gdc-0449 and Small-Cell-Lung-Carcinoma

It has long been known that the hedgehog signaling pathway is crucial for embryonic development, in both Drosophila and vertebrate systems. During the past few years its implication in carcinogenesis has become clear and today it is acknowledged that this pathway plays a role in the malignant transformation of multiple cell types, either owing to the mutation of some of its components or to its erratic activation. New molecular targeted therapies that inhibit the pathway have shown their unquestionable efficiency in several tumours -among which basal cell carcinoma, medulloblastoma, or pancreatic adenocarcinoma. The assessment of these inhibitors in other types of tumours is currently underway with promising results, suggesting that the Sonic hedgehog signalling pathway may become one of the therapeutic targets of the future.

Topics: Anilides; Animals; Carcinoma, Basal Cell; Cerebellar Neoplasms; Embryonic Development; Embryonic Induction; Hedgehog Proteins; Humans; Lung Neoplasms; Medulloblastoma; Molecular Targeted Therapy; Mutation; Neoplasms; Neoplastic Stem Cells; Pancreatic Neoplasms; Patched Receptors; Patient Selection; Pyridines; Receptors, Cell Surface; Signal Transduction; Skin Neoplasms; Small Cell Lung Carcinoma

Preclinical targeting of the hedgehog pathway by vismodegib and of insulin-like growth factor 1 receptor by cixutumumab enhances the efficacy of chemotherapy and also demonstrates activity against the tumor cell fraction responsible for disease recurrence in small cell lung cancer.. Patients with newly diagnosed extensive-stage small cell lung cancer (SCLC-ED) were randomized to receive four 21-day cycles of cisplatin and etoposide alone (cisplatin at 75 mg/m(2) on day 1 and etoposide at 100 mg/m(2) on days 1-3; arm A) or in combination with either vismodegib (150 mg/d by mouth; arm B) or cixutumumab (6 mg/kg/wk intravenously on day 1; arm C). The primary endpoint was progression-free survival (PFS). Circulating tumor cells (CTCs) were isolated/enumerated with the Veridex CellSearch platform at the baseline.. One hundred fifty-two eligible patients were treated. Patient demographics and disease characteristics were well balanced between the 3 arms except for the higher rate with a performance status of 0 in arm B (P = .03). The median PFS times in arms A, B, and C were 4.4, 4.4, and 4.6 months, respectively; the median overall survival (OS) times were 8.8, 9.8, and 10.1 months, respectively; and the response rates were 48%, 56%, and 50%, respectively. None of the comparisons of these outcomes were statistically significant. The median OS was 10.5 months for those with low CTC counts (≤100/7.5 mL) at baseline and 7.2 months for those with high CTC counts (hazard ratio, 1.74; P = .006).. There was no significant improvement in PFS or OS with the addition of either vismodegib or cixutumumab to chemotherapy in patients with SCLC-ED. A low baseline CTC count was associated with a favorable prognosis. Cancer 2016;122:2371-2378. © 2016 American Cancer Society.

Topics: Adult; Aged; Aged, 80 and over; Anilides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Cisplatin; Etoposide; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Neoplastic Cells, Circulating; Pyridines; Small Cell Lung Carcinoma; Treatment Outcome

The hedgehog (Hh) signaling pathway has been shown to be activated in the cancer stem cells of several tumor entities. The Hh inhibitor GDC-0449 has been proven to be effective in some cancers but not yet in lung cancer. We aimed at investigating whether GDC-0449 is effective in the lung cancer cell lines HCC (adenocarcinoma) and H1339 (small-cell-lung carcinoma), whether in these cell lines stem cell-like side populations (SPs) can be identified, and whether possible effects of GDC-0449 are mediated via SPs. SPs were identified by spectrum shift and decreased fluorescence after staining with 2.5 μg/ml Hoechst 33342. Expression of proteins was quantified by immunofluorescence. GDC-0449 (25 and 50 μM) inhibited concentration-dependent cell growth in HCC and H1339 cells. Further, the inhibitory effects of cisplatin on cell growth were augmented. In HCC and H1339 cell lines, SPs of 0.57 and 0.46% could be identified, respectively. SP, but not non-SP, cells were able to repopulate the original tumor population. The Hh receptor smoothened was detectable in SP but not in non-SP cells, showing the activation of the Hh pathway only in SPs. GDC-0449 considerably reduced SPs in HCC and H1339 cells. We demonstrate for the first time that GDC-0449 effectively reduces cell growth in lung cancer cell lines. This effect is mediated by the inhibition of stem cell-like SPs.

Topics: Anilides; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Cell Line, Tumor; Cisplatin; Flow Cytometry; Fluorescence; Fluorescent Antibody Technique; Gene Expression Regulation, Neoplastic; Hedgehog Proteins; Humans; Lung Neoplasms; Pyridines; Signal Transduction; Small Cell Lung Carcinoma; Time Factors

Cisplatin resistance is an important issue in lung cancer. We aimed at investigating if the Hedgehog pathway inhibitor GDC-0449 is effective in cisplatin-resistant cells and if it alters intracellular Ca(2+)-homeostasis.. The cytoplasmatic ([Ca(2+)](cyto)) and endoplasmatic ([Ca(2+)])(ER) Ca(2+) concentration of HCC (adeno carcinoma of the lung) and H1339 (small cell lung carcinoma) cells were measured with the calcium indicator dye Fura-2 AM. The expression of the inositol-1,4,5-trisphosphate receptor (IP(3)R) and sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) were analyzed using western blot analysis.. GDC-0449 inhibited cell growth in cisplatin-naïve and -resistant cells. In both cell types, GDC-0449 increased [Ca(2+)](cyto) and reduced endoplasmatic [Ca(2+)](ER). Cisplatin failed to considerably alter Ca(2+) homeostasis in resistant cells. The effects of GDC-0449 on intracellular Ca(2+) homeostasis were not mediated by an altered expression of IP(3)R or SERCA.. GDC-0449 alters intracellular Ca(2+) homeostasis and inhibits cell growth in cisplatin-resistant lung cancer cells.

Topics: Adenocarcinoma; Anilides; Antineoplastic Agents; Blotting, Western; Calcium; Cell Proliferation; Cisplatin; Cytoplasm; Drug Resistance, Neoplasm; Fura-2; Hedgehog Proteins; Homeostasis; Humans; Inositol 1,4,5-Trisphosphate Receptors; Lung Neoplasms; Pyridines; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Small Cell Lung Carcinoma; Tumor Cells, Cultured