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Molecular therapeutic targets for cholangiocarcinoma: Present challenges and future possibilities
Dan Høgdall1, Colm J O'Rourke2, Jesper B Andersen2
1Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Oncology, Herlev and Gentofte Hospital, Herlev, Copenhagen University Hospital, Copenhagen, Denmark.
Abstract:
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 9years 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.
Insights
Cholangiocarcinoma (CCA) treatment faces challenges due to limited options and resistance. Future therapies require targeting non-oncogene dependencies and integrating microenvironment factors for better patient outcomes.
Area of Science:
- Oncology
- Genomics
- Precision Medicine
Background:
- Cholangiocarcinoma (CCA) presents a poor prognosis with limited therapeutic strategies, marked by similar incidence and mortality rates.
- Precision oncology has seen success with fibroblast growth factor receptor 2 (FGFR2) rearrangements and isocitrate dehydrogenase 1 (IDH1) mutations in specific CCA subsets.
- Multikinase inhibitors in unselected populations and the emerging role of immunotherapies highlight the evolving treatment landscape for CCA.
Purpose of the Study:
- To address the challenges in developing future therapeutics for cholangiocarcinoma (CCA).
- To explore strategies for targeting non-druggable alterations and non-oncogene dependencies in CCA.
- To emphasize the need for integrating non-genetic factors and resistance mechanisms in therapeutic development.
Main Methods:
- Review of current precision oncology successes and limitations in CCA.
- Analysis of challenges posed by non-druggable driver alterations and tumor suppressor genes.
- Consideration of the role of the tumor microenvironment and immune system in treatment response.
- Examination of treatment resistance mechanisms and the need for combination therapies.
Main Results:
- Precision oncology has identified actionable targets like FGFR2 rearrangements and IDH1 mutations in CCA subsets.
- Broad application of multikinase inhibitors in unselected CCA patients has yielded limited success.
- The impact of immunotherapies in CCA is still under investigation, showing early but significant potential.
- Many critical driver alterations involve tumor suppressor genes, necessitating novel therapeutic approaches beyond direct targeting.
Conclusions:
- Future CCA therapeutics must address "non-oncogene addiction" and druggable targets.
- Biomarker-driven trials, including basket studies, are crucial due to low recurrence of genomic alterations.
- Integrating non-genetic factors, microenvironment, and immune system is essential for comprehensive treatment strategies.
- Characterizing resistance mechanisms is key to developing combination therapies for prolonged clinical benefit in advanced CCA.
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