Dual Inhibition of Hedgehog and c-Met Pathways for Pancreatic Cancer Treatment

Rucki, Agnieszka A.; Xiao, Qian; Muth, Stephen; Chen, Jianlin; Che, Xu; Kleponis, Jennifer; Sharma, Rajni; Anders, Robert A.; Jaffee, Elizabeth M.; Li, Zheng

doi:10.1158/1535-7163.mct-16-0452

Cited by 31 publications

(20 citation statements)

References 45 publications

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“…Therefore, these data indicate that this drug combination is impractical for further development, due to excessive toxicity [ 155 ]. It was recently proposed that the combined inhibition of Hedgehog and c-Met pathways could represent a useful therapeutic strategy, for their synergistic anti-tumor activity and for their capacity to bypass drug resistance occurring after single-drug treatment [ 156 ].…”

Section: Pancreatic Cancer Stem Cellsmentioning

confidence: 99%

Pancreatic Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells

2017

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Pancreatic Ductal Adenocarcinoma (PDAC) is the fourth most common cause of cancer-related death and is the most lethal of common malignancies with a five-year survival rate of <10%. PDAC arises from different types of non-invasive precursor lesions: intraductal papillary mucinous neoplasms, mucinous cystic neoplasms and pancreatic intraepithelial neoplasia. The genetic landscape of PDAC is characterized by the presence of four frequently-mutated genes: KRAS, CDKN2A, TP53 and SMAD4. The development of mouse models of PDAC has greatly contributed to the understanding of the molecular and cellular mechanisms through which driver genes contribute to pancreatic cancer development. Particularly, oncogenic KRAS-driven genetically-engineered mouse models that phenotypically and genetically recapitulate human pancreatic cancer have clarified the mechanisms through which various mutated genes act in neoplasia induction and progression and have led to identifying the possible cellular origin of these neoplasias. Patient-derived xenografts are increasingly used for preclinical studies and for the development of personalized medicine strategies. The studies of the purification and characterization of pancreatic cancer stem cells have suggested that a minority cell population is responsible for initiation and maintenance of pancreatic adenocarcinomas. The study of these cells could contribute to the identification and clinical development of more efficacious drug treatments.

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Section: Pancreatic Cancer Stem Cellsmentioning

confidence: 99%

Pancreatic Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells

2017

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“…In murine models, ormeloxifene (129) and IPI-926 (130) were successful in targeting the Hh pathway resulting in decreased stroma, reduced tumour volume and increased sensitivity to coadministered gemcitabine. Rucki et al (92) used KPC mice to demonstrate that dual inhibition of sonic hedgehog (Hh) and HGF/c-MET pathway sensitises PDAC to gemcitabine. However, targeting the Hh pathway in a clinical trial GDC-0449 using the inhibitors vismodegib, saridegib and sonidegib failed to yield a significant survival benefit (131).…”

Section: Hedgehog Pathwaymentioning

confidence: 99%

Multifunctional role of pancreatic stellate cells in pancreatic cancer

Mekapogu¹,

Pothula²,

Pirola³

et al. 2019

Ann Pancreat Cancer

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Pancreatic ductal adenocarcinoma (PDAC) constitutes 90% of all pancreatic malignancies and is characterised by extensive desmoplasia and early metastasis. The risk factors for PDAC include a family history of the disease, cigarette smoking, chronic pancreatitis, obesity and diabetes mellitus (1,2). PDAC most commonly occurs in the 60 to 80 year age group, and its incidence is 50% higher in men than in women and (1) genetic mutations such as BRCA2, CDKN2A, STK11, PRSS1, SPINK1, CFTR, PALB2 and ATM increase the risk for PDAC (3), patients with chronic pancreatitis have a 15 fold increased risk of developing PDAC (4), cigarette smoking increases the risk of PDAC by 75% even up to 10 years after cessation of smoking and (5) diabetes mellitus increases the risk by 30% up to 20 years after diagnosis (6). Obesity and high body mass index are positively correlated with the risk of developing PDAC (7). One meta-analysis showed a 19% increase in risk of developing PDAC in obese individuals (BMI ≥30 kg/m 2) compared to normal participants (BMI 22 kg/m 2) (8). The genetic mutational landscape of PDAC involves the alteration of 69 genes which affect 12 core signalling pathways (9). Both oncogenes and tumour suppressor genes are mutated of which the major genes involved in PDAC are the oncogene Kristen Rat Sarcoma Virus (KRAS), and three tumour suppressor genes-TP53, CDKN2A and SMAD4. KRAS is the earliest mutation seen in low-grade pancreatic

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“…However, clinical trials with Smo antagonists as monotherapy or in combination with chemotherapy in the palliative situation showed adverse effects, hampering further development of this approach in PDAC. Nevertheless, preclinical evaluation is still ongoing with a focus currently set on targeted combination regimens that might carry the potential to further enhance therapeutic efficacy while at the same time limiting undesired adverse toxicity [72]. Likewise, Notch signaling has now long been found to be altered and pathophysiologically involved in pancreatic carcinogenesis.…”

Section: Novel Therapeutic Targetsmentioning

confidence: 99%

Novel Targets in Pancreatic Cancer Therapy - Current Status and Ongoing Translational Efforts

Feldmann¹

2018

Oncol Res Treat

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Pancreatic ductal adenocarcinoma (PDAC, pancreatic cancer) carries one of the poorest overall prognoses of all human malignancies known to date. Despite the introduction of novel therapeutic regimens, the outcome has not markedly improved over the past decades, the incidence rates are almost identical to the mortality rates, and PDAC is projected to soon become the second most common cause of cancer-related mortality in Western countries. Despite this clear medical need to develop novel therapeutic strategies against this dire malady, this need has so far not been addressed with sufficient institutional attention and support in terms of research funding and strategical programs. Given the still growing life expectancy and projected demographic changes with a growing proportion of senior citizens in many European societies, this discrepancy is likely to become even more pressing in the future. This article provides a brief overview of ongoing preclinical efforts to identify novel targets and, based on this, to develop novel strategies to treat advanced pancreatic cancer and improve survival and the quality of life of patients suffering from this malignancy.

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Dual Inhibition of Hedgehog and c-Met Pathways for Pancreatic Cancer Treatment

Cited by 31 publications

References 45 publications

Pancreatic Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells

Pancreatic Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells

Multifunctional role of pancreatic stellate cells in pancreatic cancer

Novel Targets in Pancreatic Cancer Therapy - Current Status and Ongoing Translational Efforts

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