Project description:Perihilar cholangiocarcinoma (pCCA) is the anatomical sub-group of biliary tract cancer (BTC) arising between the second-order intrahepatic bile ducts and the cystic duct. Together with distal and intrahepatic cholangiocarcinoma (dCCA and iCCA; originating distal to, and proximal to this, respectively), gallbladder cancer (GBC) and ampulla of Vater carcinoma (AVC), these clinicopathologically and molecularly distinct entities comprise biliary tract cancer (BTC). Most pCCAs are unresectable at diagnosis, and for those with resectable disease, surgery is extensive, and recurrence is common. Therefore, the majority of patients with pCCA will require systemic treatment for advanced disease. The prognosis with cytotoxic chemotherapy remains poor, driving interest in therapies targeted to the molecular nature of a given patient's cancer. In recent years, the search for efficacious targeted therapies has been fuelled both by whole-genome and epigenomic studies, looking to uncover the molecular landscape of CCA, and by specifically testing for aberrations where established therapies exist in other indications. This review aims to provide a focus on the current molecular characterisation of pCCA, targeted therapies applicable to pCCA, and future directions in applying personalised medicine to this difficult-to-treat malignancy.
Project description:Primary tumor resection and liver transplantation are the only curative treatment options for the management of cholangiocarcinoma (CCA). However, for patients with advanced or metastatic disease, palliative systemic therapy remains the only treatment option. The development of targeted therapeutics has begun to shift the treatment paradigm in CCA. Targets of interest in CCA include mutated isocitrate dehydrogenase-1 (mIDH-1), human epidermal growth factor receptor 2 (HER2) overexpression/amplification, and fibroblast growth factor receptor 2 (FGFR2) fusion, in addition to less frequently observed targets such as BRAF V600E, deficient mismatch repair/high microsatellite instability (dMMR/MSI-H), and high tumor mutation burden (TMB-H). These targets are observed in varying frequency among patients with intrahepatic CCA and extrahepatic CCA. Multiple novel therapies have been developed to exploit each of these targets, with some having received United States Food and Drug Administration approval for use in the second-line setting. In the current review, we discuss targets of interest in CCA and summarize current evidence evaluating available therapies directed at these targets.
Project description:Anthracycline-induced cardiotoxicity (AIC) is a serious and common side effect of anthracycline therapy. Identification of genes and genetic variants associated with AIC risk has clinical potential as a cardiotoxicity predictive tool and to allow the development of personalized therapies. In this review, we provide an overview of the function of known AIC genes identified by association studies and categorize them based on their mechanistic implication in AIC. We also discuss the importance of functional validation of AIC-associated variants in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to advance the implementation of genetic predictive biomarkers. Finally, we review how patient-specific hiPSC-CMs can be used to identify novel patient-relevant functional targets and for the discovery of cardioprotectant drugs to prevent AIC. Implementation of functional validation and use of hiPSC-CMs for drug discovery will identify the next generation of highly effective and personalized cardioprotectants and accelerate the inclusion of approved AIC biomarkers into clinical practice.
Project description:Cholangiocarcinoma (CCA) is a highly-aggressive malignancy arising from the biliary tree, characterized by a steady increase in incidence globally and a high mortality rate. Most CCAs are diagnosed in the advanced and metastatic phases of the disease, due to the paucity of signs and symptoms in the early stages. This fact, along with the poor results of the local and systemic therapies currently employed, is responsible for the poor outcome of CCA patients and strongly supports the need for novel therapeutic agents and strategies. In recent years, the introduction of next-generation sequencing technologies has opened new horizons for a better understanding of the genetic pathophysiology of CCA and, consequently, for the identification and evaluation of new treatments tailored to the molecular features or alterations progressively elucidated. In this review article, we describe the potential targets under investigation and the current molecular therapies employed in biliary tract cancers. In addition, we summarize the main drugs against CCA under evaluation in ongoing trials and describe the preliminary data coming from these pioneering studies.
Project description:Richter transformation (RT) represents an uncommon (2% to 10%) but feared complication of chronic lymphocytic leukemia (CLL). The disease is characterized by rapid disease kinetics, a high-risk genetic mutational profile, chemoimmunotherapy resistance, and consequent poor survival. The typical overall survival (OS) from the pre-Bruton tyrosine kinase (BTK)/B-cell lymphoma 2 (BCL2) inhibitor CLL era is 6-12 months, and recent series of RT complicating progression on a BTK or BCL2 inhibitor in heavily pretreated relapsed CLL patients suggests an OS of only 3-4 months. Despite these sobering survival statistics, novel agents have the potential to impact the natural RT disease course. This article reviews recent therapeutic developments, focusing on inhibitors of BTK, BCL2, the PD1-PDL1 axis, and T-cell-activating/engaging therapies. Herein, I discuss the importance of randomized clinical trials in a disease where small single-arm studies dominate; industry engagement, including the role of registrational studies; and the need to integrate prospectively planned correlative biological studies embedded within future clinical trials to help discover which patient benefits most from each class or combination of novel targets.
Project description:Cholangiocarcinoma (CC) encompasses a group of related but distinct malignancies whose lack of a stereotyped genetic signature makes challenging the identification of genomic landscape and the development of effective targeted therapies. Accumulated evidences strongly suggest that the remarkable genetic heterogeneity of CC may be the result of a complex interplay among different causative factors, some shared by most human cancers while others typical of this malignancy. Currently, considerable efforts are ongoing worldwide for the genetic characterization of CC, also using advanced technologies such as next-generation sequencing (NGS). Undoubtedly this technology could offer an unique opportunity to broaden our understanding on CC molecular pathogenesis. Despite this great potential, however, the high complexity in terms of factors potentially contributing to genetic variability in CC calls for a more cautionary application of NGS to this malignancy, in order to avoid possible biases and criticisms in the identification of candidate actionable targets. This approach is further justified by the urgent need to develop effective targeted therapies in this disease. A multidisciplinary approach integrating genomic, functional and clinical studies is therefore mandatory to translate the results obtained by NGS into effective targeted therapies for this orphan disease.
Project description:Despite advanced diseases continuing to be associated with grim prognoses, the past decade has witnessed the advent of several novel treatment options for cholangiocarcinoma (CCA) patients. In fact, CCA has emerged as a heterogeneous group of malignancies harboring potentially druggable mutations in approximately 50% of cases, and thus, molecularly targeted therapies have been actively explored in this setting. Among these, fibroblast growth factor receptor (FGFR) inhibitors have reported important results, as witnessed by the FDA approval of pemigatinib in previously treated metastatic CCA patients harboring FGFR2 fusion or other rearrangements. Herein, we provide an overview of available evidence on FGFR inhibitors in CCA, especially focusing on the development, pitfalls and challenges of emerging treatments in this setting.
Project description:Although rare, intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy and the incidence of ICC has increased 14% per year in recent decades. Treatment of ICC remains difficult as most people present with advanced disease not amenable to curative-intent surgical resection. Even among patients with operable disease, margin-negative surgical resection can be difficult to achieve and the incidence of recurrence remains high. As such, there has been considerable interest in systemic chemotherapy and targeted therapy for ICC. Over the last decade, the understanding of the molecular and genetic foundations of ICC has reshaped treatment approaches and strategies. Next-generation sequencing has revealed that most ICC tumors have at least one targetable mutation. These advancements have led to multiple clinical trials to examine the safety and efficacy of novel therapeutics that target tumor-specific molecular and genetic aberrations. While these advancements have demonstrated survival benefit in early phase clinical trials, continued investigation in randomized larger-scale trials is needed to further define the potential clinical impact of such therapy.