The dual PI3K/mTOR inhibitor NVP-BGT226 induces cell cycle arrest and regulates Survivin gene expression in human pancreatic cancer cell lines.

The phosphatidylinositol-3-kinase (PI3K) pathway is one of the most commonly activated signaling pathways in pancreatic cancer and is a target of interest for new therapeutic approaches. NVP-BGT226 is a novel dual class PI3K/mammalian target of rapamycin (mTOR) inhibitor that has entered Phase I/II clinical trials. We analyzed the effect of NVP-BGT226 (10-100 nM) on the pancreatic cell lines Panc-1, BxPc-3, AsPC-1 and MiaPaCa-2 in regard to cell viability, induction of apoptosis, cell cycle, and expression of the antiapoptotic genes Survivin, MCL-1, BCL-2 and BCL-xL. Cell viability decreased within 24-72 h after exposure to about 50% compared to untreated control cells in a concentration- but not time-dependent manner. Cell cycle analysis revealed that NVP-BGT226 induced predominantly G0/G1 cell cycle arrest. Additionally, real-time RT-PCR and Western blot analysis showed a remarkable decrease of Survivin expression. Originally designed as a dual inhibitor, there was only a significant inhibition of p-mTOR. In summary, the dual PI3K/mTOR inhibitor NVP-BGT226 induces G0/G1 arrest and acts, at least, partially via downregulation of Survivin.

A Randomized Phase IIa Trial with Temsirolimus versus Sunitinib in Advanced Non-Clear Cell Renal Cell Carcinoma: An Intergroup Study of the CESAR Central European Society for Anticancer Drug Research-EWIV and the Interdisciplinary Working Group on Renal Cell Cancer (IAGN) of the German Cancer Society.

BACKGROUND: Non-clear cell renal cell cancers (nccRCC) are rare entities, and the optimal therapy in metastatic disease has still to be defined. METHODS: In this small prospectively randomized phase IIa multicenter trial, we investigated temsirolimus (TEM) versus sunitinib (SUN) as first-line therapy in patients with metastatic nccRCC. The patients were randomized 1:1 to either TEM in a dose of 25 mg i.v. once a week or SUN with 50 mg p.o. daily for 4 weeks on and 2 weeks off. Primary endpoint was progression-free survival (PFS). In total, 22 patients were included with predominantly papillary RCC (16/22) followed by chromophobe RCC and others. RESULTS: The male to female ratio was 16:6. The tumor control rate (CR + PR + SD) was 58% for TEM and 90% for SUN-treated patients. There was also a trend for improved PFS with 9.3 versus 13.2 months (HR 1.64; 95% CI 0.65-4.18) in favor of SUN. There was no trend for overall survival. CONCLUSIONS: Despite this trial had to be terminated earlier due to low recruitment, the results match the other studies published so far with the mTOR inhibitor everolimus and SUN, which show a trend in favor of SUN for ORR and PFS.

[Systemic therapy of metastatic renal cell carcinoma]. / Systemtherapie des metastasierten Nierenzellkarzinoms.

In metastatic ccRCC , the treatment options in 1st line treatment are still the tyrosinkinase inhibitors (TKI) pazopanib and sunitinib, for patients with low or intermediate risk additionally IFNα/bevacizumab and for high risk patients the mTOR inhibitor temsirolimus. In 2nd line following cytokine therapy, axitinib or pazopanib and following TKI /VEGF directed therapy axitinib or everolimus may be administered. New upcoming agents in RCC are the PD1 antibody nivolumab and the multikinase inhibitor Cabozantinib, which both showed an OS advantage compared to everolimus. After marketing authorization in Europe, these agents should therefore be preferred in 2nd and 3rd line therapy. Further agents are under investigation.

Temsirolimus for advanced renal cell carcinoma.

Renal cell carcinomas (RCCs) represent one of the ten leading cancer entities with an increasing incidence especially in the western world. Unfortunately, about 25% of the patients develop metastatic RCC (mRCC) associated with a most unfavorable prognosis. In the recent years, various new agents targeting VEGF or VEGF receptor (VEGFR) or the mTOR pathway have been approved for the treatment of mRCC with significant prolongation of progression-free survival and, in part, of overall survival (OS). Targeting the mTOR kinase is an interesting option for mRCC. Temsirolimus, one of the available mTOR inhibitors, has been approved as a single agent in poor-risk mRCC patients based on the pivotal Phase III trial showing a significant superiority in OS versus IFN-α or temsirolimus + IFN-α, which has been verified by a pivotal Phase III trial. The benefit has been shown for clear cell carcinoma and papillary RCC as well. For poor prognosis patients, temsirolimus improves median survival by 3.6 months. In second-line treatment compared with sorafenib following first-line treatment with sunitinib temsirolimus showed a relative progression-free survival benefit for patients with nonclear cell RCC with temsirolimus. The median OS for the temsirolimus group was 12.27 and 16.64 months for the sorafenib group. In 2007, the US FDA granted approval for temsirolimus for the treatment of advanced RCC.

Therapy of mRCC beyond mTOR-inhibition in clinical practice: results of a retrospective analysis.

PURPOSE: Renal cell carcinoma (RCC) is the most common renal tumor and accounts for nearly 3 % of adult cancers. In the recent years, seven new targeted agents have been approved changing the treatment in metastatic RCC dramatically. So far, however, it remains unclear which sequence is best for those patients. This study analyzed retrospectively the outcome of patients treated with everolimus after failure of a vascular endothelial growth factor receptor-directed therapy and which therapies were used after everolimus. PATIENTS AND METHODS: In a retrospective analysis, patients receiving everolimus after failure of first-line VEGFR-directed therapy have been analyzed in regard to response, duration of treatment and subsequent therapies. In total, the data of 81 patients have been analyzed. RESULTS: The most observed first-line therapy was sunitinib followed by sorafenib. Thirty-two patients received everolimus as second-line therapy, and 49 as third-line therapy. The median duration of treatment with everolimus was 4.5 months. Seventy-seven of eighty-one patients (95 %) received a further therapy after discontinuation of everolimus. The agents administered beyond were sunitinib (28.6 %), sorafenib (28.6 %) and 42.8 % received other therapies. Twenty-seven patients received an additional sequence of therapy (fourth to fifth line). Fifty-eight percentage of patients have still been alive at time of analysis. CONCLUSION: The duration of everolimus therapy beyond failure of anti-VEGF-directed therapy and the reported time to progression was in the range of the RECORD-1 trial in daily practice as well. After failure of everolimus, reexposure to tyrosine kinase inhibitors is a common clinical practice and demonstrates a clinical benefit of therapies beyond everolimus.

Initial experience with 18F-fluoroethylcholine PET/CT in staging and monitoring therapy response of advanced renal cell carcinoma.

OBJECTIVE: The use of 18F-fluoroethylcholine (FEC) PET/ CT in staging and monitoring therapy response of advanced renal cell carcinoma (RCC) was prospectively analysed. METHODS: Preliminary results of two patients with metastatic RCC who underwent tumour nephrectomy as well as FEC PET/CT before and 10 weeks after two cycles of tyrosine kinase inhibitor therapy are presented. RESULTS: All in all, 18 tumour lesions were detected by baseline PET/CT, of which 10 (56%) were positive in FEC PET and 17 (94%) visible on contrast-enhanced computed tomography (ceCT). Mainly, small lung metastases resulted in the lower detection rate of FEC PET compared with ceCT. In follow-up PET/CT of the first case, progressive disease (PD) occurred with increase in tumour diameters of all metastases but non-uniform metabolic response. In the second case, partial response (PR) was achieved with concordant results of PET and CT. These results were confirmed by further CT in the course of disease. CONCLUSIONS: In this small sample more than half of the RCC metastases were evident in baseline FEC PET. Monitoring therapy, FEC PET showed heterogeneous results in the first case with PD and was consistent with ceCT in the second one displaying PR.

Feasibility of sequential use of sunitinib and temsirolimus in advanced renal cell carcinoma.

Targeted agents sunitinib and temsirolimus are effective in advanced renal cell carcinoma. Treatment algorithms for single-agent use have been proposed in order to optimize timing and type of therapy. The aim of this study was to investigate the tolerability and adverse event profile of patients who received sunitinib and temsirolimus in sequence. We performed a retrospective analysis of patients with advanced renal cell carcinoma who received temsirolimus after disease progression under sunitinib therapy. Dosages of both drugs were in accordance with the recommendations given by the respective manufacturers. Temsirolimus was provided before its official approval within a compassionate use program. Adverse event assessment followed the National Cancer Institute Common Toxicity Criteria. Thirteen patients receiving temsirolimus after progression under sunitinib were identified. Overall treatment time with targeted drugs (sunitinib/temsirolimus) was 34.8 (17-78) weeks, treatment with sunitinib was 28.6 (12-72), and with temsirolimus 6.2 (2-16) weeks, respectively, whereas mean therapy interruption time between both approaches was 4.4 (2-12) weeks. Under sunitinib, we observed 52 transient adverse events, 49 (94.2%) were of grade I/II, whereas 3 (5.8%) were of grade III. Under temsirolimus 36 adverse events, only grade I/II in nature were remarked. Sequential use of temsirolimus after progression under sunitinib seems to be feasible and results in a predictable, medically manageable side effect profile. Further evaluation is necessary to define the oncological validity of this sequencing approach.

Wilms' tumour gene 1 (WT1) as a target in curcumin treatment of pancreatic cancer cells.

The transcription factor WT1 plays an important role in cellular proliferation and survival of various cancer cells, and is frequently expressed in pancreatic cancer. Curcumin has been shown to be a potentially effective agent in pancreatic cancer. In this context, the purpose of this study was to determine the role of WT1 in a curcumin-treated pancreatic cancer cell line. To study the effect of curcumin on the expression of WT1, we incubated the pancreatic cancer cell line PANC-1 with different amounts of curcumin. The expression of WT1 on mRNA and protein level was measured with real-time RT-PCR and Western blot analysis. The incubation of the pancreatic cancer cell line PANC-1 with curcumin resulted in an inhibition of cellular proliferation as measured with MTT assay. The expression of WT1 on mRNA and protein level was significantly down-regulated in a concentration-dependent manner after treatment with curcumin. The WT1 mRNA levels were decreased by 20%, 25%, 40%, 78% and 88% in response to 10, 20, 30, 40 and 50 microM curcumin. The use of small inhibitory RNA (siRNA) targeting WT1 down-regulated the expression of WT1 about 90%. Combined treatment with curcumin and siRNA targeting WT1 resulted in a significant inhibition of cell proliferation compared to curcumin-treated cells alone. In conclusion, WT1 is involved in cellular proliferation of PANC-1 cells. Targeting WT1 gene expression with siRNA may enhance the efficacy of curcumin to inhibit cell proliferation.

Experiences and practical conclusions concerning temsirolimus use and adverse event management in advanced renal cell carcinoma within a compassionate use program in Germany.

PURPOSE: To detail tolerance of temsirolimus in a routine practice setting within a compassionate use program for patients with renal cell carcinoma. METHODS: We treated 32 patients with advanced renal cell carcinoma with temsirolimus within the German compassionate use program on an individual patient basis free of charge according to EU guidelines at our two institutions. Twenty-five milligrams of temsirolimus was applied weekly in an inpatient clinical setting. Adverse events were classified following National Cancer Institute Common Toxicity Criteria. RESULTS: No dose modification or therapy interruptions were necessary due to adverse events. Adverse events like asthenia/fatigue were observed in 43.8%, increased creatinine in 40.6%, mucositis in 31.3%, secondary diabetes in 28.1%, hypothyreosis in 12.5% and rash in 12.5%, hypercholesterolemia and hypertriglyceridemia in 9.3% of the patients. CONCLUSION: Therapy with temsirolimus in advanced renal cell carcinoma is well tolerated. In a routine practice setting it results in a predictable adverse event profile that can be managed medically.