TY - CHAP

T1 - Molecular therapeutic targets for cholangiocarcinoma

T2 - Present challenges and future possibilities

AU - Høgdall, Dan

AU - O'Rourke, Colm J.

AU - Andersen, Jesper B.

N1 - Publisher Copyright: © 2022 Elsevier Inc.

PY - 2022

Y1 - 2022

N2 - A diagnosis of cholangiocarcinoma (CCA) is implicit with poor prognosis and limited treatment options, underscoring the near equivalence of incidence and mortality rates in this disease. In less than 9 years from genomic identification to FDA-approval of the corresponding inhibitors, fibroblast growth factor receptor 2 (FGFR2) rearrangements and isocitrate dehydrogenase 1 (IDH1) mutations became exemplary successes of precision oncology in subsets of patients with CCA. However, clinical trial results from multikinase inhibitors in unselected populations have been less successful, while the impact of immunotherapies are only beginning to impact this setting. Development of future therapeutics is incumbent with new challenges. Many driver alterations occur in tumor suppressor-like genes which are not directly druggable. Therapeutically, this will require identification of ensuant “non-oncogene addiction” involving genes which are not themselves oncogenes but become tumor survival dependencies when a specific driver alteration occurs. The low recurrence frequency of genomic alterations between CCA patients will require careful evaluation of targeted agents in biomarker-enrolled trials, including basket trial settings. Systematic expansion of candidate drug targets must integrate genes affected by non-genetic alterations which incorporates the fundamental contribution of the microenvironment and immune system to treatment response, disease facets which have been traditionally overlooked by DNA-centric analyses. As treatment resistance is an inevitability in advanced disease, resistance mechanisms require characterization to guide the development of combination therapies to increase the duration of clinical benefit. Patient-focused clinical, technological and analytical synergy is needed to deliver future solutions to these present therapeutic challenges.

AB - A diagnosis of cholangiocarcinoma (CCA) is implicit with poor prognosis and limited treatment options, underscoring the near equivalence of incidence and mortality rates in this disease. In less than 9 years from genomic identification to FDA-approval of the corresponding inhibitors, fibroblast growth factor receptor 2 (FGFR2) rearrangements and isocitrate dehydrogenase 1 (IDH1) mutations became exemplary successes of precision oncology in subsets of patients with CCA. However, clinical trial results from multikinase inhibitors in unselected populations have been less successful, while the impact of immunotherapies are only beginning to impact this setting. Development of future therapeutics is incumbent with new challenges. Many driver alterations occur in tumor suppressor-like genes which are not directly druggable. Therapeutically, this will require identification of ensuant “non-oncogene addiction” involving genes which are not themselves oncogenes but become tumor survival dependencies when a specific driver alteration occurs. The low recurrence frequency of genomic alterations between CCA patients will require careful evaluation of targeted agents in biomarker-enrolled trials, including basket trial settings. Systematic expansion of candidate drug targets must integrate genes affected by non-genetic alterations which incorporates the fundamental contribution of the microenvironment and immune system to treatment response, disease facets which have been traditionally overlooked by DNA-centric analyses. As treatment resistance is an inevitability in advanced disease, resistance mechanisms require characterization to guide the development of combination therapies to increase the duration of clinical benefit. Patient-focused clinical, technological and analytical synergy is needed to deliver future solutions to these present therapeutic challenges.

KW - Cholangiocarcinoma

KW - Clinical trials

KW - Genomics

KW - Immunotherapy

KW - Predictive biomarkers

KW - Targeted therapy

U2 - 10.1016/bs.acr.2022.01.012

DO - 10.1016/bs.acr.2022.01.012

M3 - Book chapter

C2 - 35961705

AN - SCOPUS:85124734918

VL - 156

T3 - Advances in Cancer Research

SP - 343

EP - 366

BT - Advances in Cancer Research

PB - Academic Press

ER -