Sunitinib and Evofosfamide (<scp>TH</scp>-302) in Systemic Treatment-Naïve Patients with Grade 1/2 Metastatic Pancreatic Neuroendocrine Tumors: The <scp>GETNE</scp>-1408 Trial

Grande, Enrique; Rodríguez‐Antona, Cristina; López, Carlos; Alonso‐Gordoa, Teresa; Benavent, Marta; Capdevila, Jaume; Teulé, Àlex; Custodio, Ana; Sevilla, Isabel; Hernando, Jorge; Gajate, Pablo; Molina‐Cerrillo, Javier; Díez, Juan J.; Santos, María; Lanillos, Javier; García‐Carbonero, Rocío

doi:10.1002/onco.13885

Cited by 14 publications

(9 citation statements)

References 25 publications

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“…FDA has approved sunitinib for the treatment of renal cell carcinoma and gastrointestinal stromal tumors ( Ebos et al, 2007 ; Brooks et al, 2012 ). In addition, sunitinib also shows activity in clinical studies of neuroendocrine tumors, NSCLC, colon cancer, primary liver cancer, and breast cancer ( Ang et al, 2020 ; Li H et al, 2021 ; Chen et al, 2021 ; Grande et al, 2021 ; Symonds et al, 2021 ). What’s more, sunitinib also has been suggested as a radiosensitizing agent ( Curigliano et al, 2013 ; El Kaffas et al, 2013 ; Affolter et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Implantable Bioresponsive Hydrogel Prevents Local Recurrence of Breast Cancer by Enhancing Radiosensitivity

Xue

et al. 2022

Front. Bioeng. Biotechnol.

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Breast cancer is one of the most common types of cancer. Patients are often concerned about regional recurrence after breast cancer surgery. Radiotherapy plays a vital role in reducing recurrence and prolonging the survival of patients undergoing breast-conserving surgery and high-risk mastectomy. However, 8–15% of patients still have disease progression due to radiation resistance. Therefore, new strategies for combination radiotherapy sensitization must be investigated. In this study, an implantable drug loading system, sunitinib nanoparticles @ matrix metalloproteinases -response hydrogel (NSMRH), uses enzyme-sensitive hydrogel as a carrier to load sunitinib nanoparticles, was identified. The releasing profile demonstrated that sunitinib nanoparticles may be continuously released from the hydrogels. Functional experiments revealed that, when paired with NSMRH, radiation may significantly inhibit tumor cell proliferation, migration, and invasion in vitro. Further animal experiments showed that NSMRH combined with radiotherapy could more effectively control the recurrence of subcutaneous xenograft tumors, prolong the survival time, and have no obvious toxicity in nude mice. Finally, by studying the molecular mechanism of NSMRH, it was hypothesized that in breast cancer cells, NSMRH cooperated with sensitized radiotherapy, mainly due to significantly blocking the G2/M phase, reducing the DNA repair efficiency, inhibiting tumor angiogenesis, promoting apoptosis, and reversing the abnormal expression of platelet-derived growth factor receptor alpha (PDGFRA) after radiotherapy. These findings suggest that NSMRH’s radiation sensitization and anti-tumor activity may aid in the development of a novel method in future clinical applications.

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Section: Discussionmentioning

confidence: 99%

Implantable Bioresponsive Hydrogel Prevents Local Recurrence of Breast Cancer by Enhancing Radiosensitivity

Xue

et al. 2022

Front. Bioeng. Biotechnol.

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“…Brenner et al [43] reported a Phase II trial of bevacizumab and evofosfamide in bevacizumab-refractory glioblastoma, on the basis of induced hypoxia being an aspect of resistance to bevacizumab, but the response rate was very low (9%). Grande et al [44] carried out a recent Phase II clinical trial in pancreatic neuroendocrine tumours of Evofosfamide and the tyrosine kinase inhibitor sunitinib, suggesting that increased sunitinib-induced tumour hypoxia might promote activation of the prodrug, but the combination had high toxicity. Tran et al [45] used the kinase inhibitor sorafenib, but again with limited effectiveness.…”

Section: -Nitroimidazole Triggersmentioning

confidence: 99%

Nitroaromatic Hypoxia-Activated Prodrugs for Cancer Therapy

Denny

2022

Pharmaceuticals

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The presence of “hypoxic” tissue (with O2 levels of <0.1 mmHg) in solid tumours, resulting in quiescent tumour cells distant from blood vessels, but capable of being reactivated by reoxygenation following conventional therapy (radiation or drugs), have long been known as a limitation to successful cancer chemotherapy. This has resulted in a sustained effort to develop nitroaromatic “hypoxia-activated prodrugs” designed to undergo enzyme-based nitro group reduction selectively in these hypoxic regions, to generate active drugs. Such nitro-based prodrugs can be classified into two major groups; those activated either by electron redistribution or by fragmentation following nitro group reduction, relying on the extraordinary difference in electron demand between an aromatic nitro group and its reduction products. The vast majority of hypoxia-activated fall into the latter category and are discussed here classed by the nature of their nitroaromatic trigger units.

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“…However, drug combinations still need to focus on the occurrence of adverse reactions. Sunitinib and evofosfamide had 88.2% systemic toxicity, failing in phase II clinical trials for G1/2 in metastatic pancreatic NETs [ 122 ]. During combined use, attention should be paid to the differences in pharmacokinetic properties and the in vivo distribution of different drugs, insufficient tumor accumulation, uncertain drug interactions in tumor tissues, and serious side effects.…”

Section: Tme-associated Combination Treatmentmentioning

confidence: 99%

The Landscape and Clinical Application of the Tumor Microenvironment in Gastroenteropancreatic Neuroendocrine Neoplasms

Chen

et al. 2022

Cancers

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Gastroenteropancreatic neuroendocrine neoplasms feature high heterogeneity. Neuroendocrine tumor cells are closely associated with the tumor microenvironment. Tumor-infiltrating immune cells are mutually educated by each other and by tumor cells. Immune cells have dual protumorigenic and antitumorigenic effects. The immune environment is conducive to the invasion and metastasis of the tumor; in turn, tumor cells can change the immune environment. These cells also form cytokines, immune checkpoint systems, and tertiary lymphoid structures to participate in the process of mutual adaptation. Additionally, the fibroblasts, vascular structure, and microbiota exhibit interactions with tumor cells. From bench to bedside, clinical practice related to the tumor microenvironment is also regarded as promising. Targeting immune components and angiogenic regulatory molecules has been shown to be effective. The clinical efficacy of immune checkpoint inhibitors, adoptive cell therapy, and oncolytic viruses remains to be further discussed in clinical trials. Moreover, combination therapy is feasible for advanced high-grade tumors. The regulation of the tumor microenvironment based on multiple omics results can suggest innovative therapeutic strategies to prevent tumors from succeeding in immune escape and to support antitumoral effects.

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Sunitinib and Evofosfamide (TH-302) in Systemic Treatment-Naïve Patients with Grade 1/2 Metastatic Pancreatic Neuroendocrine Tumors: The GETNE-1408 Trial

Cited by 14 publications

References 25 publications

Implantable Bioresponsive Hydrogel Prevents Local Recurrence of Breast Cancer by Enhancing Radiosensitivity

Implantable Bioresponsive Hydrogel Prevents Local Recurrence of Breast Cancer by Enhancing Radiosensitivity

Nitroaromatic Hypoxia-Activated Prodrugs for Cancer Therapy

The Landscape and Clinical Application of the Tumor Microenvironment in Gastroenteropancreatic Neuroendocrine Neoplasms

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