A phase I trial of escalating doses of cixutumumab (IMC-A12) and sorafenib in the treatment of advanced hepatocellular carcinoma

El-Khoueiry, Anthony B.; O’Donnell, Robert T.; Semrad, Thomas J.; Mack, Philip C.; Blanchard, Suzette; Bahary, Nathan; Jiang, Yixing; Yen, Yun; Wright, John J.; Chen, Helen; Lenz, Heinz Josef; Gandara, David R.

doi:10.1007/s00280-018-3553-4

Cited by 12 publications

(4 citation statements)

References 22 publications

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“…The investigators recruited 21 unselected patients with advanced HCC and Child-Pugh A to B7. Patients received sorafenib 400 mg twice a day and escalating doses of cixutumumab (2, 4, or 6 mg/kg weekly), and PFS and OS were recorded [ 260 ]. Although the toxicity profile was similar to that of sorafenib monotherapy, the clinical efficacy of the combination of cixutumumab and sorafenib remained limited.…”

Section: Igf/igf-1 Signaling As a Potential Target For The Treatmementioning

confidence: 99%

The Role of IGF/IGF-1R Signaling in Hepatocellular Carcinomas: Stemness-Related Properties and Drug Resistance

Ngo

Jeng

Kuo

et al. 2021

IJMS

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Insulin-like Growth Factor (IGF)/IGF-1 Receptor (IGF-1R) signaling is known to regulate stem cell pluripotency and differentiation to trigger cell proliferation, organ development, and tissue regeneration during embryonic development. Unbalanced IGF/IGF-1R signaling can promote cancer cell proliferation and activate cancer reprogramming in tumor tissues, especially in the liver. Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, with a high incidence and mortality rate in Asia. Most patients with advanced HCC develop tyrosine kinase inhibitor (TKI)-refractoriness after receiving TKI treatment. Dysregulation of IGF/IGF-1R signaling in HCC may activate expression of cancer stemness that leads to TKI refractoriness and tumor recurrence. In this review, we summarize the evidence for dysregulated IGF/IGF-1R signaling especially in hepatitis B virus (HBV)-associated HCC. The regulation of cancer stemness expression and drug resistance will be highlighted. Current clinical treatments and potential therapies targeting IGF/IGF-1R signaling for the treatment of HCC will be discussed.

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Section: Igf/igf-1 Signaling As a Potential Target For The Treatmementioning

confidence: 99%

The Role of IGF/IGF-1R Signaling in Hepatocellular Carcinomas: Stemness-Related Properties and Drug Resistance

Ngo

Jeng

Kuo

et al. 2021

IJMS

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“…The CSC-like cells are responsible for drug resistance and tumor metastasis, and are the principal reason for tumor treatment failure and cancer-associated mortality (12). Clinically, sorafenib is the first-line treatment drug to prolong the overall survival rate of patients with advanced liver cancer (13). However, drug resistance of sorafenib remains a primary challenge in improving the prognoses of patients with liver cancer (14).…”

Section: Introductionmentioning

confidence: 99%

PDCD2 sensitizes HepG2 cells to sorafenib by suppressing epithelial‑mesenchymal transition

Liu

Wang

Liang³

et al. 2019

Mol Med Report

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Epithelial-mesenchymal transition (EMT) has an established role in the acquisition of therapeutic resistance. Programmed cell death domain 2 (PDCD2) is involved in the progression of multiple types of cancer. However, its mechanism underlying chemoresistance in liver cancer has not been elucidated. In the present study, it was demonstrated that the sorafenib-resistant HepG2 cell line exhibited EMT and multidrug resistance (MDR) phenotypes, and reduced expression of PDCD2, by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blot analysis and Cell Counting Kit-8. Annexin V/fluorescein isothiocyanate and cell migration assays further demonstrated that PDCD2 effectively promoted sorafenib-induced cell apoptosis and reduced cell metastasis. Mechanistically, PDCD2 inhibited the expression of Vimentin and increased the expression of E-cadherin in a Snail-dependent manner by RT-qPCR and western blot analysis. In conclusion, the present study elucidated for the first time, to the best of our knowledge, that PDCD2 sensitizes sorafenib-resistant HepG2 cells to sorafenib by the downregulation of EMT. PDCD2 may serve as a potential therapeutic target in the treatment of sorafenib-resistant liver cancer.

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“…Cixutumumab, a monoclonal antibody targeting the type I IGF receptor, demonstrated only limited clinical efficacy in unselected treatment-naive patients with advanced HCC. In a phase II trial (NCT00906373), the combination of cixutumumab plus sorafenib resulted in an mPFS of 6.0 months and an mOS of 10.5 months [343]. Cixutumumab monotherapy also failed to show clinically meaningful activity in unselected patients with HCC (phase II, NCT00639509) [344].…”

Section: Therapeutic Vaccination Strategies In the Setting Of Hccmentioning

confidence: 99%

Insights in Molecular Therapies for Hepatocellular Carcinoma

Heumann,

Albert,

Gülow

et al. 2024

Cancers

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We conducted a comprehensive review of the current literature of published data and clinical trials (MEDLINE), as well as published congress contributions and active recruiting clinical trials on targeted therapies in hepatocellular carcinoma. Combinations of different agents and medical therapy along with radiological interventions were analyzed for the setting of advanced HCC. Those settings were also analyzed in combination with adjuvant situations after resection or radiological treatments. We summarized the current knowledge for each therapeutic setting and combination that currently is or has been under clinical evaluation. We further discuss the results in the background of current treatment guidelines. In addition, we review the pathophysiological mechanisms and pathways for each of these investigated targets and drugs to further elucidate the molecular background and underlying mechanisms of action. Established and recommended targeted treatment options that already exist for patients are considered for systemic treatment: atezolizumab/bevacizumab, durvalumab/tremelimumab, sorafenib, lenvatinib, cabozantinib, regorafenib, and ramucirumab. Combination treatment for systemic treatment and local ablative treatment or transarterial chemoembolization and adjuvant and neoadjuvant treatment strategies are under clinical investigation.

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A phase I trial of escalating doses of cixutumumab (IMC-A12) and sorafenib in the treatment of advanced hepatocellular carcinoma

Abstract: While the combination of cixutumumab and sorafenib had a toxicity profile similar to that of sorafenib monotherapy, it manifested limited clinical efficacy in unselected patients with HCC.

Cited by 12 publications

References 22 publications

The Role of IGF/IGF-1R Signaling in Hepatocellular Carcinomas: Stemness-Related Properties and Drug Resistance

The Role of IGF/IGF-1R Signaling in Hepatocellular Carcinomas: Stemness-Related Properties and Drug Resistance

PDCD2 sensitizes HepG2 cells to sorafenib by suppressing epithelial‑mesenchymal transition

Insights in Molecular Therapies for Hepatocellular Carcinoma

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