Phase Ib of Sorafenib in Combination With Everolimus in Patients With Advanced Solid Tumors, Selected on the Basis of Molecular Targets

Toffalorio, Francesca; Spitaleri, Gianluca; Catania, Chiara; Zotto, Laura Dal; Noberasco, Cristina; Delmonte, Angelo; Santarpía, Mariacarmela; Vecchio, Fabio Maria; Brunelli, Veronica; Rampinelli, Cristiano; Barberis, Massimo; Fumagalli, Caterina; Zucchetti, Massimo; Zangarini, Monique; Diena, Tullia; Danesi, Romano; Braud, Filippo de; Pas, Tommaso De

doi:10.1634/theoncologist.2013-0335

Cited by 9 publications

(3 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Multi-kinase inhibitors targeting mainly FLT3 are generally accepted for acute myeloid leukemia (AML) treatment but are not clinically used on solid tumors due to low efficacy. Currently, combination treatments, instead of single therapeutic agents, are being extensively investigated for the treatment of solid tumors [9,10,11,12,13].…”

Section: Introductionmentioning

confidence: 99%

Antitumor Activity of a Novel Tyrosine Kinase Inhibitor AIU2001 Due to Abrogation of the DNA Damage Repair in Non-Small Cell Lung Cancer Cells

Ryu

Choi

Kim

et al. 2019

IJMS

View full text Add to dashboard Cite

Class III receptor tyrosine kinase (RTK) inhibitors targeting mainly FLT3 or c-KIT have not been well studied in lung cancer. To identify a small molecule potentially targeting class III RTK, we synthesized novel small molecule compounds and identified 5-(4-bromophenyl)-N-(naphthalen-1-yl) oxazol-2-amine (AIU2001) as a novel class III RKT inhibitor. In an in vitro kinase profiling assay, AIU2001 inhibited the activities of FLT3, mutated FLT3, FLT4, and c-KIT of class III RTK, and the proliferation of NSCLC cells in vitro and in vivo. AIU2001 induced DNA damage, reactive oxygen species (ROS) generation, and cell cycle arrest in the G2/M phase. Furthermore, AIU2001 suppressed the DNA damage repair genes, resulting in the ‘BRCAness’/‘DNA-PKness’ phenotype. The mRNA expression level of STAT5 was downregulated by AIU2001 treatment and knockdown of STAT5 inhibited the DNA repair genes. Our results show that compared to either drug alone, the combination of AIU2001 with a poly (ADP-ribose) polymerase (PARP) inhibitor olaparib or irradiation showed synergistic efficacy in H1299 and A549 cells. Hence, our findings demonstrate that AIU2001 is a candidate therapeutic agent for NSCLC and combination therapies with AIU2001 and a PARP inhibitor or radiotherapy may be used to increase the therapeutic efficacy of AIU2001 due to inhibition of DNA damage repair.

show abstract

Section: Introductionmentioning

confidence: 99%

Antitumor Activity of a Novel Tyrosine Kinase Inhibitor AIU2001 Due to Abrogation of the DNA Damage Repair in Non-Small Cell Lung Cancer Cells

Ryu

Choi

Kim

et al. 2019

IJMS

View full text Add to dashboard Cite

show abstract

“…Hypophosphataemia occurs frequently with everolimus [Toffalorio et al 2014] and has also been reported for HDAC, MEK and ALK inhibitors. Dr Roila believes that periodic monitoring is recommended with phosphate supplementation and drug interruption need only occur in severe cases.…”

Section: Endocrine Toxicitymentioning

confidence: 99%

Targeting precision medicine toxicity: recent developments

Mallarkey¹,

Mangoni

2015

Therapeutic Advances in Drug Safety

View full text Add to dashboard Cite

The European Society of Medical Oncology conference was held in Madrid, 26-30 September 2014. Its overriding theme was precision medicine in cancer care. A special symposium entitled 'Targeting precision medicine toxicity' looked specifically at the various toxicities caused by new targeted therapies. Cardiac toxicity Dr Lillian L. Siu (Princess Margaret Cancer Centre, Toronto, Canada) presented an overview of cardiac toxicities encountered with molecularly targeted agents. These include ventricular dysfunction, hypertension and corrected QT interval (QTc) prolongation. There are distinct mechanisms for drug-induced ventricular dysfunction. For example, cytotoxic agents such as anthracyclines can cause a type I injury, i.e. myocyte cell death that is usually cumulative-dose related. However, molecularly targeted agents, such as trastuzumab, may cause a type II injury, i.e. myocyte dysfunction without cell death that is not cumulative-dose related and potentially reversible. By way of examples, trastuzumab causes cardiotoxicity via ERBB2 signalling inhibition, whereas imatinib does this by ABL signalling inhibition [Force et al. 2007].

show abstract

“…Although bryostatin-1 development has been halted, studies such as this must be published to inform the future development of other protein kinase C inhibitors. Exhibit C is a combination of sorafenib with everolimus selected on the basis of molecular targets [4]; the reader can decide, is this progress or are we running in place?…”

mentioning

confidence: 99%

Clinical Trial Results: A Clinical Trial Bazaar!

Fojo

Bates

2014

The Oncologist

View full text Add to dashboard Cite

show abstract

Phase Ib of Sorafenib in Combination With Everolimus in Patients With Advanced Solid Tumors, Selected on the Basis of Molecular Targets

Abstract: Background. Molecular alterations of the PI3K and Ras pathways often occur in human cancer. In this trial, the pharmacokinetics, toxicity, and activity of two drugs inhibiting these pathways-everolimus and sorafenib-were investigated.

Cited by 9 publications

References 0 publications

Antitumor Activity of a Novel Tyrosine Kinase Inhibitor AIU2001 Due to Abrogation of the DNA Damage Repair in Non-Small Cell Lung Cancer Cells

Antitumor Activity of a Novel Tyrosine Kinase Inhibitor AIU2001 Due to Abrogation of the DNA Damage Repair in Non-Small Cell Lung Cancer Cells

Targeting precision medicine toxicity: recent developments

Clinical Trial Results: A Clinical Trial Bazaar!

Contact Info

Product

Resources

About