Phase I trial of the oral smoothened inhibitor sonidegib in combination with paclitaxel in patients with advanced solid tumors

Stathis, Anastasios; Hess, Dagmar; Moos, Roger von; Homicsko, Krisztian; Griguolo, Gaia; Joerger, Markus; Mark, Michael; Ackermann, Christoph; Allegrini, Sara; Catapano, Carlo V.; Xyrafas, A.; Enoiu, Milica; Berardi, Simona; Gargiulo, Piera; Sessa, C.

doi:10.1007/s10637-017-0454-z

Cited by 28 publications

(13 citation statements)

References 25 publications

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“…Acquired resistance to sonidegib in a mouse model of MB was associated with mutations in mouse SMO, including N223D, L225R, D388N, S391N, and G457S [84], residues conserved in human SMO (Table 1; Figure 3). Several phase I and II trials for sonidegib in monotherapy and in combination are currently underway in both solid and hematological malignancies [140,141,142,143].…”

Section: Smoothened Inhibitorsmentioning

confidence: 99%

Targeting the Oncoprotein Smoothened by Small Molecules: Focus on Novel Acylguanidine Derivatives as Potent Smoothened Inhibitors

Pietrobono¹,

Stecca²

2018

Cells

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Hedgehog-GLI (HH) signaling was originally identified as a critical morphogenetic pathway in embryonic development. Since its discovery, a multitude of studies have reported that HH signaling also plays key roles in a variety of cancer types and in maintaining tumor-initiating cells. Smoothened (SMO) is the main transducer of HH signaling, and in the last few years, it has emerged as a promising therapeutic target for anticancer therapy. Although vismodegib and sonidegib have demonstrated effectiveness for the treatment of basal cell carcinoma (BCC), their clinical use has been hampered by severe side effects, low selectivity against cancer stem cells, and the onset of mutation-driven drug resistance. Moreover, SMO antagonists are not effective in cancers where HH activation is due to mutations of pathway components downstream of SMO, or in the case of noncanonical, SMO-independent activation of the GLI transcription factors, the final mediators of HH signaling. Here, we review the current and rapidly expanding field of SMO small-molecule inhibitors in experimental and clinical settings, focusing on a class of acylguanidine derivatives. We also discuss various aspects of SMO, including mechanisms of resistance to SMO antagonists.

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Section: Smoothened Inhibitorsmentioning

confidence: 99%

Targeting the Oncoprotein Smoothened by Small Molecules: Focus on Novel Acylguanidine Derivatives as Potent Smoothened Inhibitors

Pietrobono¹,

Stecca²

2018

Cells

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“…In a phase I clinical trial (GEICAM/2012-12, EDALINE), three of 12 patients with metastatic TNBC were shown to benefit from the combination therapy of sonidegib and docetaxel, with one patient experiencing a complete response [256,257]. Further phase I trials demonstrated that sonidegib in combination with paclitaxel is well-tolerated and may exert antitumor effects in patients with advanced solid tumors including breast cancer [258]. Similar effects were observed in combination with docetaxel in advanced TNBC patients [256,259].…”

Section: Gpcrs In Breast Cancer: Signaling Biology and Modulatorsmentioning

confidence: 99%

GPCR Modulation in Breast Cancer

Lappano

Jacquot

Maggiolini

2018

IJMS

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Breast cancer is the most prevalent cancer found in women living in developed countries. Endocrine therapy is the mainstay of treatment for hormone-responsive breast tumors (about 70% of all breast cancers) and implies the use of selective estrogen receptor modulators and aromatase inhibitors. In contrast, triple-negative breast cancer (TNBC), a highly heterogeneous disease that may account for up to 24% of all newly diagnosed cases, is hormone-independent and characterized by a poor prognosis. As drug resistance is common in all breast cancer subtypes despite the different treatment modalities, novel therapies targeting signaling transduction pathways involved in the processes of breast carcinogenesis, tumor promotion and metastasis have been subject to accurate consideration. G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors involved in the development and progression of many tumors including breast cancer. Here we discuss data regarding GPCR-mediated signaling, pharmacological properties and biological outputs toward breast cancer tumorigenesis and metastasis. Furthermore, we address several drugs that have shown an unexpected opportunity to interfere with GPCR-based breast tumorigenic signals.

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“…However, its antitumor therapeutic performance is reduced by certain issues, such as strong side effects, poor aqueous solubility, and inadequate specificity. [41][42][43] Hence, herein, we generated targeted drug-loaded NBs, namely, PTX-AMD070 NBs, which incorporated AMD070, a small-molecule CXCR4 antagonist, and PTX, a commonly used chemotherapeutic drug. The goal of this study was to study the specific binding of AMD070 and PTX to various tumor cells, targeted ultrasound imaging contrast enhancement, and the therapeutic effect of concurrent use of the NBs with UTND.…”

Section: Discussionmentioning

confidence: 99%

<p>Preparation Of Nanobubbles Modified With A Small-Molecule CXCR4 Antagonist For Targeted Drug Delivery To Tumors And Enhanced Ultrasound Molecular Imaging</p>

Peng

Zhu

Wang

et al. 2019

IJN

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To construct nanobubbles (PTX-AMD070 NBs) for targeted delivery of paclitaxel (PTX) and AMD070, examine their performance in ultrasound molecular imaging of breast cancer and cervical cancer and their therapeutic effect combined with ultrasound targeted nanobubble destruction (UTND). Materials and methods: PTX-AMD070 NBs were prepared via an amide reaction, and the particle size, zeta potential, encapsulation rate and drug loading efficiency were examined. Laser confocal microscopy and flow cytometry were used to analyze the targeted binding ability of PTX-AMD070 NBs to CXCR4 + MCF-7 cells and C33a cells. The effect of PTX-AMD070 NBs combined with UTND on cell proliferation inhibition and apoptosis induction was detected by CCK-8 assays and flow cytometry. The contrast-enhanced imaging features of PTX-AMD070 NBs and paclitaxel-loaded nanobubbles were compared in xenograft tumors. The penetration ability of PTX-AMD070 NBs in xenograft tissues was evaluated by immunofluorescence. The therapeutic effect of PTX-AMD070 NBs combined with UTND on xenograft tumors was assessed. Results: PTX-AMD070 NBs showed a particle size of 494.3±61.2 nm, a zeta potential of −22.4±1.75 mV, an encapsulation rate with PTX of 53.73±7.87%, and a drug loading efficiency with PTX of 4.48±0.66%. PTX-AMD070 NBs displayed significantly higher targeted binding to MCF-7 cells and C33a cells than that of PTX NBs (P<0.05), and combined with UTND manifested a more pronounced effect in inhibiting cell proliferation and promoting apoptosis than other treatments. PTX-AMD070 NBs aggregated specifically in xenograft tumors in vivo, and significantly improved the image quality. Compared with other treatment groups, PTX-AMD070 NBs combined with UTND exhibited the smallest tumor volume and weight, and the highest degree of apoptosis and necrosis. Conclusion: PTX-AMD070 NBs improved the ultrasound imaging effect in CXCR4 + xenograft tumors and facilitated targeted therapy combined with UTND. Therefore, this study provides an effective method for the integration of ultrasound molecular imaging and targeted therapy of malignant tumors.

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Phase I trial of the oral smoothened inhibitor sonidegib in combination with paclitaxel in patients with advanced solid tumors

Cited by 28 publications

References 25 publications

Targeting the Oncoprotein Smoothened by Small Molecules: Focus on Novel Acylguanidine Derivatives as Potent Smoothened Inhibitors

Targeting the Oncoprotein Smoothened by Small Molecules: Focus on Novel Acylguanidine Derivatives as Potent Smoothened Inhibitors

GPCR Modulation in Breast Cancer

<p>Preparation Of Nanobubbles Modified With A Small-Molecule CXCR4 Antagonist For Targeted Drug Delivery To Tumors And Enhanced Ultrasound Molecular Imaging</p>

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