lde225 and Lung-Neoplasms

The Hedgehog pathway has been implicated in small cell lung cancer (SCLC) tumor initiation and progression. Pharmacologic blockade of the key Hedgehog regulator, Smoothened, may inhibit these processes. We performed a phase I study to determine the maximum tolerated dose (MTD) of sonidegib (LDE225), a selective, oral Smoothened antagonist, in combination with etoposide/cisplatin in newly diagnosed patients with extensive stage SCLC.. Patients received 4-6 21-day cycles of etoposide/cisplatin with daily sonidegib. Patients with response or stable disease were continued on sonidegib until disease progression or unacceptable toxicity. Two dose levels of sonidegib were planned: 400mg and 800mg daily, with 200mg daily de-escalation if necessary. Next generation sequencing was performed on available specimens. Circulating tumor cells (CTCs) were quantified at baseline and with disease evaluation.. Fifteen patients were enrolled. 800mg was established as the recommended phase II dose of sonidegib in combination with etoposide/cisplatin. Grade 3 or greater toxicities included: anemia (n=5), neutropenia (n=8), CPK elevation (n=2), fatigue (n=2), and nausea (n=2). Toxicity led to removal of one patient from study. Partial responses were confirmed in 79% (11/14; 95% CI: 49-95%). One patient with SOX2 amplification remains progression-free on maintenance sonidegib after 27 months. CTC count, at baseline, was associated with the presence of liver metastases and after 1 cycle of therapy, with overall survival.. Sonidegib 800mg daily was the MTD when administered with EP. Further genomic characterization of exceptional responders may reveal clinically relevant predictive biomarkers that could tailor use in patients most likely to benefit.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biphenyl Compounds; Cisplatin; Etoposide; Female; Hedgehog Proteins; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Neoplasm Staging; Neoplastic Cells, Circulating; Pyridines; Small Cell Lung Carcinoma; Treatment Outcome

A man in his 50s presented with an ulcerative lesion within the left axillary fold that had progressively worsened over 18 months. Biopsy revealed an ulcerative basal cell carcinoma (BCC), which was surgically managed. CT chest scans done 7 months later assessed post-treatment of radiotherapy. This revealed pulmonary lesions, which were biopsy-proven metastatic BCC. Sonidegib, a hedgehog signalling inhibitor, was used for first-line treatment. Due to progressive disease, sonidegib was ceased. Cemiplimab, a checkpoint inhibitor, was used as second-line treatment based on a phase II trial demonstrating efficacy in the setting of metastatic BCC. CT reports were initially consistent with response but after 6 months of cemiplimab treatment, repeat CT chest scans revealed a decrease in size of the previously cited pulmonary lesions.This is a rare case of BCC metastases which has limited treatment options. This case provides insight of the patient experience on such treatment.

Topics: Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Lung Neoplasms; Male; Pyridines; Skin Neoplasms

Sonidegib (LDE-225) is a Hedgehog pathway inhibitor used for the therapy of basal cell carcinoma. In addition, the drug is a subject of clinical trials for the treatment of other solid tumors including non-small cell lung cancer (NSCLC). In this study, we explored the potential of sonidegib to act as a perpetrator of drug-drug interactions (DDIs) and modulator of transporter- and enzyme-mediated multidrug resistance (MDR). First, we found that transport functions of ABCB1 and ABCG2 were effectively inhibited by sonidegib in accumulation studies. In contrast, the drug did not cause fluctuations in mRNA levels of tested efflux transporters. In drug combination assays, sonidegib synergistically enhanced the cytotoxicity of daunorubicin and mitoxantrone in ABCB1- and ABCG2-overexpressing cells, respectively. Notably, similar phenomena were also observed in explant tumor cultures derived from NSCLC-suffering patients. In addition, the anticancer effects of sonidegib were not hampered by the expression of the ABC transporters associated with MDR. Last, sonidegib had no significant influence on the activity of CYP3A4 isoform in vitro. In summary, our work suggests that sonidegib can be considered a potential perpetrator of clinical DDIs on ABCB1 and ABCG2. After in vivo evaluation, its chemosensitizing properties might be projected into efficient and safe treatment regimen for the clinical management of NSCLC patients with high ABCB1/ABCG2 expression.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cytostatic Agents; Drug Resistance, Neoplasm; Hedgehog Proteins; Humans; Lung Neoplasms; Neoplasm Proteins; Pyridines

Resistance to tyrosine kinase inhibitors (TKI) of EGF receptor (EGFR) is often related to activation of other signaling pathways and evolution through a mesenchymal phenotype.. Because the Hedgehog (Hh) pathway has emerged as an important mediator of epithelial-to-mesenchymal transition (EMT), we studied the activation of Hh signaling in models of EGFR-TKIs intrinsic or acquired resistance from both EGFR-mutated and wild-type (WT) non-small cell lung cancer (NSCLC) cell lines.. Activation of the Hh pathway was found in both models of EGFR-mutated and EGFR-WT NSCLC cell line resistant to EGFR-TKIs. In EGFR-mutated HCC827-GR cells, we found SMO (the Hh receptor) gene amplification, MET activation, and the functional interaction of these two signaling pathways. In HCC827-GR cells, inhibition of SMO or downregulation of GLI1 (the most important Hh-induced transcription factor) expression in combination with MET inhibition exerted significant antitumor activity.In EGFR-WT NSCLC cell lines resistant to EGFR inhibitors, the combined inhibition of SMO and EGFR exerted a strong antiproliferative activity with a complete inhibition of PI3K/Akt and MAPK phosphorylation. In addition, the inhibition of SMO by the use of LDE225 sensitizes EGFR-WT NSCLC cells to standard chemotherapy.. This result supports the role of the Hh pathway in mediating resistance to anti-EGFR-TKIs through the induction of EMT and suggests new opportunities to design new treatment strategies in lung cancer.

Topics: Animals; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; ErbB Receptors; Female; Gene Amplification; Hedgehog Proteins; Humans; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; Pyridines; Receptors, G-Protein-Coupled; Signal Transduction; Smoothened Receptor

Multiple lines of evidence support that the Hedgehog (Hh) signalling has a role in the maintenance and progression of different human cancers. Therefore, inhibition of the Hh pathway represents a valid anticancer therapeutic approach for renal cell carcinoma (RCC) patients. NVP-LDE225 is a Smoothened (Smo) antagonist that induces dose-related inhibition of Hh and Smo-dependent tumour growth.. We assayed the effects of NVP-LDE225 alone or in combination with everolimus or sunitinib on the growth and invasion of human RCC models both in vitro and in vivo. To this aim, we used a panel of human RCC models, comprising cells with acquired resistance to sunitinib - a multiple tyrosine kinase inhibitor approved as a first-line treatment for RCC.. NVP-LDE225 cooperated with either everolimus or sunitinib to inhibit proliferation, migration, and invasion of RCC cells even in sunitinib-resistant (SuR) cells. Some major transducers involved in tumour cell motility, including paxillin, were also efficiently inhibited by the combination therapy, as demonstrated by western blot and confocal microscopy assays. Moreover, these combined treatments inhibited tumour growth and increased animal survival in nude mice xenografted with SuR RCC cells. Finally, lung micrometastasis formation was reduced when mice were treated with NVP-LDE225 plus everolimus or sunitinib, as evidenced by artificial metastatic assays.. Hedgehog inhibition by NVP-LDE225 plus sunitinib or everolimus bolsters antitumour activity by interfering with tumour growth and metastatic spread, even in SuR cells. Thus, this new evidence puts forward a new promising therapeutic approach for RCC patients.

Topics: Actin Cytoskeleton; Actins; Animals; Antineoplastic Combined Chemotherapy Protocols; Biphenyl Compounds; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Synergism; Everolimus; Hedgehog Proteins; Humans; Indoles; Inhibitory Concentration 50; Kidney Neoplasms; Kruppel-Like Transcription Factors; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinases; Neoplasm Micrometastasis; Nuclear Proteins; Paxillin; Proto-Oncogene Proteins c-akt; Pyridines; Pyrroles; Receptors, G-Protein-Coupled; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Smoothened Receptor; Sunitinib; Transcription Factors; Tumor Burden; Xenograft Model Antitumor Assays; Zinc Finger Protein GLI1; Zinc Finger Protein Gli2