Development of a novel genetically engineered mouse model to study the role of HDAC6 in oncogenesis and metastasis of non-small cell lung cancer.

Projektinformationen

HDAC6_GEMM

ID Finanzhilfevereinbarung: 799724

DOI

10.3030/799724

Das Projekt endete am 31 August 2020

EK-Unterschriftsdatum 15 März 2018

Startdatum 1 Oktober 2018

Enddatum 30 September 2021

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 248 063,40

EU-Beitrag

€ 248 063,40

Koordiniert durch

ROYAL COLLEGE OF SURGEONS IN IRELAND
Ireland

Periodic Reporting for period 1 - HDAC6_GEMM (Development of a novel genetically engineered mouse model to study the role of HDAC6 in oncogenesis and metastasis of non-small cell lung cancer.)

Berichtszeitraum: 2018-10-01 bis 2020-09-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Problem/issue being addressed: In this project we are investigating a new treatment option for non-small cell lung cancer patients. NSCLC accounts for nearly 85% of all cases of lung cancer. Despite the discovery of novel targeted therapies there is still a poor prognosis for lung cancer due to drug resistance and tumor recurrence.


Why is it important for society: In Europe lung cancer is the second most common cancer in men and the third most common cancer in women. Besides a high mortality rate, lung cancer also causes a considerable socio-economic burden estimated to be about 18.1 billion Euro per year. Approximately 70% of all newly diagnosed patients present with local advanced or metastatic disease, requiring systemic chemotherapy. This project offers the potential to provide new treatment options to help reduce the impact of this disease on society.

What are the overall objectives: The overall research aim is to understand the molecular mechanisms of a protein called Histone Deacetylase 6 (HDAC6) in the oncogenesis and metastasis of NSCLC. Drugs to target this protein have been used for many years in the clinic for the treatment of various cancers. However, the exact role that HDAC6 plays in the development of cancer remains poorly understood. In this project we hope to unravel these exact roles and so help development good treatment strategies for the use of these drugs in the treatment of NSCLC.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

A number of the objectives outlined in the project proposal have now been addressed. Firstly, an allograft mouse model was established to study the consequences of targeting HDAC6 in NSCLC. Moreover, we complemented this with genetically engineered mouse models that were available in Dr. Wong’s laboratory. I have also perfected the necessary skills to integrate these models into my own laboratory in Ireland. Following this, we utilised these models to examine the effect of inhibiting histone deacetylase 6 (HDAC6) on the tumor microenvironment. To execute this, we used multi-parametric flow cytometry to characterize the immune population. We found a change in the myeloid derived suppressor cell population and the polarisation of macrophages in tumors treated with HDAC6 inhibitors. Our previous findings indicate that HDAC6 plays a role in cancer cell glycolysis. Considering this, we investigated the metabolic phenotype of tumors from our NSCLC mouse models. Interestingly, we identified differences in the metabolic role of HDAC6 when comparing distinct genotypes of NSCLC. We are currently investigating the influence of this HDAC6 driven metabolic changes on the tumor microenvironment in NSCLC models. Moreover, we are examining potential combination drug candidates to help further reduce the tumor burden in the NSCLC mouse models.

Overview of results: We have identified a distinct HDAC6 driven metabolic phenotype in a specific genotype of NSCLC. Targeting this metabolic pathway helps reduce tumor burden in NSCLC mice.

Exploitation and dissemination: Some aspect of this work are now in final preparation for publication in Cancer Research. When published the work will be highlighted through social media platforms. Moreover, this work will be presented at the Irish Association of Cancer Research. The MSCA logo and EU funding reference will be acknowledged in all incidences.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

Progress beyond the state of the art: This project goes beyond the current state of the art as it uses pre-clinical mouse models for studying the role of HDAC6 in NSCLC. Dr. Wong’s laboratory has generated various inducible bitransgenic mice harboring mutations in oncogenes such as KRAS, BRAF, HER2 and EGFR in lung cancer. Moreover, we also used allograft lung mouse models. Both these mouse models are well beyond the current-state-of-the-art as the disease is driven by clinically relevant genetic changes, the tumour arises from normal organs, native vasculature is present and the mice are immune-competent. When investigating the changes of the immune microenvironment we used state-of-the art multi-parametric flow cytometry. This allowed us to look at changes in the populations of T cell, B cell, MDSCs, dendritic cells and macrophages together. Finally, we used state-of-the art metabolic mass spectrometry techniques to examine the metabolic phenotypes of NSCLC tumors

Expected results and potential impacts: This project encompassed highly innovative, collaborative research that will deliver impact, both to Europe and globally. The project was focused on examining the role of HDAC6 in NSCLC and developing new treatment options for this disease. The deliverables in this project will provide potential impact in the following ways: Economic Impact; the potential new treatment options generated in this project will help reduce the number of cancer deaths, decreasing the economic impact of cancer. Societal Impact; the discovery of new treatment options will also save lives and lessen the strain on the society, health services, families and carers. Health and Wellbeing; the dissemination and public engagement will help educate and improve the health and wellbeing of the general population. Human Capacity; this project has greatly impacted my career progression and will pay a major role in helping me become a successful woman in science.

Summary of Methods Used To Generate Main Results