The Role of the Hedgehog Pathway in Cholangiocarcinoma

Anichini, Giulia; Carrassa, Laura; Stecca, Barbara; Marra, Fabio; Raggi, Chiara

doi:10.3390/cancers13194774

Cited by 11 publications

(9 citation statements)

References 175 publications

(299 reference statements)

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“…Hyperactivation of the HH pathway was confirmed by the analysis of transcriptomic datasets from surgically resected human iCCA samples, which revealed increased expression of GLI1, GLI2 , and the target PTCH1 in the tumor compared with the surrounding nontumor tissue. Overall, these data identified a wide subgroup of patients with CCA that may benefit from pharmacologic targeting of the HH pathway, which has been recently been correlated with poor prognosis and tumor progression in patients with CCA ( 44 ).…”

Section: Discussionmentioning

confidence: 84%

Combined Inhibition of Smoothened and the DNA Damage Checkpoint WEE1 Exerts Antitumor Activity in Cholangiocarcinoma

Anichini

Raggi

Pastore

et al. 2022

Molecular Cancer Therapeutics

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Cholangiocarcinoma (CCA) is characterized by resistance to chemotherapy and a poor prognosis. Therefore, treatments that can effectively suppress tumor growth are urgently needed. Aberrant activation of hedgehog (HH) signaling has been implicated in several cancers, including those of the hepatobiliary tract. However, the role of HH signaling in intrahepatic CCA (iCCA) has not been completely elucidated. In this study, we addressed the function of the main transducer Smoothened (SMO) and the transcription factors (TFs) GLI1 and GLI2 in iCCA. In addition, we evaluated the potential benefits of the combined inhibition of SMO and the DNA damage kinase WEE1. Transcriptomic analysis of 152 human iCCA samples showed increased expression of GLI1, GLI2, and Patched 1 (PTCH1) in tumor tissues compared with nontumor tissues. Genetic silencing of SMO, GLI1, and GLI2 inhibited the growth, survival, invasiveness, and self-renewal of iCCA cells. Pharmacologic inhibition of SMO reduced iCCA growth and viability in vitro, by inducing double-strand break DNA damage, leading to mitotic arrest and apoptotic cell death. Importantly, SMO inhibition resulted in the activation of the G2–M checkpoint and DNA damage kinase WEE1, increasing the vulnerability to WEE1 inhibition. Hence, the combination of MRT-92 with the WEE1 inhibitor AZD-1775 showed increased antitumor activity in vitro and in iCCA xenografts compared with single treatments. These data indicate that combined inhibition of SMO and WEE1 reduces tumor burden and may represent a strategy for the clinical development of novel therapeutic approaches in iCCA.

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Section: Discussionmentioning

confidence: 84%

Combined Inhibition of Smoothened and the DNA Damage Checkpoint WEE1 Exerts Antitumor Activity in Cholangiocarcinoma

Anichini

Raggi

Pastore

et al. 2022

Molecular Cancer Therapeutics

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“…When Hh ligand is present in extracellular environment, it binds to Ptch‐1 on the cell membrane, and then Ptch‐1 is endocytosed, abolishing Smo inhibition and allowing Smo to accumulate and send a signal to the suppressor of fused homolog (Sufu) to release Gli activator (GliA). Then GliA migrates to the nucleus and activates target gene expression 186 …”

Section: Related Signaling Pathways In Hccmentioning

confidence: 99%

Hepatocellular carcinoma: signaling pathways, targeted therapy, and immunotherapy

Luo,

He,

Zhang

et al. 2024

MedComm

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Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a high mortality rate. It is regarded as a significant public health issue because of its complicated pathophysiology, high metastasis, and recurrence rates. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Traditional treatment methods such as surgical resection, radiotherapy, chemotherapy, and interventional therapies have limited therapeutic effects for HCC patients with recurrence or metastasis. With the development of molecular biology and immunology, molecular signaling pathways and immune checkpoint were identified as the main mechanism of HCC progression. Targeting these molecules has become a new direction for the treatment of HCC. At present, the combination of targeted drugs and immune checkpoint inhibitors is the first choice for advanced HCC patients. In this review, we mainly focus on the cutting‐edge research of signaling pathways and corresponding targeted therapy and immunotherapy in HCC. It is of great significance to comprehensively understand the pathogenesis of HCC, search for potential therapeutic targets, and optimize the treatment strategies of HCC.

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“…Itraconazole in cholangiocarcinoma: 5-LO and its leukotriene products contribute to the growth of cholangiocarcinoma [207][208][209]. Hh signaling is a core growth-driving element in cholangiocarcinoma, and prominently so in the stem subset [210][211][212][213][214][215]. 5-LO is one of the drivers of both myeloid-derived suppressor cell immunosuppression and stemness in cholangiocarcinoma [216].…”

Section: Itraconazolementioning

confidence: 99%

MDACT: A New Principle of Adjunctive Cancer Treatment Using Combinations of Multiple Repurposed Drugs, with an Example Regimen

Kast¹,

Alfieri

Assi

et al. 2022

Cancers

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In part one of this two-part paper, we present eight principles that we believe must be considered for more effective treatment of the currently incurable cancers. These are addressed by multidrug adjunctive cancer treatment (MDACT), which uses multiple repurposed non-oncology drugs, not primarily to kill malignant cells, but rather to reduce the malignant cells’ growth drives. Previous multidrug regimens have used MDACT principles, e.g., the CUSP9v3 glioblastoma treatment. MDACT is an amalgam of (1) the principle that to be effective in stopping a chain of events leading to an undesired outcome, one must break more than one link; (2) the principle of Palmer et al. of achieving fractional cancer cell killing via multiple drugs with independent mechanisms of action; (3) the principle of shaping versus decisive operations, both being required for successful cancer treatment; (4) an idea adapted from Chow et al., of using multiple cytotoxic medicines at low doses; (5) the idea behind CUSP9v3, using many non-oncology CNS-penetrant drugs from general medical practice, repurposed to block tumor survival paths; (6) the concept from chess that every move creates weaknesses and strengths; (7) the principle of mass—by adding force to a given effort, the chances of achieving the goal increase; and (8) the principle of blocking parallel signaling pathways. Part two gives an example MDACT regimen, gMDACT, which uses six repurposed drugs—celecoxib, dapsone, disulfiram, itraconazole, pyrimethamine, and telmisartan—to interfere with growth-driving elements common to cholangiocarcinoma, colon adenocarcinoma, glioblastoma, and non-small-cell lung cancer. gMDACT is another example of—not a replacement for—previous multidrug regimens already in clinical use, such as CUSP9v3. MDACT regimens are designed as adjuvants to be used with cytotoxic drugs.

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The Role of the Hedgehog Pathway in Cholangiocarcinoma

Cited by 11 publications

References 175 publications

Combined Inhibition of Smoothened and the DNA Damage Checkpoint WEE1 Exerts Antitumor Activity in Cholangiocarcinoma

Combined Inhibition of Smoothened and the DNA Damage Checkpoint WEE1 Exerts Antitumor Activity in Cholangiocarcinoma

Hepatocellular carcinoma: signaling pathways, targeted therapy, and immunotherapy

MDACT: A New Principle of Adjunctive Cancer Treatment Using Combinations of Multiple Repurposed Drugs, with an Example Regimen

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