1528P Phase I trial of the first-in-class agent CEND-1 in combination with gemcitabine and nab-paclitaxel in patients with metastatic pancreatic cancer

Dean, Andrew; Gill, Sanjeev; McGregor, Mark; Broadbridge, Vy; Järveläinen, Harri A.; Price, Timothy

doi:10.1016/j.annonc.2020.08.2011

Cited by 7 publications

(13 citation statements)

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“…We would hypothesize that such variability in β5 integrin expression levels may vastly affect the outcome of iRGD therapy. In a recent phase 1 clinical trial, iRGD (in the name of CEND-1) in combination with gemcitabine/nab-paclitaxel safely achieved a response rate (RR) of 59% and a disease control rate (DCR) of 93% in metastatic PDAC patients (NCT03517176) 49 . As a reference, a previous landmark phase 3 study for gemcitabine/nab-paclitaxel alone showed an RR of 23% and DCR of 50% 50 , suggesting the potential of iRGD to serve as a tumor-specific potentiator of standard of care chemotherapy for PDAC patients.…”

Section: Discussionmentioning

confidence: 99%

Tumor-penetrating therapy for β5 integrin-rich pancreas cancer

et al. 2021

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by marked desmoplasia and drug resistance due, in part, to poor drug delivery to extravascular tumor tissue. Here, we report that carcinoma-associated fibroblasts (CAFs) induce β5 integrin expression in tumor cells in a TGF-β dependent manner, making them an efficient drug delivery target for the tumor-penetrating peptide iRGD. The capacity of iRGD to deliver conjugated and co-injected payloads is markedly suppressed when β5 integrins are knocked out in the tumor cells. Of note, β5 integrin knock-out in tumor cells leads to reduced disease burden and prolonged survival of the mice, demonstrating its contribution to PDAC progression. iRGD significantly potentiates co-injected chemotherapy in KPC mice with high β5 integrin expression and may be a powerful strategy to target an aggressive PDAC subpopulation.

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Section: Discussionmentioning

confidence: 99%

Tumor-penetrating therapy for β5 integrin-rich pancreas cancer

et al. 2021

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“…Similar to cilengitide, CEND-1 is an Arg-Gly-Asp cyclic peptide (iRGD) targeting αvβ3 and αvβ5 integrins in the tumour vasculature, promoting tumour penetration to enhance the efficacy and specificity of chemotherapy treatment. A phase I clinical trial in pancreatic ductal adenocarcinoma (PDAC) patients combining CEND-1 with nabpaclitaxel and gemcitabine was successfully completed [NCT03517176 ( Dean et al, 2020 )]. The use of CEND-1 in melanoma patients has not been examined in clinical trials.…”

Section: Mechanisms Of Anoikis Resistance and Potential Therapiesmentioning

confidence: 99%

Therapeutic targeting of anoikis resistance in cutaneous melanoma metastasis

Neuendorf

Simmons

Boyle

2023

Front. Cell Dev. Biol.

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The acquisition of resistance to anoikis, the cell death induced by loss of adhesion to the extracellular matrix, is an absolute requirement for the survival of disseminating and circulating tumour cells (CTCs), and for the seeding of metastatic lesions. In melanoma, a range of intracellular signalling cascades have been identified as potential drivers of anoikis resistance, however a full understanding of the process is yet to be attained. Mechanisms of anoikis resistance pose an attractive target for the therapeutic treatment of disseminating and circulating melanoma cells. This review explores the range of small molecule, peptide and antibody inhibitors targeting molecules involved in anoikis resistance in melanoma, and may be repurposed to prevent metastatic melanoma prior to its initiation, potentially improving the prognosis for patients.

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“…The first-in-class agent CEND-1 binds tumor cells and enhances delivery of co-administered anti-cancer agents. In a recently completed phase I clinical trial the safety and efficacy of CEND-1 was already explored ( Dean et al, 2020 ; Dean et al, 2021 ) (NCT03517176). Based on the trial data, the combination treatment was regarded as safe.…”

Section: Ongoing Clinical Trials Exploring Integrin Therapeuticsmentioning

confidence: 99%

Targeting Integrins for Cancer Therapy - Disappointments and Opportunities

Bergonzini

Kroese

Zweemer

et al. 2022

Front. Cell Dev. Biol.

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Integrins mediate adhesive interactions between cells and their environment, including neighboring cells and extracellular matrix (ECM). These heterodimeric transmembrane receptors bind extracellular ligands with their globular head domains and connect to the cytoskeleton through multi-protein interactions at their cytoplasmic tails. Integrin containing cell–matrix adhesions are dynamic force-responsive protein complexes that allow bidirectional mechanical coupling of cells with their environment. This allows cells to sense and modulate tissue mechanics and regulates intracellular signaling impacting on cell faith, survival, proliferation, and differentiation programs. Dysregulation of these functions has been extensively reported in cancer and associated with tumor growth, invasion, angiogenesis, metastasis, and therapy resistance. This central role in multiple hallmarks of cancer and their localization on the cell surface makes integrins attractive targets for cancer therapy. However, despite a wealth of highly encouraging preclinical data, targeting integrin adhesion complexes in clinical trials has thus far failed to meet expectations. Contributing factors to therapeutic failure are 1) variable integrin expression, 2) redundancy in integrin function, 3) distinct roles of integrins at various disease stages, and 4) sequestering of therapeutics by integrin-containing tumor-derived extracellular vesicles. Despite disappointing clinical results, new promising approaches are being investigated that highlight the potential of integrins as targets or prognostic biomarkers. Improvement of therapeutic delivery at the tumor site via integrin binding ligands is emerging as another successful approach that may enhance both efficacy and safety of conventional therapeutics. In this review we provide an overview of recent encouraging preclinical findings, we discuss the apparent disagreement between preclinical and clinical results, and we consider new opportunities to exploit the potential of integrin adhesion complexes as targets for cancer therapy.

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1528P Phase I trial of the first-in-class agent CEND-1 in combination with gemcitabine and nab-paclitaxel in patients with metastatic pancreatic cancer

Cited by 7 publications

References 0 publications

Tumor-penetrating therapy for β5 integrin-rich pancreas cancer

Tumor-penetrating therapy for β5 integrin-rich pancreas cancer

Therapeutic targeting of anoikis resistance in cutaneous melanoma metastasis

Targeting Integrins for Cancer Therapy - Disappointments and Opportunities

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