Personalized prescription of tyrosine kinase inhibitors in unresectable metastatic cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma is an aggressive tumor with poor prognosis. Most of the cases are not available for surgery at the stage of the diagnosis and the best clinical practice chemotherapy results in about 12-month median survival. Several tyrosine kinase inhibitors (TKIs) are currently under investigation as an alternative treatment option for cholangiocarcinoma. Thus, the report of personalized selection of effective inhibitor and case outcome are of clinical interest. CASE PRESENTATION: Here we report a case of aggressive metastatic cholangiocarcinoma (MCC) in 72-year-old man, sequentially treated with two targeted chemotherapies. Initially disease quickly progressed during best clinical practice care (gemcitabine in combination with cisplatin or capecitabine), which was accompanied by significant decrease of life quality. Monotherapy with TKI sorafenib was prescribed to the patient, which resulted in stabilization of tumor growth and elimination of pain. The choice of the inhibitor was made based on high-throughput screening of gene expression in the patient's tumor biopsy, utilized by Oncobox platform to build a personalized rating of potentially effective target therapies. However, time to progression after start of sorafenib administration did not exceed 6 months and the regimen was changed to monotherapy with Pazopanib, another TKI predicted to be effective for this patient according to the same molecular test. It resulted in disease progression according to RECIST with simultaneous elimination of sorafenib side effects such as rash and hand-foot syndrome. After 2 years from the diagnosis of MCC the patient was alive and physically active, which is substantially longer than median survival for standard therapy. CONCLUSION: This case evidences that sequential personalized prescription of different TKIs may show promising efficacy in terms of survival and quality of life in MCC.

Direct control of somatic stem cell proliferation factors by the Drosophila testis stem cell niche.

Niches have traditionally been characterised as signalling microenvironments that allow stem cells to maintain their fate. This definition implicitly assumes that the various niche signals are integrated towards a binary fate decision between stemness and differentiation. However, observations in multiple systems have demonstrated that stem cell properties, such as proliferation and self-renewal, can be uncoupled at the level of niche signalling input, which is incompatible with this simplified view. We have studied the role of the transcriptional regulator Zfh1, a shared target of the Hedgehog and Jak/Stat niche signalling pathways, in the somatic stem cells of the Drosophila testis. We found that Zfh1 binds and downregulates salvador and kibra, two tumour suppressor genes of the Hippo/Wts/Yki pathway, thereby restricting Yki activation and proliferation to the Zfh1+ stem cells. These observations provide an unbroken link from niche signal input to an individual aspect of stem cell behaviour that does not, at any step, involve a fate decision. We discuss the relevance of these findings for an overall concept of stemness and niche function.

Nox4 and Duox1/2 Mediate Redox Activation of Mesenchymal Cell Migration by PDGF.

Platelet derived growth factor (PDGF) orchestrates wound healing and tissue regeneration by regulating recruitment of the precursor mesenchymal stromal cells (MSC) and fibroblasts. PDGF stimulates generation of hydrogen peroxide that is required for cell migration, but the sources and intracellular targets of H2O2 remain obscure. Here we demonstrate sustained live responses of H2O2 to PDGF and identify PKB/Akt, but not Erk1/2, as the target for redox regulation in cultured 3T3 fibroblasts and MSC. Apocynin, cell-permeable catalase and LY294002 inhibited PDGF-induced migration and mitotic activity of these cells indicating involvement of PI3-kinase pathway and H2O2. Real-time PCR revealed Nox4 and Duox1/2 as the potential sources of H2O2. Silencing of Duox1/2 in fibroblasts or Nox4 in MSC reduced PDGF-stimulated intracellular H2O2, PKB/Akt phosphorylation and migration, but had no such effect on Erk1/2. In contrast to PDGF, EGF failed to increase cytoplasmic H2O2, phosphorylation of PKB/Akt and migration of fibroblasts and MSC, confirming the critical impact of redox signaling. We conclude that PDGF-induced migration of mesenchymal cells requires Nox4 and Duox1/2 enzymes, which mediate redox-sensitive activation of PI3-kinase pathway and PKB/Akt.