Cisplatin Plus Ifosfamide with/without Etoposide as Salvage Treatment in Heavily-pre-treated Patients with Metastatic Breast Cancer.

BACKGROUND: The efficacy of platinum- and ifosfamide-based chemotherapy regimens as salvage treatment in metastatic breast cancer (MBC) has not yet been sufficiently evaluated. PATIENTS AND METHODS: Patients with MBC treated with cisplatin plus ifosfamide with (PEI) and without (PI) etoposide in our clinic between 04/2005 and 04/2014 were retrospectively analyzed. RESULTS: A total of 20 patients (median four prior chemotherapies) treated with PEI/PI were identified, out of whom 18 were evaluable for objective response. Treatment with PEI/PI resulted in one complete remission, nine partial remissions and two cases of stable disease. The median (range) progression-free survival was 4 (0-18) months and median overall survival from therapy initiation was 8.5 (0-50) months. PEI/PI therapy caused grade 3/4 toxicities (mainly hematological) in 80% of patients. CONCLUSION: PEI/PI is an adequate salvage treatment for patients with MBC but cannot be generally recommended due to toxicity. However, comparison with platinum monotherapy trials suggests that PEI/PI might be a more effective treatment for patients with triple-negative breast cancer.

Inhibition of pan-class I phosphatidyl-inositol-3-kinase by NVP-BKM120 effectively blocks proliferation and induces cell death in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most frequent aggressive lymphoma, with a great demand for novel treatments for relapsing and refractory disease. Constitutive activation of the phosphatidyl-inositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is often detected in this lymphoma. Inhibition of this signaling cascade with the pan-class I PI3K inhibitor NVP-BKM120 decreased cell proliferation and increased apoptotic cell death. DLBCL proliferation was further decreased if NVP-BKM120-induced autophagy was blocked. Treatment with NVP-BKM120 was associated with an increase of the pro-apoptotic BH3-only proteins Puma and Bim and down-regulation of the anti-apoptotic Bcl-xL and Mcl-1. Translation of Bcl-xL and Mcl-1 is facilitated by cap-dependent mRNA translation, a process that was partially inhibited by NVP-BKM120. Overall, we demonstrated here the potential of NVP-BKM120 for the treatment of DLBCL.

Concurrent inhibition of PI3-kinase and mTOR induces cell death in diffuse large B cell lymphomas, a mechanism involving down regulation of Mcl-1.

Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling is frequently dysregulated in diffuse large B cell lymphoma (DLBCL) including the favorable germinal centre B-cell (GCB) and the unfavorable activated B-cell (ABC) subtypes. mTOR promotes cap-dependent translation of proteins, like Mcl-1, through inhibitory phosphorylation of the eukaryotic translation initiation factor 4E binding protein 1 (4EBP1). Inhibition of mTOR by RAD001 reduces proliferation but fails to dephosphorylate 4EBP1 and to induce cell death in either DLBCL subtype. In contrast, concurrent inhibition of PI3K and mTOR with NVP-BEZ235 inhibits proliferation, dephosphorylates 4EBP1, and induces cells death, notably more pronounced in CGB cells. Small RNA interference identifies Mcl-1 as a crucial cell death mediator of both DLBCL subtypes. Inhibition of the PI3K/mTOR/4EBP1 by NVP-BEZ235 results in suppression of the cap-dependent translation initiation complex and concomitant downregulation of Mcl-1 in GCB cell lines. In ABC cell lines, this suppression is possibly compensated by NF-κB- or Pim kinase-mediated signaling.