EphB4/EphrinB2 therapeutics in Rhabdomyosarcoma

Randolph, Matthew; Cleary, Megan M.; Bajwa, Zia; Svalina, Matthew N.; Young, Michael C.; Mansoor, Atiya; Kaur, Pali; Bult, Carol J.; Goros, Martin; Michalek, Joel E.; Xiang, Sunny; Keck, James; Krasnoperov, Valery; Gill, Parkash S.; Keller, Charles

doi:10.1371/journal.pone.0183161

Cited by 11 publications

(21 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ephrin type-B receptor 4 (EPHB4), a member of the largest family of receptor tyrosine kinases (RTKs), is highly expressed in various tumors, such as lung cancer, 12 colorectal cancer, 13 breast cancer, 14 esophageal cancer, 15 melanoma, 16 and malignant soft tissue sarcoma, including rhabdomyosarcoma (RMS). 17 Ephrin receptors bind to Eph receptor-interacting ligands, which are transmembrane ligands located at sites of cell-to-cell contact. 18 , 19 EPHB4 is mainly expressed in the developmental phase of three-dimensionally organized human tissue structures such as vascular formations and tissue border formations.…”

Section: Introductionmentioning

confidence: 99%

Development of non-viral, ligand-dependent, EPHB4-specific chimeric antigen receptor T cells for treatment of rhabdomyosarcoma

Kubo

Yagyu

Nakamura

et al. 2021

Molecular Therapy - Oncolytics

View full text Add to dashboard Cite

Ephrin type-B receptor 4 (EPHB4), expressed in tumors including rhabdomyosarcoma, is a suitable target for chimeric antigen receptor (CAR)-T cells. Ligand-independent activation of EPHB4 causes cell proliferation and malignant transformation in rhabdomyosarcoma, whereas ligand-dependent stimulation of EPHB4 induces apoptosis in rhabdomyosarcoma. Therefore, we hypothesized that ligand-based, EPHB4-specific CAR-T cells may kill rhabdomyosarcoma cells without stimulating downstream cell proliferation mechanisms. We developed novel CAR-T cells by targeting EPHB4 via EPHRIN B2, a natural ligand of EPHB4. The generation of EPHB4-CAR-T cells via piggyBac (PB) transposon-based gene transfer resulted in sufficient T cell expansion and CAR positivity (78.5% ± 5.9%). PB-EPHB4-CAR-T cells displayed a dominant stem cell memory fraction (59.4% ± 7.2%) as well as low PD-1 expression (0.60% ± 0.21%) after 14 days of expansion. The PB-EPHB4-CAR-T cells inhibited EPHB4-positive tumor cells without activating cell proliferation downstream of EPHB4, even after multiple tumor re-challenges and suppressed tumor growth in xenograft-bearing mice. Therefore, PB-EPHB4-CAR-T cells possess a memory-rich fraction without early T cell exhaustion and show potential as promising therapeutic agents for treating rhabdomyosarcoma and other EPHB4-positive tumors.

show abstract

Section: Introductionmentioning

confidence: 99%

Development of non-viral, ligand-dependent, EPHB4-specific chimeric antigen receptor T cells for treatment of rhabdomyosarcoma

Kubo

Yagyu

Nakamura

et al. 2021

Molecular Therapy - Oncolytics

View full text Add to dashboard Cite

show abstract

“…U48484 has been previously described ( 17 ). PCB-00380 has been previously described ( 18 ). PCB-00232 has been previously described ( 19 ).…”

Section: Methodsmentioning

confidence: 99%

Defining the Extracellular Matrix of Rhabdomyosarcoma

et al. 2021

Self Cite

View full text Add to dashboard Cite

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood with a propensity to metastasize. Current treatment for patients with RMS includes conventional systemic chemotherapy, radiation therapy, and surgical resection; nevertheless, little to no improvement in long term survival has been achieved in decades—underlining the need for target discovery and new therapeutic approaches to targeting tumor cells or the tumor microenvironment. To evaluate cross-species sarcoma extracellular matrix production, we have used murine models which feature knowledge of the myogenic cell-of-origin. With focus on the RMS/undifferentiated pleomorphic sarcoma (UPS) continuum, we have constructed tissue microarrays of 48 murine and four human sarcomas to analyze expression of seven different collagens, fibrillins, and collagen-modifying proteins, with cross-correlation to RNA deep sequencing. We have uncovered that RMS produces increased expression of type XVIII collagen alpha 1 (COL18A1), which is clinically associated with decreased long-term survival. We have also identified significantly increased RNA expression of COL4A1, FBN2, PLOD1, and PLOD2 in human RMS relative to normal skeletal muscle. These results complement recent studies investigating whether soft tissue sarcomas utilize collagens, fibrillins, and collagen-modifying enzymes to alter the structural integrity of surrounding host extracellular matrix/collagen quaternary structure resulting in improved ability to improve the ability to invade regionally and metastasize, for which therapeutic targeting is possible.

show abstract

“…To date, a functional interaction between the IGF system and the Eph axis has not been described in sarcoma models. However, Eph and IGF1 signaling pathways cross-talk to regulate bone and skeletal muscle cells function [211,212] and EphA2 and EphB4 exert oncogenic effects in different types of sarcomas, supporting the rationale for targeting Eph-dependent pathways in those tumors [208,[213][214][215][216][217][218][219][220].…”

Section: Ephrin Receptorsmentioning

confidence: 97%

“…EphA2 is up-regulated in osteosarcoma, Ewing sarcoma and rhabdomyosarcoma [208,[213][214][215][216][217][218][219][220].…”

Section: Ephrin Receptorsmentioning

confidence: 99%

Unraveling the IGF System Interactome in Sarcomas Exploits Novel Therapeutic Options

Mancarella

Morrione

Scotlandi

2021

Cells

View full text Add to dashboard Cite

Aberrant bioactivity of the insulin-like growth factor (IGF) system results in the development and progression of several pathologic conditions including cancer. Preclinical studies have shown promising anti-cancer therapeutic potentials for anti-IGF targeted therapies. However, a clear but limited clinical benefit was observed only in a minority of patients with sarcomas. The molecular complexity of the IGF system, which comprises multiple regulators and interactions with other cancer-related pathways, poses a major limitation in the use of anti-IGF agents and supports the need of combinatorial therapeutic strategies to better tackle this axis. In this review, we will initially highlight multiple mechanisms underlying IGF dysregulation in cancer and then focus on the impact of the IGF system and its complexity in sarcoma development and progression as well as response to anti-IGF therapies. We will also discuss the role of Ephrin receptors, Hippo pathway, BET proteins and CXCR4 signaling, as mediators of sarcoma malignancy and relevant interactors with the IGF system in tumor cells. A deeper understanding of these molecular interactions might provide the rationale for novel and more effective therapeutic combinations to treat sarcomas.

show abstract

EphB4/EphrinB2 therapeutics in Rhabdomyosarcoma

Cited by 11 publications

References 25 publications

Development of non-viral, ligand-dependent, EPHB4-specific chimeric antigen receptor T cells for treatment of rhabdomyosarcoma

Development of non-viral, ligand-dependent, EPHB4-specific chimeric antigen receptor T cells for treatment of rhabdomyosarcoma

Defining the Extracellular Matrix of Rhabdomyosarcoma

Unraveling the IGF System Interactome in Sarcomas Exploits Novel Therapeutic Options

Contact Info

Product

Resources

About