Molecular Landscape and Therapeutic Strategies in Cholangiocarcinoma: An Integrated Translational Approach towards Precision Medicine

Casadio, M; Biancaniello, Francesca; Overi, Diletta; Venere, Rosanna; Carpino, Guido; Gaudio, Eugenio; Alvaro, Domenico; Cardinale, Vincenzo

doi:10.3390/ijms22115613

Cited by 9 publications

(12 citation statements)

References 71 publications

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“…Genetic alterations in CCA, including mutations, gene fusions, and copy number variations, can disrupt DNA repair, cell cycle regulation, signal transduction of receptor tyrosine kinases, and epigenetic regulation. Table 2 shows a list of genetic alterations in CCA and corresponding clinical trials [ 16 , 17 , 18 ]. Some of the genetic alterations currently have no clinical features; therefore, we provided potential targeted agents based on preclinical studies that are yet to be validated in human studies ( Figure 2 ).…”

Section: Genetic Alterations In Cca and Clinical Trials Of Targeted T...mentioning

confidence: 99%

Precision Medicine in Cholangiocarcinoma: Past, Present, and Future

Cheng

Chen

2022

Life

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Cholangiocarcinoma (CCA), or biliary tract cancer, has a poor prognosis. The median survival time among patients with CCA is under 2 years from diagnosis, and the global 5-year survival rate is only 10%. First-line therapy with chemotherapeutic agents, gemcitabine plus cisplatin, has traditionally been used to treat unresectable advanced CCA. In recent years, precision medicine has become a mainstream cancer treatment due to innovative next-generation sequencing technology. Several genetic alterations, including mutations, gene fusions, and copy number variations, have been found in CCA. In this review, we summarized the current understanding of genetic profiling in CCA and targeted therapy in CCA. Owing to the high heterogeneity of CCA, tumor microenvironmental factors, and the complexity of tumor biology, only pemigatinib, infigratinib, ivosidenib, larotrbctinib, and entrectinib are currently approved for the treatment of CCA patients with fibroblast growth factor receptor 2 gene (FGFR2) fusion, isocitrate dehydrogenase gene (IDH1) mutation, and neurotrophin receptor tyrosine kinase gene (NRTK) fusion, respectively. Additional targeted therapies, including other FGFR2 inhibitors, PI3K/AKT/mTOR inhibitors, and BRAF-directed targeted therapy, have been discussed for the management of CCA, and immune checkpoint inhibitors, particularly pembrolizumab, can be administered to patients with high microsatellite instability tumors. There is a further need for improvement in precision medicine therapies in the treatment of CCA and discuss the approved and potential targeted therapies for CCA.

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Section: Genetic Alterations In Cca and Clinical Trials Of Targeted T...mentioning

confidence: 99%

Precision Medicine in Cholangiocarcinoma: Past, Present, and Future

Cheng

Chen

2022

Life

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“…In the last decade, several research groups have proposed their own molecular classification based on high throughput techniques such as whole exome or genome sequencing, DNA methylation profiling, targeted sequencing, or single nucleotide polymorphism (SNP) array [ 5 ]. The description of each of these analyses goes beyond the purposes of this manuscript, but we can affirm that BTC generally lacks a predominant oncogenic pathway.…”

Section: Carcinogenesis Pathways In Btcsmentioning

confidence: 99%

A review of molecularly targeted therapy in biliary tract carcinoma: what is the next step?

Aimar,

Paratore,

Zichi

et al. 2021

Exploration of Targeted Anti-Tumor Therapy

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Patients with unresectable biliary tract carcinomas (BTCs) have a poor prognosis with a median overall survival of fewer than 12 months following systemic chemotherapy. In recent years, the identification of distinct molecular alterations with corresponding targeted therapies is modifying this therapeutic algorithm. The aim of this review is to present an overview of targeted therapy for BTCs, describing published available data and potential future challenges in ongoing trials. From clinicaltrials.gov online database all ongoing trials for BTCs (any stage) was examinated in July 2021, and data regarding study design, disease characteristics and type of treatments were registered. Oncogenic-driven therapy (targeted therapy) was investigated in 67 trials. According to research, 15 ongoing trials (22.4%) are investigating fibroblast growth factor (FGF) receptor (FGFR)-inhibitors in BTCs. Three (18.7%) are open-label randomized multicenter phase 3 trials, 8 (50%) are single-arm phase two trials, and 4 (25%) are phase one studies. Twelve (17.9%) clinical trials dealt with isocitrate dehydrogenase (IDH) 1/2 targeting therapy either in combination with cisplatin (Cis) and gemcitabine (Gem) as first-line treatment for BTCs or in monotherapy in patients with IDH1 mutant advanced malignancies, including cholangiocarcinoma (CCA). Nine (13.4%) clinical trials tested human epidermal growth factor receptor (HER) 2 targeting therapy. Four (44.4%) studies are phase I trials, two (22.2%) are phase I/II trials, and three (33.3%) phase II trials. Rare molecular alterations in BTCs, such as anaplastic lymphoma kinase (ALK), c-ros oncogene1 receptor tyrosine kinase (ROS1), and v-RAF murine sarcoma viral oncogene homologue B1 (BRAF), are also under investigation in a few trials. Forty-four clinical trials (17.2%) are investigating not oncogenic-driven multitarget therapy like multireceptor tyrosin kinase inhibitors and antiangiogenetic agents. In conclusion, this review shows that BTCs management is experiencing important innovations, especially in biomarker-based patient selection and in the new emerging therapeutic approach. Many ongoing trials could answer questions regarding the role of molecular inhibitors leading to new therapeutic frontiers for molecular subcategories of BTCs.

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“…Although several clinical trials adopting criteria of personalized therapy in CCA are ongoing, a real impact on its poor prognosis remains a long way off. 14,15,23,24…”

Section: Key Pointsmentioning

confidence: 99%

“…Overall, these refined molecular classifications, although methodologically sound and relevant as role models for experimental protocols applied to the study of heterogeneous cancers, still have limited translational value, in terms of generation of new diagnostic tools to enable early tumour detection, and better allocation of patients to appropriate tailored therapies. Although several clinical trials adopting criteria of personalized therapy in CCA are ongoing, a real impact on its poor prognosis remains a long way off 14,15,23,24 …”

Section: Genetics Molecular Profiling and Classificationmentioning

confidence: 99%