Hedgehog pathway inhibitors – current status and future prospects

Sheikh, A; Alvi, Arsalan Ahmad; Aslam, Hafiz Muhammad; Haseeb, Abdul

doi:10.1186/1750-9378-7-29

Cited by 16 publications

(10 citation statements)

References 26 publications

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“…Therefore, molecular and/or chemical intervention to target Hh signaling and disrupt the microenvironment in tumors could be an interesting therapeutic approach for pancreatic cancer (12). Some of the well-known Hh signaling antagonists such as vismodegib (GDC-0449) have been investigated alone or as an adjuvant to the traditional anti-cancer drugs but have not yielded clinically meaningful results (14, 15) and have shown notable adverse effects including teratogenic properties (16, 17). Thus, identification of novel therapies with high therapeutic index that can target Hh and tumor progression signaling pathways with no or minimal adverse effects is required.…”

Section: Introductionmentioning

confidence: 99%

Ormeloxifene Suppresses Desmoplasia and Enhances Sensitivity of Gemcitabine in Pancreatic Cancer

et al. 2015

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The management of pancreatic ductal adenocarcinoma (PDAC) is extremely poor due to lack of an efficient therapy and development of chemoresistance to the current standard therapy, gemcitabine (GEM). Recent studies implicate the intimate reciprocal interactions between epithelia and underlying stroma due to paracrine Sonic hedgehog (SHH) signaling in producing desmoplasia and chemoresistance in PDAC. Herein, we report for the first time that a nonsteroidal drug, ormeloxifene (ORM), has potent anti-cancer properties and depletes tumor-associated stromal tissue by inhibiting the SHH signaling pathway in PDAC. We found that ORM inhibited cell proliferation and induced death in PDAC cells, which provoked us to investigate the combinatorial effects of ORM with GEM at the molecular level. ORM caused potent inhibition of the SHH signaling pathway via downregulation of SHH and its related important downstream targets such as Gli-1, SMO, PTCH1/2, NFκB, p-AKT and Cyclin D1. ORM potentiated the anti-tumorigenic effect of GEM by 75% in PDAC xenograft mice. Further, ORM depleted tumor-associated stroma in xenograft tumor tissues by inhibiting the SHH cellular signaling pathway and mouse/human collagen I expression. Xenograft tumors treated with ORM in combination with GEM restored the tumor suppressor miR-132, and inhibited stromal cell infiltration into the tumor tissues. Additionally, invasiveness of tumor cells co-cultivated with TGFβ-stimulated human pancreatic stromal cells was effectively inhibited by ORM treatment alone or in combination with GEM. We propose that ORM has high therapeutic index and in a combination therapy with GEM it possesses great promise as a treatment of choice for PDAC/pancreatic cancer.

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Section: Introductionmentioning

confidence: 99%

Ormeloxifene Suppresses Desmoplasia and Enhances Sensitivity of Gemcitabine in Pancreatic Cancer

et al. 2015

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“…This analysis has allowed us to identify molecular pathways active in GVHD, many of which represent druggable targets for which candidate interventions are immediately available. One of the most prominent pathways identified within the NHP GVHD transcriptome, the aurora kinase A pathway, encodes proteins controlling cell cycle progression, cell growth, differentiation and survival(16, 17), and inhibitors of this pathway are in clinical trials as targeted cancer therapies(18, 19). Our results identify Aurora Kinase A as a lead pathway for allo-specific T cell activation, representing a novel targetable strategy for controlling this disease.…”

Section: Introductionmentioning

confidence: 99%

Transcriptome analysis of GVHD reveals aurora kinase A as a targetable pathway for disease prevention

et al. 2015

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Graft versus host disease (GVHD) is the most common complication of hematopoietic stem cell transplant (HCT). However, our understanding of the molecular pathways that cause this disease remains incomplete, leading to inadequate treatment strategies. To address this, we measured the gene expression profile of non-human primate (NHP) T cells during acute GVHD. Utilizing microarray technology, we measured the expression profiles of CD3+ T cells from five cohorts: allogeneic transplant recipients receiving 1) no immunoprophylaxis (No Rx); 2) sirolimus monotherapy (Siro); 3) tacrolimus-methotrexate (Tac-Mtx); as well as 4) autologous transplant recipients (Auto) and 5) healthy controls (HC). This comparison allowed us to identify transcriptomic signatures specific for allo-reactive T cells and determine the impact of both mTOR and calcineurin inhibition on GVHD-mediated pathway dysregulation. We found that the transcriptional profile of unprophylaxed GVHD was characterized by significant perturbation of pathways regulating T cell proliferation, effector function and cytokine synthesis. Within these pathways we discovered potentially druggable targets not previously implicated in GVHD, prominently including aurora kinase A (AURKA). Utilizing a murine GVHD model, we demonstrated that pharmacologic inhibition of AURKA could improve survival. Moreover, we found enrichment of AURKA transcripts both in allo-proliferating T cells and in sorted T cells from patients with clinical GVHD. These data provide a comprehensive elucidation of the T cell transcriptome in primate acute GVHD. This transcriptome enables a systems-based approach to the identification of targets for disease control, many of which are immediately amenable for clinical evaluation. The first such target identified, AURKA should now be considered a lead target for prevention of GVHD, which, given the many available AURKA inhibitors in clinical development, could be quickly deployed for the prevention of GVHD.

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“…305 Aberrant Hedgehog signaling can contribute to tumor initiation, angiogenesis, and cancer cell survival via gain-of-function SMO mutations, loss-of-function PTCH mutations, aberrant GLI2 and GLI3 expression, upregulation of drug resistance genes (e.g., p-glycoprotein, MDR1, BCRP, and ABCG2) or by influencing the interaction of cancer stem cells with the stroma. 306–312 The expression of SHH, GLI1, and GLI2 has been demonstrated in AML blasts, and an anti-leukemic effect was observed in vitro in response to cyclopamine, an SMI of Hedgehog/SMO signaling. 309 …”

Section: Hedgehog Pathwaymentioning

confidence: 99%

Small molecule inhibitors in acute myeloid leukemia: from the bench to the clinic

Al-Hussaini

DiPersio

2014

Expert Review of Hematology

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Many patients with acute myeloid leukemia (AML) will eventually develop refractory or relapsed disease. In the absence of standard therapy for this population, there is currently an urgent unmet need for novel therapeutic agents. Targeted therapy with small molecule inhibitors (SMIs) represents a new therapeutic intervention that has been successful for the treatment of multiple tumors (e.g., gastrointestinal stromal tumors, chronic myelogenous leukemia). Hence, there has been great interest in generating selective small molecule inhibitors targeting critical pathways of proliferation and survival in AML. This review highlights a selective group of intriguing therapeutic agents and their presumed targets in both preclinical models and in early human clinical trials.

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Hedgehog pathway inhibitors – current status and future prospects

Cited by 16 publications

References 26 publications

Ormeloxifene Suppresses Desmoplasia and Enhances Sensitivity of Gemcitabine in Pancreatic Cancer

Ormeloxifene Suppresses Desmoplasia and Enhances Sensitivity of Gemcitabine in Pancreatic Cancer

Transcriptome analysis of GVHD reveals aurora kinase A as a targetable pathway for disease prevention

Small molecule inhibitors in acute myeloid leukemia: from the bench to the clinic

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