Final Report Summary - NOTCHLUNG (Explore novel connections between oncogenic pathways in lung cancer)
Lung cancer causes about a million deaths per year and the estimation is that 250 million people will die during the 21st century for this reason. A major challenge in treating this and other cancers is the intrinsic resistance to conventional therapies demonstrated by the cancerous cells that are responsible for the sustained growth, survival, and invasion of the tumour. Identifying new pathways involved in the biological processes necessary for the survival of lung cancerous cells is paramount in developing new clinical approaches with the goal of preventing disease recurrence.
There are two main types of lung cancers: small cell lung carcinoma, accounting for about 20% of lung cancers, and non-small cell lung carcinoma (NSCLC), which affects 80% of lung cancer patients. Three are the more important oncogenes in human NSCLC: oncogenically mutated KRAS and EGFR, and EML4-ALK translocation, accounting from more than 50% of patients in western countries to almost 80% of patients in some Asian countries as Korea. The life expectancy of NSCLC patients that harbour mutations in EGFR and ALK has, importantly, been improved thanks to the development of specific inhibitors for both these two molecules. In stark contrast, there is no treatment for NSCLC patients with driving oncogenic mutations in KRAS where, depending on the study, the percentage of patients with KRAS mutations can be as high as 35%. Also of relevance is the fact that, contrary to other common solid tumours such as breast or colon, the outcomes after curative tumour resection in patients of early-stage NSCLC are poor, with recurrence rates between 35–50%, where patients sucumb to metastatic lesions not detected at the early stages.
These two events constitute the most important reasons that have made lung cancer the leading cause of cancer-related deaths worldwide. The main objectives of the project NOTCHLUNG (631390) aimed to seeking solutions to both problems.
We have previously demonstrated that KrasV12-driven NSCLC are addicted to the Notch pathway but it could possible that the Notch pathway would be needed also in other NSCLC subsets. In NOTCHLUNG we have explored the effect of Notch inhibition on NSCLC driven by the erlotinib resistant EGFRL858R/T790M and EML4-ALK translocation using available mouse models we have obtained from Dr. Kwok K. Wong at Dana Farber (Boston, USA) and Dr. Andrea Ventura at Sloan Kettering (NYC, NY). Even more, we have generated also a preclinical mouse model with lung specific expression of c-MET that develops c-MET-driven NSCLC. Finally, we have developed a technique to generate orthotopic lung PDTX through a complex thoracic surgery in nude mice. With all these preclinical models we have analysed the role of the Notch pathway in tumor development and tumor relapse. Most of our findings are about to be published and hence will be publically available. Even more, we have already published several articles as it can be found in the appropriate section.
Of note, thanks to the NOTCHLUNG grant we have developed enough preliminary data to obtain a very competitive national grant from Cancer National Institute (INCa) where I’m coordinator. As partner, I’m involved in another INCa grant as well as another contract with the Roche company. In total I’ve been able to obtain around 1M€ that will sustain the research in my laboratory for the coming years. Since the beginning of this project, I have been able hire 2 technicians and attracting 3 talented post-docs as well as 1 PhD student, and importantly, the head of thoracic oncology of Montpellier University Hospital, as well as another clinical researcher from Montpellier Cancer Hospital (ICM) have joined my lab to perform research with us. Even more, I have attracted a staff scientist with a permanent position. For the whole composition of the lab please take a look:
https://ircm.fr/index.php?project=crcm_en&pagendx=408
Hence NOTCHLUNG have already allowed me to fully establish my laboratory at IRCM and put me in a very good position to achieve my ultimate goal, that is to find new therapeutic approaches for the treatment of lung cancer, the leading cause of death by Cancer in the world today.
There are two main types of lung cancers: small cell lung carcinoma, accounting for about 20% of lung cancers, and non-small cell lung carcinoma (NSCLC), which affects 80% of lung cancer patients. Three are the more important oncogenes in human NSCLC: oncogenically mutated KRAS and EGFR, and EML4-ALK translocation, accounting from more than 50% of patients in western countries to almost 80% of patients in some Asian countries as Korea. The life expectancy of NSCLC patients that harbour mutations in EGFR and ALK has, importantly, been improved thanks to the development of specific inhibitors for both these two molecules. In stark contrast, there is no treatment for NSCLC patients with driving oncogenic mutations in KRAS where, depending on the study, the percentage of patients with KRAS mutations can be as high as 35%. Also of relevance is the fact that, contrary to other common solid tumours such as breast or colon, the outcomes after curative tumour resection in patients of early-stage NSCLC are poor, with recurrence rates between 35–50%, where patients sucumb to metastatic lesions not detected at the early stages.
These two events constitute the most important reasons that have made lung cancer the leading cause of cancer-related deaths worldwide. The main objectives of the project NOTCHLUNG (631390) aimed to seeking solutions to both problems.
We have previously demonstrated that KrasV12-driven NSCLC are addicted to the Notch pathway but it could possible that the Notch pathway would be needed also in other NSCLC subsets. In NOTCHLUNG we have explored the effect of Notch inhibition on NSCLC driven by the erlotinib resistant EGFRL858R/T790M and EML4-ALK translocation using available mouse models we have obtained from Dr. Kwok K. Wong at Dana Farber (Boston, USA) and Dr. Andrea Ventura at Sloan Kettering (NYC, NY). Even more, we have generated also a preclinical mouse model with lung specific expression of c-MET that develops c-MET-driven NSCLC. Finally, we have developed a technique to generate orthotopic lung PDTX through a complex thoracic surgery in nude mice. With all these preclinical models we have analysed the role of the Notch pathway in tumor development and tumor relapse. Most of our findings are about to be published and hence will be publically available. Even more, we have already published several articles as it can be found in the appropriate section.
Of note, thanks to the NOTCHLUNG grant we have developed enough preliminary data to obtain a very competitive national grant from Cancer National Institute (INCa) where I’m coordinator. As partner, I’m involved in another INCa grant as well as another contract with the Roche company. In total I’ve been able to obtain around 1M€ that will sustain the research in my laboratory for the coming years. Since the beginning of this project, I have been able hire 2 technicians and attracting 3 talented post-docs as well as 1 PhD student, and importantly, the head of thoracic oncology of Montpellier University Hospital, as well as another clinical researcher from Montpellier Cancer Hospital (ICM) have joined my lab to perform research with us. Even more, I have attracted a staff scientist with a permanent position. For the whole composition of the lab please take a look:
https://ircm.fr/index.php?project=crcm_en&pagendx=408
Hence NOTCHLUNG have already allowed me to fully establish my laboratory at IRCM and put me in a very good position to achieve my ultimate goal, that is to find new therapeutic approaches for the treatment of lung cancer, the leading cause of death by Cancer in the world today.