) • entospletinib (GS-9973) • S63845 • Epkinly (epcoritamab-bysp) • luxeptinib (CG-806) • zilovertamab (UC-961) • AZD5991 • Actemra IV (tocilizumab) • Monjuvi (tafasitamab-cxix) • tapotoclax (AMG 176) • NX-2127 • BGB-16673 • MS-553 • ianalumab (VAY736)
11ms
Association of baseline ROR1 and ROR2 gene expression with clinical outcomes in the I-SPY2 neoadjuvant breast cancer trial. (PubMed, Breast Cancer Res Treat)
High ROR1 or high ROR2 distinctly identified subsets of breast cancer patients with adverse outcomes. Further studies are warranted to determine if high ROR1 or high ROR2 may identify high-risk populations for studies of targeted therapies.
Clinical data • Journal
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HER-2 (Human epidermal growth factor receptor 2) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • ROR2 (Receptor Tyrosine Kinase Like Orphan Receptor 2)
|
HER-2 negative • HR negative • ROR1 expression
12ms
A Small Molecule Targeting the Intracellular Tyrosine Kinase Domain of ROR1 (KAN0441571C) Induced Significant Apoptosis of Non-Small Cell Lung Cancer (NSCLC) Cells. (PubMed, Pharmaceutics)
The combination of KAN0441571C and erlotinib showed a synergistic apoptotic effect. KAN0441571C also inhibited proliferative (cell cycle analyses, colony formation assay) and migratory (scratch wound healing assay) functions. Targeting NSCLC cells by a combination of ROR1 and EGFR inhibitors may represent a novel promising approach for the treatment of NSCLC patients.
Journal • PARP Biomarker • IO biomarker
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TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • CASP3 (Caspase 3) • ANXA5 (Annexin A5)
|
ROR1 expression
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erlotinib • Imbruvica (ibrutinib)
12ms
Study of Cirmtuzumab and Paclitaxel for Metastatic or Locally Advanced, Unresectable Breast Cancer (clinicaltrials.gov)
P1b, N=22, Active, not recruiting, Barbara Parker, MD | Trial completion date: Jan 2023 --> Jan 2024
Trial completion date • Combination therapy • Metastases
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HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1)
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HER-2 negative • ER negative • ER positive + PGR positive • PGR positive • ROR1 expression • PGR negative
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paclitaxel • zilovertamab (UC-961)
1year
miR-379-5p regulates the proliferation, cell cycle, and cisplatin resistance of oral squamous cell carcinoma cells by targeting ROR1. (PubMed, Am J Transl Res)
miR-379-5p in OSCC regulates the proliferation, cell cycle, and DDP resistance of tumor cells by targeting ROR1.
Journal
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ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1)
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ROR1 expression
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cisplatin
1year
The anti-ROR1 ADC STRO-003 demonstrates immune-modulating properties that may enhance checkpoint blockade (AACR 2023)
Follow-up vaccination studies were performed to further explore the significance of STRO-003-induced ICD and protective immunity in vivo. These results demonstrate that tumor cells pre-treated with STRO-003 or SC3386 undergo potent immunogenic cell damage which can, in turn, mount protective immunity in vivo.
Checkpoint inhibition • IO biomarker • Checkpoint block
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ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • HMGB1 (High Mobility Group Box 1) • CALR (Calreticulin)
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ROR1 expression
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STRO-003
1year
ROR1 targeted 4-1BB costimulatory bispecific antibody, ABL102, exhibits potent in vitro and vivo antitumor activity and superior safety profile (AACR 2023)
In conclusion, ABL102 exhibited potent in vitro and vivo anti-tumor activity and it was well tolerated and safe in the NHP toxicity study. These results strongly suggest that ABL102 is promising therapeutics for ROR1 positive cancer patients.
Preclinical
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IFNG (Interferon, gamma) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1)
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ROR1 expression • ROR1 positive
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ABL102
1year
NKTR-255, a polymer-conjugated IL-15, dramatically improves ROR1 CAR-T cell persistence and anti-tumor efficacy in an autochthonous model of ROR1+ lung cancer (AACR 2023)
Together, our work shows that NKTR-255 dramatically improves the persistence, function, and anti-tumor activity of ROR1 CAR-T cells in an aggressive autochthonous model of ROR1+ lung cancer. Our findings provide rationale to combine NKTR-255 with CAR-T cell therapy as a strategy to enhance the anti-tumor efficacy of CAR-T cells in patients with solid tumors.
Clinical • CAR T-Cell Therapy • IO biomarker
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KRAS (KRAS proto-oncogene GTPase) • CD8 (cluster of differentiation 8) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • IL2 (Interleukin 2) • IL15 (Interleukin 15)
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KRAS G12D • KRAS G12 • ROR1 expression • KRAS expression
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NKTR-255
1year
Anti-ROR1 CAR-T cells: Architecture and performance. (PubMed, Front Med (Lausanne))
Finally, the feasibility of applying the ROR1 CAR-T cell strategy in combination with therapies targeting other tumor antigens or with inhibitors that prevent tumor antigenic escape is also discussed. https://clinicaltrials.gov/, identifier NCT02706392.
Review • Journal • CAR T-Cell Therapy
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ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1)
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ROR1 expression
1year
MIR-379-5p Expression in Endometrial Cancer and Its Correlation with ROR1 Expression. (PubMed, Asian Pac J Cancer Prev)
In EC, miR-379-5p can be used as a diagnostic marker, and ROR1 could be a potential target of miR-379-5p.
Journal
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ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1)
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ROR1 expression