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    • Type IIIa b the ligand dependent oncogenic

    2022-01-13

    Type IIIa/b – the ligand dependent oncogenic Hh pathway (paracrine or reverse paracrine mode) is mediated by paracrine activation and is usually encountered in embryonic development, but also in installation and progression of cancer [58]. Specifically, Hh ligands secreted by malignant U 73343 activate the Ptch1 receptor found on tumor associated stromal cells; in turn, the stromal cells emit growth factors such as VEGF, PDGF, BMP and IGF stimulating the proliferation and differentiation of cancer cells [71]. In special contexts, reverse paracrine signaling can be found in hematological malignancies, where the tumor cells are stimulated by Hh ligands secreted in lymph node or bone marrow stromal cells. In this case, the stromal cells can become a therapeutic target due to their significant involvement in the establishment of pro-malignant environments [72].
    Clinical impacts of hedgehog inhibition In the past decade, strategies for inhibiting Hh signaling U 73343 pathway have been studied intensively (Table 1) but often with contradictory results. One of the first and most studied inhibitors of the tumor-promoting Hh signaling pathway has been Vismodegib (also called HhAntag691, and GDC-0449), a molecule that serves as a cyclopamine-competitive antagonist of Smo. This low molecular weight compound entered clinical trials about ten years ago and is used to treat some types of solid tumors [73]. In 2009, Von Hoff et al. published the results of an open-label, multicenter (three centers), two stage phase 1 clinical trial aimed at studying the adverse effects of the use of Vismodegib, at three increasing doses/day (150, 270 and 540 mg) orally administered to 33 patients (8 women and 25 men) with metastatic (18 patients) or locally advanced (15 patients) basal-cell carcinoma. This kind of tumor, which is associated with mutations in Hh pathway signaling, is successfully treated with surgery, radio- and chemo-therapy in the early stages. However, advanced and metastatic basal-cell carcinoma are usually unresponsive to standard therapies, with a median time of survival of about 8 months. The study showed that of 33 patients, 18 had a response, 11 presented stable conditions for about 11 months, and four did not show any effects and progression of the disease was registered. An interesting point to consider is that one of these last patients did not show significant Hh signaling pathway activation. These results justify the failure of the therapeutic strategy in this case. On the contrary, two of these four patients showed an increase in the HH signaling pathway, suggesting that other mechanisms lay behind Vismodegib ineffectiveness. Based on the results of this clinical trial, the authors concluded that the use of a Hh signaling pathway inhibitor could be a good strategy against advanced and/or metastatic basal-cell carcinoma unresponsive to standard therapies [74]. Three years later, Kaye et al. investigated the effects of Vismodegib administered to patients affected by epithelial ovarian carcinoma, fallopian tube carcinoma, or primary peritoneal carcinoma [75]. These types of cancer are considered to be part of the same category of malignancies and are treated with the same standard therapy including surgery and chemotherapy (platinum agents in combination with taxane). The aim of this phase II, randomized, double-blind, placebo controlled clinical trial was to investigate progression-free survival (PFS) following Vismodegib maintenance therapy (150 mg/day for 14 weeks after chemotherapy) in 104 patients (18 years or older), in which a second or third complete remission (that means no symptoms suggestive of persistent cancer) was achieved and measured by radiographic assessment (computed tomography scan of the chest/abdomen/pelvis). Unfortunately, the results showed that in the selected population no statistical differences were registered in PFS, though PFS was greater for the treated patient group (7.5 months) in comparison with the placebo one (5.8 months). Moreover, Hh ligand expression was found in only 13.5% of archival tumor tissue, suggesting that no correlation can be established between Hh ligand overexpression and clinical benefits. This result is in agreement with that reached by another placebo controlled trial conducted on patients affected by metastatic colorectal cancer who received Vismodegib or placebo in combination with bevacizumab and chemotherapy [76].