MK-4101 - a potent inhibitor of the hedgehog pathway - is highly active against medulloblastoma and basal cell carcinoma (original) (raw)
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Faculty of 1000 evaluation for Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449
F1000 - Post-publication peer review of the biomedical literature, 2011
Medulloblastoma is the most common malignant brain tumor in children. Aberrant activation of the hedgehog signaling pathway is strongly implicated in the development of some cases of medulloblastoma. A 26-year-old man with metastatic medulloblastoma that was refractory to multiple therapies was treated with a novel hedgehog pathway inhibitor, GDC-0449; treatment resulted in rapid (although transient) regression of the tumor and reduction of symptoms. Molecular analyses of tumor specimens obtained before treatment suggested that there was activation of the hedgehog pathway, with loss of heterozygosity and somatic mutation of the gene encoding patched homologue 1 (PTCH1), a key negative regulator of hedgehog signaling. Medulloblastoma is a malignant tumor of the cerebellum. The median age at diagnosis is 5 years, with the age range extending into young adulthood. Primary management consists of surgical resection followed by radiation therapy and chemotherapy. Current therapies have serious short-term and long-term adverse effects, including postoperative mutism, neurocognitive deficits, endocrinopathies, sterility, and the risk of secondary high-grade glioma or meningioma. 1 Patients with recurrent disease after primary therapy have a particularly poor prognosis, with a median survival of less than 6 months; the 2-year survival rate among these patients is approximately 9%. 2 The hedgehog pathway is an essential embryonic signaling cascade that regulates stem-cell and progenitor-cell differentiation in multiple developmental processes. 3 Smoothened homologue (SMO) is a transmembrane protein that activates the downstream hedgehog signaling pathway. PTCH1 is an inhibitory cell-surface receptor that constitutively
Review: Targeting the Hedgehog pathway in cancer
Therapeutic Advances in Medical Oncology, 2010
The Hedgehog (Hh) pathway is a major regulator of many fundamental processes in vertebrate embryonic development including stem cell maintenance, cell differentiation, tissue polarity and cell proliferation. Constitutive activation of the Hh pathway leading to tumorigenesis is seen in basal cell carcinomas and medulloblastoma. A variety of other human cancers, including brain, gastrointestinal, lung, breast and prostate cancers, also demonstrate inappropriate activation of this pathway. Paracrine Hh signaling from the tumor to the surrounding stroma was recently shown to promote tumorigenesis. This pathway has also been shown to regulate proliferation of cancer stem cells and to increase tumor invasiveness. Targeted inhibition of Hh signaling may be effective in the treatment and prevention of many types of human cancers. The discovery and synthesis of specific Hh pathway inhibitors have significant clinical implications in novel cancer therapeutics. Several synthetic Hh antagonists are now available, several of which are undergoing clinical evaluation. The orally available compound, GDC-0449, is the farthest along in clinical development. Initial clinical trials in basal cell carcinoma and treatment of select patients with medulloblastoma have shown good efficacy and safety. We review the molecular basis of Hh signaling, the current understanding of pathway activation in different types of human cancers and we discuss the clinical development of Hh pathway inhibitors in human cancer therapy.
Hedgehog signalling pathway: Carcinogenesis and targeted therapy
Iranian Journal of Cancer Prevention, 2013
Hedgehog signalling pathway has not only a critical role in cell proliferation, differentiation and tissue polarity at embryonic period but also has a vital role in stem cell proliferation, tissue healing and carcinogenesis. Recent research has increased our understanding of this pathway and its relation to other signalling pathways. In addition, a large number of studies confirmed the alteration of Hh signalling pathway in various types of human malignancies including basal cell carcinomas, medulloblastomas, lung, gastrointestinal, ovarian, breast, prostate cancers and leukemia. More than 50 small biomolecules have been introduced which have inhibitory effects on Hh signalling pathway. Although, in many tumors some acceptable results have been showed in phase I clinical trial, closer studies are required to improve drug bioavailability, to decrease the side effects and to find the right small molecules for specific types of cancers, considering patients overall benefits as well.
Cancer Cell, 2004
Medulloblastoma is the most common malignant pediatric brain tumor. Current treatment is associated with major longterm side effects; therefore, new nontoxic therapies, targeting specific molecular defects in this cancer, need to be developed. We use a mouse model of medulloblastoma to show that inhibition of the Sonic Hedgehog (Shh) pathway provides a novel therapy for medulloblastoma. A small molecule inhibitor of the Shh pathway, HhAntag, blocked the function of Smoothened in mice with medulloblastoma. This resulted in suppression of several genes highly expressed in medulloblastoma, inhibition of cell proliferation, increase in cell death and, at the highest dose, complete eradication of tumors. Long-term treatment with HhAntag prolonged medulloblastoma-free survival. These findings support the development of Shh antagonists for the treatment of medulloblastoma.
A Smo/Gli Multitarget Hedgehog Pathway Inhibitor Impairs Tumor Growth
Cancers
Pharmacological Hedgehog (Hh) pathway inhibition has emerged as a valuable anticancer strategy. A number of small molecules able to block the pathway at the upstream receptor Smoothened (Smo) or the downstream effector glioma-associated oncogene 1 (Gli1) has been designed and developed. In a recent study, we exploited the high versatility of the natural isoflavone scaffold for targeting the Hh signaling pathway at multiple levels showing that the simultaneous targeting of Smo and Gli1 provided synergistic Hh pathway inhibition stronger than single administration. This approach seems to effectively overcome the drug resistance, particularly at the level of Smo. Here, we combined the pharmacophores targeting Smo and Gli1 into a single and individual isoflavone, compound 22, which inhibits the Hh pathway at both upstream and downstream level. We demonstrate that this multitarget agent suppresses medulloblastoma growth in vitro and in vivo through antagonism of Smo and Gli1, which is a novel mechanism of action in Hh inhibition.
Hedgehog beyond medulloblastoma and basal cell carcinoma
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2010
The Hedgehog (Hh) signaling pathway is of central importance during embryo development in metazoans and governs a diverse array of processes including cell proliferation, differentiation, and tissue patterning. In normal adult physiology, the pathway is implicated in stem cell maintenance, tissue repair and regeneration. However, the pathway's darker side is its involvement in several types of human cancer, to which it confers growth promoting and/or survival capabilities to the cancer cell to varying degrees, and by different mechanisms. The Hh pathway is firmly linked to the etiology of basal cell carcinoma and to at least a subset of medulloblastoma. There is increasing evidence that other sporadic cancers, including those in pancreas, prostate, lung, and breast, could also be dependent on Hh pathway activity. In this review, we provide an overview of the pathway's role in various tumor types, where much of the framework for Hh-dependent malignancies has been elucidated in experimental mouse models. We discuss three different signal transduction models for the pathway's involvement in cancer: i) ligand-independent signaling, ii) ligand-dependent autocrine/juxtacrine signaling, and iii) ligand-dependent paracrine signaling. These different modes of signaling may have implications for future therapeutic interventions aimed at inhibiting the pathway during disease. In addition, crosstalk with other pathways, and indications of non-canonical Hh signaling in cancer cells may further cause complications, or perhaps possibilities, in the treatment regimen. Finally, we review the rapid progress and promising results in the development of smallmolecule inhibitors of the Hh pathway.
International Journal of Oncology
The aberrant activation of hedgehog (HH) signaling is a leading cause of the development of medulloblastoma, a pediatric tumor of the cerebellum. The FDA-approved HH inhibitor, Vismodegib, which targets the transmembrane transducer SMO, has shown limited efficacy in patients with medulloblastoma, due to compensatory mechanisms that maintain an active HH-GLI signaling status. Thus, the identification of novel actionable mechanisms, directly affecting the activity of the HH-regulated GLI transcription factors is an important goal for these malignancies. In this study, using gene expression and reporter assays, combined with biochemical and cellular analyses, we demonstrate that mitogen-activated kinase kinase kinase 1 (MEKK1), the most upstream kinase of the mitogen-activated protein kinase (MAPK) phosphorylation modules, suppresses HH signaling by associating and phosphorylating GLI1, the most potent HH-regulated transcription factor. Phosphorylation occurred at multiple residues in the C-terminal region of GLI1 and was followed by an increased association with the cytoplasmic proteins 14-3-3. Of note, the enforced expression of MEKK1 or the exposure of medulloblastoma cells to the MEKK1 activator, Nocodazole, resulted in a marked inhibitory effect on GLI1 activity and tumor cell proliferation and viability. Taken together, the results of this study shed light on a novel regulatory mechanism of HH signaling, with potentially relevant implications in cancer therapy.
Proceedings of The National Academy of Sciences, 2003
The link between basal cell carcinoma (BCC) and aberrant activation of the Hedgehog (Hh) signaling pathway has been well established in humans and in mouse models. Here we report the development of assays, including two novel in vitro BCC models, which allowed us to screen for Hh inhibitors and test their validity as potential treatments for BCC. We identified a novel small molecule Hh inhibitor (CUR61414) that can block elevated Hh signaling activity resulting from oncogenic mutations in Patched-1. Moreover, CUR61414 can suppress proliferation and induce apoptosis of basaloid nests in the BCC model systems, whereas having no effect on normal skin cells. These findings directly demonstrate that the use of Hh inhibitors could be a valid therapeutic approach for treating BCC.
Hedgehog signaling inhibitors fail to reduce Merkel cell carcinoma viability
The Journal of investigative dermatology, 2017
Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer. Surgical resection and radiotherapy can successfully treat localized disease, but treatments for advanced MCC are needed. Aberrant activation of the Hedgehog (Hh) signaling pathway plays a role in several cancers, including basal cell carcinoma (BCC) and medulloblastoma (MDB) (Gupta et al., 2010). One study has reported increased immunohistochemical staining of Hh pathway components (Hh ligands, PTCH, SMO, and Gli family members) in MCC tumors, suggesting that Hh pathway activation plays a role in MCC pathogenesis (Brunner et al., 2010). This resulted in speculation that Hh inhibitors may be effective in treating MCC (Li et al., 2011). However, this hypothesis conflicts with mouse studies in which genetic activation of Hh signaling in the Merkel cell lineage failed to produce neuroendocrine skin tumors (Peterson et al., 2015; Xiao et al., 2015). Additionally, the loss-of-function PTCH1 mutations