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CURATOR
A pinboard by
Catherine Cochrane

PhD Student - Centre for Cancer Research, Hudson Institute of Medical Research, Melbourne, Australia

PINBOARD SUMMARY

p53 and Rb, Potential Predictive Biomarkers for the Treatment of Hedgehog-driven Cancers

Cover Image - Neural progenitor cells in an embryonic mouse spinal cord dependent on Hedgehog Signalling for development

The Hedgehog (Hh) signalling pathway plays a critical role in biological processes that occurs in fetal development, such as stem cell maintenance, cell to cell interactions and tissue development. Secreted Hh proteins, termed Hh ligands, activate the pathway in a concentration and time dependent manner, by initiating a series of cellular responses that promotes organ development. The processes of brain, bone, heart, testis and limb development all require Hh pathway activity for successful growth and function. In addition to Hh’s multifaceted roles during normal development, aberrant Hh signalling is responsible for the initiation of progression of various cancers. Overactive Hh signalling has been established in basal cell carcinoma, medulloblastoma, lung, prostate, ovarian and breast cancer, to name a few, making the Hh pathway an area of intense study in both developmental and cancer biology. Because tumour growth and malignancy depend on Hh signalling in various cancers, drugs that block the Hh pathway have been developed to treat Hh cancers. However, recent entry of Hh-inhibitors into clinical trials have revealed mixed patient responses and prompts further exploration of Hh pathway activation, inhibition and resistance to treatment.

Cancer biomarkers, an identifiable or measurable biological molecule that is linked to disease, has made a large impact in cancer research, particularly in cancer diagnosis and how well a patient will respond to a treatment. In Hh-driven cancers, therapeutic translation of Hh-inhibitors has been impeded by lack of predictive genetic biomarkers. Loss or inactivation of the genes p53 and Rb is a common feature in Hh-cancers, where dual loss occurs in over 80% of patients. Although the link between p53 and Rb loss in Hh cancers has been clearly established, a direct association has not been investigated. From inactivating the genes p53 and Rb in various Hh research models of development and cancer, overactivation of the Hh pathway is observed. From pharmacologically blocking the pathway with Hh-inhibitor drugs, upon loss of p53 and Rb, tumours stop growing in lab mice and prolong their survival. Our data implicates p53 and Rb as genetic biomarkers for increased Hh signalling in cancer and potential responsiveness to Hh-inhibitor therapy in patients.

12 ITEMS PINNED

β-arrestin1-mediated acetylation of Gli1 regulates Hedgehog/Gli signaling and modulates self-renewal of SHH medulloblastoma cancer stem cells.

Abstract: Aberrant Sonic Hedgehog/Gli (Hh/Gli) signaling pathway is a critical regulator of Sonic hedgehog medulloblastoma (SHH-MB). Cancer stem cells (CSCs), thought to be largely responsible for tumor initiation, maintenance, dissemination and relapse, have been identified in SHH-MB. Since we previously demonstrated that Hh/Gli signaling controls CSCs features in SHH-MB and that in these tumors miR-326 is down regulated, here we investigated whether there is a functional link between Hh/Gli signaling and miR-326.We evaluated β-arrestin1 (Arrb1) and its intragenic miR-326 levels in CSCs derived from SHH-MB. Subsequently, we modulated the expression of Arrb1 and miR-326 in CSCs in order to gain insight into their biological role. We also analyzed the mechanism by which Arrb1 and miR-326 control Hh/Gli signaling and self-renewal, using luciferase and protein immunoprecipitation assays.Low levels of Arrb1 and miR-326 represent a feature of CSCs derived from SHH-MB. We observed that re-expression of Arrb1 and miR-326 inhibits Hh/Gli signaling pathway at multiple levels, which cause impaired proliferation and self-renewal, accompanied by down regulation of Nanog levels. In detail, miR-326 negatively regulates two components of the Hh/Gli pathway the receptor Smoothened (Smo) and the transcription factor Gli2, whereas Arrb1 suppresses the transcriptional activity of Gli1, by potentiating its p300-mediated acetylation.Our results identify a new molecular mechanism involving miR-326 and Arrb1 as regulators of SHH-MB CSCs. Specifically, low levels of Arrb1 and miR-326 trigger and maintain Hh/Gli signaling and self-renewal.

Pub.: 19 Jul '17, Pinned: 30 Sep '17

The role of canonical and non-canonical Hedgehog signaling in tumor progression in a mouse model of small cell lung cancer.

Abstract: Hedgehog (Hh) signaling regulates cell fate and self-renewal in development and cancer. Canonical Hh signaling is mediated by Hh ligand binding to the receptor Patched (Ptch), which in turn activates Gli-mediated transcription through Smoothened (Smo), the molecular target of the Hh pathway inhibitors used as cancer therapeutics. Small cell lung cancer (SCLC) is a common, aggressive malignancy with universally poor prognosis. Although preclinical studies have shown that Hh inhibitors block the self-renewal capacity of SCLC cells, the lack of activating pathway mutations have cast doubt over the significance of these observations. In particular, the existence of autocrine, ligand-dependent Hh signaling in SCLC has been disputed. In a conditional Tp53;Rb1 mutant mouse model of SCLC, we now demonstrate a requirement for the Hh ligand Sonic Hedgehog (Shh) for the progression of SCLC. Conversely, we show that conditional Shh overexpression activates canonical Hh signaling in SCLC cells, and markedly accelerates tumor progression. When compared to mouse SCLC tumors expressing an activating, ligand-independent Smo mutant, tumors overexpressing Shh exhibited marked chromosomal instability and Smoothened-independent upregulation of Cyclin B1, a putative non-canonical arm of the Hh pathway. In turn, we show that overexpression of Cyclin B1 induces chromosomal instability in mouse embryonic fibroblasts lacking both Tp53 and Rb1. These results provide strong support for an autocrine, ligand-dependent model of Hh signaling in SCLC pathogenesis, and reveal a novel role for non-canonical Hh signaling through the induction of chromosomal instability.Oncogene advance online publication, 5 June 2017; doi:10.1038/onc.2017.173.

Pub.: 06 Jun '17, Pinned: 30 Sep '17

ATOH1 promotes leptomeningeal dissemination and metastasis of Sonic Hedgehog subgroup medulloblastomas.

Abstract: Medulloblastoma (MB) arising from the cerebellum is the most common pediatric brain malignancy, with leptomeningeal metastases often present at diagnosis and recurrence associated with poor clinical outcome. In this study, we employed mouse MB models to explore the relationship of tumor pathophysiology and dysregulated expression of the Notch pathway transcription factor ATOH1, which is present in aggressive MB subtypes driven by aberrant Sonic Hedgehog/Patched (SHH/PTCH) signaling. In experiments with conditional Atoh1 mouse mutants crossed to Ptch1(+/-) mice which develop SHH-driven MB[63], animals with Atoh1 transgene expression developed highly penetrant MB at a young age with extensive leptomeningeal disease and metastasis to the spinal cord and brain, resembling xenografts of human SHH MB. Metastatic tumors retained abnormal SHH signaling like tumor xenografts. Conversely, Atoh1 expression was detected consistently in recurrent and metastatic SHH MB. ChIP-seq and gene expression profiling identified candidate ATOH1 targets in tumor cells involved in development and tumorigenesis. Among these targets specific to metastatic tumors, there was an enrichment in those implicated in extracellular matrix remodeling activity, cytoskeletal network and interaction with microenvironment, indicating a shift in transcriptomic and epigenomic landscapes during metastasis. Treatment with bone morphogenetic protein (BMP) or SHH pathway inhibitors decreased tumor cell proliferation and suppressed metastatic tumor growth, respectively. Our work reveals a dynamic ATOH1-driven molecular cascade underlying MB metastasis that offers possible therapeutic opportunities.

Pub.: 12 May '17, Pinned: 30 Sep '17

Phase I study of oral sonidegib (LDE225) in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma.

Abstract: Sonidegib (LDE225) is a potent, selective Hedgehog (Hh) inhibitor of SMOOTHENED. This study explored the safety and pharmacokinetics (PK) of sonidegib in children with relapsed/recurrent tumors followed by a phase II trial in pediatric and adult patients with relapsed medulloblastoma (MB) to assess tumor response.Pediatric patients aged ≥1-<18 years were included according to a Bayesian design starting at 372mg/m2 of continuous once daily oral sonidegib. Tumor samples were analyzed for Hh pathway activation using a validated 5-gene Hh signature assay. In phase II, pediatric patients were treated at the recommended phase II dose (RP2D) while adults received 800mg daily.Sixteen adult (16 MB) and 60 pediatric (39 MB, 21 other) patients with an age range of 2-17 years were enrolled. The RP2D of sonidegib in pediatric patients was established at 680mg/m2 once daily. The phase II study was closed prematurely. The 5-gene Hh signature assay showed that the 4 complete responders (2 pediatric and 2 adult) and 1 partial responder (adult), all had Hh‑activated tumors, while 5 patients with activated Hh had either stable disease (n=3) or progressive disease (n=2). No patients with Hh-negative signatures (n=50) responded. The safety profile for pediatric patients was generally consistent with the one established for adult patients; however, growth plate changes were observed in pre-pubertal pediatric patients'.Sonidegib was well tolerated and the RP2D in pediatric patients was 680mg/m2 once daily. Five of the 10 MB patients with activated Hh pathway demonstrated complete or partial responses.

Pub.: 13 Jun '17, Pinned: 30 Sep '17