A Non-Interventional Study on Vismodegib for Basal Cell Carcinoma in Swedish Patients.

INTRODUCTION: Real-life data on vismodegib in advanced basal cell carcinoma (aBCC) are limited. Optimal treatment duration is left to the discretion of the physician. OBJECTIVES: To assess the effectiveness, safety and treatment pattern for vismodegib in aBCC in clinical practice. METHODS: In this multicenter, non-interventional, prospective study, 49 Swedish patients planned for vismodegib treatment were included. The treatment pattern observed was treatment until remission, allowing unlimited discontinuations/pauses. RESULTS: The majority of patients (93.8%), discontinued at least once during the study. Compared to earlier studies there was a decrease of more than 2 months with actual drug intake, reducing the patients burden and costs, at the same time as a high number of responses were seen (87.8%). Median progression-free-survival was 16.7 months, and 90% of the patients were alive at 13.3 months. Ten patients were re-challenged with vismodegib at recurrence or progression, resulting in five partial remissions and three complete remissions. CONCLUSIONS: Clinical response rates with vismodegib for aBCC were comparable to those of similar trials despite a shorter and more intermittent treatment duration. The majority of re-challenges lead to partial or complete remissions.

Potentiation of chemotherapeutic drugs by energy metabolism inhibitors 2-deoxyglucose and etomoxir.

Inhibition of energy production as a strategy for potentiation of anticancer chemotherapy was investigated using 1 glycolysis inhibitor and 1 fatty acid beta-oxidation inhibitor-2-deoxyglucose and etomoxir, respectively, both known to be clinically well tolerated. Eighteen anticancer drugs were screened for potentiation by these inhibitors. 2-deoxyglucose potentiated acute apoptosis (24 hr) induced mainly by some, but not all, genotoxic drugs, whereas etomoxir had effect only on cisplatin. By contrast, etomoxir did potentiate the overall, 48 hr effects of some genotoxic drugs, and was in addition more efficient than deoxyglucose in potentiating the overall effects of several non-genotoxic drugs. Both types of potentiation were largely lost in the absence of p53. Because cisplatin was potentiated by both energy inhibitors in both types of assay, it was investigated at additional concentrations and over longer time. Both energy inhibitors strongly potentiated non-apoptotic concentrations of cisplatin in p53-wildtype as well as in p53-deficient, cisplatin-resistant HCT-116 colon carcinoma cells. Reduced ATP levels correlated with, but were not sole determinants, the antiproliferative effects. We conclude that the long-term effects of cisplatin potentiation are important and either p53-independent or improved by a lack of p53. We also conclude that although the potentiated drugs as yet have no obvious mechanistic factor in common, the strategy holds promise with genotoxic as well non-genotoxic anticancer drugs.

3-Bromopyruvate as inhibitor of tumour cell energy metabolism and chemopotentiator of platinum drugs.

Tumour cells depend on aerobic glycolysis for adenosine triphosphate (ATP) production, making energy metabolism an interesting therapeutic target. 3-Bromopyruvate (BP) has been shown by others to inhibit hexokinase and eradicate mouse hepatocarcinomas. We report that similar to the glycolysis inhibitor 2-deoxyglucose (DG), BP rapidly decreased cellular ATP within hours, but unlike DG, BP concomitantly induced mitochondrial depolarization without affecting levels of reducing equivalents. Over 24h, and at equitoxic doses, DG reduced glucose consumption more than did BP. The observed BP-induced loss of ATP is therefore largely due to mitochondrial effects. Cell death induced over 24h by BP, but not DG, was blocked by N-acetylcysteine, indicating involvement of reactive oxygen species. BP-induced cytotoxicity was independent of p53. When combined with cisplatin or oxaliplatin, BP led to massive cell death. The anti-proliferative effects of low-dose platinum were strikingly potentiated also in resistant p53-deficient cells. Together with the reported lack of toxicity, this indicates the potential of BP as a clinical chemopotentiating agent.

Two distinct steps of Bak regulation during apoptotic stress signaling: different roles of MEKK1 and JNK1.

Stress-activated protein (SAP) kinases and the mitochondrial pro-apoptotic Bcl-2 protein Bak are important regulators of apoptosis. Reduced expression of Bak increases cellular resistance to the anticancer agent cisplatin, and we report here that mouse embryo fibroblasts deficient in the SAP kinase jnk1 are highly resistant to apoptosis induced by cisplatin. When human melanoma cells were treated with cisplatin, Bak function was found to be regulated in two distinct steps by two SAP kinases, MEKK1 and JNK1. The first of these steps involves MEKK1-controlled conformational activation of Bak. The second step leads to formation of 80-170 kDa Bak complexes correlating with apoptosis, and is controlled by JNK1. Inhibition of MEKK1 blocked the initial Bak conformational activation but did not block JNK1 activation, and deficiency in, or inhibition of, JNK1 did not prevent conformational activation of Bak. Furthermore, inducible expression of a constitutively active form of MEKK1 led to Bak conformational activation, but not to 80-170 kDa complexes. Consequently, apoptosis was delayed unless JNK was exogenously stimulated, indicating that Bak conformational activation is not necessarily an apoptotic marker. The two-step regulation of Bak revealed here may be important for tight control of mitochondrial factor release and apoptosis.