Project title: Comprehensive molecular characterization of lung supra-carcinoids

Description

Fernandez-Cuesta will conduct the first molecular characterization of a new aggressive pulmonary carcinoid subtype called supra-carcinoids to identify potential drug targets for treating this disease.

What question will the researchers try to answer?

What are the molecular underpinnings of supra-carcinoids, a new aggressive subtype of NETs with a poor outlook, and what opportunities exist to interrupt cellular pathways to stop or slow tumor growth?

Why is this important?

The molecular characteristics of lung NETs are mostly unknown. To date, there is no explanation of why some cases grow slowly, and others very aggressively. Understanding the characteristics of aggressive lung NETs will help find screening and treatment approaches and better care for patients with the highest risks.

What will researchers do?

Researchers will molecularly characterize lung supra-carcinoids to look for opportunities to slow and stop tumor growth. By generating laboratory models that mimic the growth of supra-carcinoids, they will establish a valuable resource for continued study of this new lung NET subtype. Any diagnostic and therapeutic biomarkers identified will be validated by researchers.

How might this improve the treatment of NETs?

This study will better inform the clinical management of lung NETs to improve the survival of patients and to identify those at highest risk for relapse. Initial research by Fernandez-Cuesta and colleagues showed supra-carcinoids had a high expression of immune checkpoint genes. These experiments will further explore the potential of immunotherapy.

What is the next step?

The laboratory models established in this study will serve as a valuable platform for future preclinical testing of specific drugs to treat supra-carcinoids. In addition, the molecular profiling data generated will inform future research on how supra-carcinoids develop and grow.

Outcomes:

Typical and atypical carcinoids show relatively good prognosis but metastatic disease and relapse do occur. In a previous study, we identified groups of tumors with different genetic information, which did not clearly correspond to the groups made based on the aspects these tumors show under the microscope. The patients with tumors in one of these groups live shorter than for the other groups. Additionally, we identified six tumors, termed supra-carcinoids, that displayed the same aspect as normal carcinoids but with the genetic characteristics and survival of more aggressive tumors. As yet, little is known about the biological reasons for these differences, hampering efforts to identify markers that could help identify the patients at risk and to find the most suitable therapeutic options.

To address these questions, we used state-of-the-art technologies to deeply characterise all the genetic layers that could provide some hints on the reasons for the differences in survival. For this, we have used a new cohort of 201 patients, enriched for the most aggressive tumor types. Our analyses allowed us to identify the genetic features and biological processes responsible for the clinical behaviour of these diseases so through this work we have identified molecular and morphological characteristics of aggressive pulmonary carcinoids, which may assist in the clinical management of this rare disease.

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