Biliary tract cancers, which are also known as cholangiocarcinomas (CCA), describe malignancies that occur in the biliary tract and include the pancreas, gallbladder, and bile ducts. These are relatively rare cancers but are associated with a poor prognosis given that these cancers are difficult to detect and are usually diagnosed at later stages of the disease.
Biliary tract cancers, which are also known as cholangiocarcinomas (CCA), describe malignancies that occur in the biliary tract and include the pancreas, gallbladder, and bile ducts. These are relatively rare cancers but are associated with a poor prognosis given that these cancers are difficult to detect and are usually diagnosed at later stages of the disease.
CCAs are classified by growth pattern as mass forming, intraductal, or periductal, anatomical location as intrahepatic or extrahepatic (perihilar, or distal), and histology (predominantly adenocarcinomas with mixed hepatocellular CCAs are defined as a separate subtype of primary hepatic cancer) [1].
CCAs can arise de novo with no discernable risk factors, but a variety of genetic and nongenetic risk factors are associated with CCA, including liver cirrhosis, obesity, type 2 diabetes, chronic hepatitis B or C infection, or infection with hepatobiliary flukes [2]. Individuals with primary sclerosing cholangitis have higher levels of chronic liver inflammation and increased incidence of CCA [3] as well. CCAs are typically aggressive cancers with a median overall survival of < 24 months. The only treatment options have been surgical resection or liver transplantation for early-stage patients or aggressive chemotherapy for patients with advanced stages of the disease [4].
Next-generation sequencing technology has allowed the identification of molecular subtypes associated with several gene mutations that are linked to increased CCA risk, including mutations in chromatin remodeling genes (ARID1A, BAP1, and PBRM1) [5,6]. IDH1 mutations have been linked to intrahepatic CCA and mutations in ERBB2 are more closely associated with extrahepatic CCA [7].
Mutations in the fibroblast growth factor (FGF) signaling pathway, including mutations or translocations in FGF receptor (FGFR) genes, have also been identified in CCA, and an FGFR fusion has been linked specifically to intrahepatic CCA [8]. Moreover, patients with IDH1/2 mutations also exhibit elevated FGFR expression, even without FGFR mutations or fusions, further affirming a role for FGF/FGFR signaling in CCA progression[9]. In addition to tumor cell alterations, the tumor microenvironment is also being extensively explored and has led to the identification of an inflamed intrahepatic CCA subtype potentially treatable with checkpoint blockade immunotherapy [10].
The FGF/FGFR pathway has become one of the most encouraging targets for novel
CCA therapeutics. As FGFRs are receptor tyrosine kinases, nonselective FGFR inhibitors that target the conserved ATP-binding domain were the first drugs to be tested in clinical trials. A recent trial exploring the use of the nonselective FGFR kinase inhibitor pazopanib combined with a MEK inhibitor showed little efficacy [11].
Pemagatinib is the first FDA-approved targeted therapy for advanced CCA with FGFR2 fusions or rearrangements. Pemagatinib is a selective inhibitor of FGFR1, 2, and 3 and was approved in 2020 and given breakthrough therapy designation as the first drug to specifically treat CCA [12].
In 2021, Ivosidenib (Tibsovo), a small molecule IDH1 inhibitor, was approved by the FDA for treating IDH1 mutated locally advanced or metastatic CCA [13].
Very recently, the FDA has granted accelerated approval to two FGFR inhibitors: Infigratinib (Truseltiq), for the treatment of previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma with FGFR2 fusion (and a companion diagnostic to identify patients eligible to receive this treatment) [14,15]; and Futinatinib (TAS-120) for patients with previously treated, unresectable, locally advanced or metastatic intrahepatic CCA with FGFR2 gene fusions or other rearrangements [16,17].
Alternative FGF/FGFR inhibitors are also under development and target the extracellular domain or function as FGF ligand traps [18]. These alternative inhibitors can be used potentially in combination with FGFR kinase inhibitors that have lost efficacy due to the development of resistance [19].
In addition to mutation-driven therapeutic approaches, immune checkpoint inhibitors are currently tested in combination with chemotherapy to improve efficacy. A very recent study conducted on patients with advanced biliary tract cancer showed that Durvalumab, a PD-L1 inhibitor, significantly improves survival compared to chemotherapy alone [20].
New research on novel inhibitors and combination therapies will likely identify other therapeutic options for CCA, and these cancers will not be the terminal diagnoses they once were.
Razumilava N, Gores Cholangiocarcinoma. Lancet. 2014;383(9935):2168- 79.
Yao KJ, Jabbour S, et al. Increasing mortality in the United States from cholangiocarcinoma: an analysis of the National Center for Health Statistics Database. BMC Gastroenterol. 2016;16(1):117.
Hirschfield GM, Karlsen TH, et Primary sclerosing cholangitis. Lancet. 2013;382(9904):1587-99.
Yazici C, Niemeyer DJ, et al. Hepatocellular carcinoma and cholangiocarcinoma: an Expert Rev Gastroenterol Hepatol. 2014;8(1):63-82.
Jusakul A, Cutcutache I, et al. Whole‐genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma. Cancer Discov 2017;7:1116‐1135
Jiao Y, Pawlik TM, et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A, and PBRM1 in intrahepatic Nat Genet. 2013;45:1470–3.
Churi CR, Shroff R, et Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications. PLoS One. 2014;9:e115383.
Graham RP, Barr Fritcher EG, et al. Fibroblast growth factor receptor 2 translocations in intrahepatic Hum Pathol. 2014;45(8):1630- 1638.
Wang P, Dong Q, et Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene. 2013;32(25):3091-3100.
Job S, Rapoud D, et al.. Identification of Four Immune Subtypes Characterized by Distinct Composition and Functions of Tumor Microenvironment in Intrahepatic Cholangiocarcinoma. Hepatology. 2020 Sep;72(3):965-981
Shroff RT, Yarchoan M, O’Connor A, et The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma. Br J Cancer. 2017;116(11):1402-1407.
Patel TH, Marcus L, et al. FDA Approval Summary: Pemigatinib for Previously Treated, Unresectable Locally Advanced or Metastatic Cholangiocarcinoma with FGFR2 fusion or other rearrangements. Clin Cancer Res. 2022 Oct 7:CCR-22-2036.
Sumbly V, Landry I, Rizzo V. Ivosidenib for IDH1 Mutant Cholangiocarcinoma: A Narrative Review. Cureus. 2022 Jan 7;14(1):e21018
Javle M, Roychowdhury S, et al. Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study. Lancet Gastroenterol Hepatol. 2021 Oct;6(10):803-815.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-infigratinib-metastatic-cholangiocarcinoma
Goyal L, Meric-Bernstam F, et al. Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma. N Engl J Med. 2023 Jan 19;388(3):228-239. doi: 10.1056/NEJMoa2206834. PMID: 36652354.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-futibatinib-cholangiocarcinoma
Tolcher AW, Papadopoulos KP, Patnaik A, et A phase I, first in human study of FP-1039 (GSK3052230), a novel FGF ligand trap, in patients with advanced solid tumors. Ann Oncol. 2016;27(3):526-532.
Touat M, Ileana E, et Targeting FGFR signaling in cancer. Clin Cancer Res. 2015;21(12):2684-2694.
https://meetings.asco.org/abstracts-presentations/204876
DNA damage is one of the primary triggers of cancer development and has been linked to many types of cancers, including prostate, stomach, liver, and skin cancers, as well as leukemia. Within cells, the DNA sequence encodes all the instructions required for building proteins that are needed for cellular functions such as metabolism, replication, tissue, and organ maintenance.
The fidelity of the DNA sequence in a cell is maintained by multiple mechanisms, including the DNA damage repair mechanism, but errors and mutations can occur, which sets off a chain of events that leads to tumor growth.
DNA damage can be caused by exogenous sources, such as UV radiation, chemical carcinogens, and infection with human papillomavirus or Helicobacter pylori. Endogenous DNA damage can also be caused by multiple factors, including unchecked metabolites like reactive oxygen species (ROS) and defects in DNA damage repair enzymes. Since DNA damage mechanisms have been known to cause numerous cancers, several drugs, particularly small molecule inhibitors, have been developed to target DNA damage repair pathways.
Improvements in animal models for cancer have revolutionized how anti-cancer drugs are evaluated and developed, including drugs targeting DNA damage. Patient-derived xenograft (PDX) models have been particularly powerful tools since they use patient-derived tumor tissue engrafted into mice. Tumor cell lines, solid tumor tissue, or hematological tumors can be transplanted into immunodeficient mice to study DNA damage repair mechanisms. These immunocompromised mice can also be humanized by inoculating human immune cells or made to express components of the human immune system, like immune checkpoint molecules, to better screen for the effectiveness of various anti-cancer treatments.
In this era of rapid, high-throughput DNA sequencing, individual tumors can be sequenced and specific defects in DNA damage repair pathways can be defined. This same tumor tissue can be engrafted into a PDX mouse model for screening of drugs or therapeutics that tackle the appropriate DNA damage repair defect.
Different assays can also be used to study DNA damage and repair mechanisms:
This approach is powerful for screening preclinical drug candidates targeting DNA damage and repair for efficacy against a range of tumors and it also provides insights into potential off-target effects or toxicities. From the patient's perspective, pre-screening potential treatment options in mice can lead to the selection of the most appropriate drug or therapeutic targeting DNA damage and repair and help avoid treatments that may be ineffective.
DNA damage events can lead to tumor growth and this area of research continues to inform drug development on the bench and patient care in the clinic.
Champions Oncology is the ideal partner to accelerate your DNA damage-targeted drug pipeline. We offer a large bank of PDX models, particularly PDX models with high microsatellite instability (MSI-H), that have dysregulated DNA damage repair mechanisms, for ex vivo and in vivo studies. We also provide DNA sequencing, comet assay, and γH2AX detection by IHC staining or western blot, to support your DNA damage targeting drug programs. To add DNA damage evaluation to your upcoming study, contact us today.
