Periodic Reporting for period 1 - SALMYB (MYB rearrangements in Adenoid Cystic Carcinoma: protagonists or secondary characters?)
Periodo di rendicontazione: 2020-10-19 al 2022-10-18
Adenoid cystic carcinoma (ACC) is a relatively rare but life-threatening cancer that occurs mainly in the glands that produce our saliva. However, even though it is more common in salivary glands, ACC can develop in many other organs, including the breast.
Salivary gland ACC is considered a difficult cancer to manage and to predict the outcome of the disease in any one patient. The main issues are the risks of late recurrences (more than 10 years after the initial diagnosis) and dissemination to other parts of the body (distant metastasis), including lung, bones and brain. Also, a major problem is the lack of drugs that have a significant impact on disease progression for patients with advanced disease. Patients diagnosed with breast ACC, on the other hand, have a better chance of remaining free of disease for longer periods or never experiencing relapse or dissemination. Scientists still don’t fully understand why ACC in the salivary glands and the breast have different behaviours.
Rare cancers, such as ACC, combine the challenges of being both a rare disease (limited scientific data and professional expertise) and cancer (complex tumour biology and resistance to conventional therapies). In many cases, patients with rare cancers have to deal with uncertainties from diagnosis to treatment. Being diagnosed with a rare cancer usually means that it is harder to find doctors who have expertise (often having to travel long distances to access treatment) and, due to the lack of scientific evidence, doctors disagree more often regarding the best treatment available. For physicians, rare cancers are more difficult to handle: there is less evidence to support clinical decisions and, in many cases, less personal experience.
SALMYB is a basic-science research project designed to expand our knowledge of this disease. ACC has an associated, recurrent molecular event, chromosomal translocation. This means that a piece of one chromosome, at a specific gene sequence, breaks off and attaches to another chromosome, at another specific gene sequence. In ACC the main genes involved with the translocation are MYB and NFIB. To date we do not understand the full implications of this translocation and the biological implications of the joining of these two genes, however, it is thought that the MYB gene may allow cells to maintain an undifferentiated status, more embryonic-like,which would allow tumours to form, grow and migrate to other sites in the body. Our investigation, studying the biological impacts of the translocation, contributes to the understanding of ACC development benefiting patients suffering from this rare form of cancer at different primary sites.
Salivary gland ACC is considered a difficult cancer to manage and to predict the outcome of the disease in any one patient. The main issues are the risks of late recurrences (more than 10 years after the initial diagnosis) and dissemination to other parts of the body (distant metastasis), including lung, bones and brain. Also, a major problem is the lack of drugs that have a significant impact on disease progression for patients with advanced disease. Patients diagnosed with breast ACC, on the other hand, have a better chance of remaining free of disease for longer periods or never experiencing relapse or dissemination. Scientists still don’t fully understand why ACC in the salivary glands and the breast have different behaviours.
Rare cancers, such as ACC, combine the challenges of being both a rare disease (limited scientific data and professional expertise) and cancer (complex tumour biology and resistance to conventional therapies). In many cases, patients with rare cancers have to deal with uncertainties from diagnosis to treatment. Being diagnosed with a rare cancer usually means that it is harder to find doctors who have expertise (often having to travel long distances to access treatment) and, due to the lack of scientific evidence, doctors disagree more often regarding the best treatment available. For physicians, rare cancers are more difficult to handle: there is less evidence to support clinical decisions and, in many cases, less personal experience.
SALMYB is a basic-science research project designed to expand our knowledge of this disease. ACC has an associated, recurrent molecular event, chromosomal translocation. This means that a piece of one chromosome, at a specific gene sequence, breaks off and attaches to another chromosome, at another specific gene sequence. In ACC the main genes involved with the translocation are MYB and NFIB. To date we do not understand the full implications of this translocation and the biological implications of the joining of these two genes, however, it is thought that the MYB gene may allow cells to maintain an undifferentiated status, more embryonic-like,which would allow tumours to form, grow and migrate to other sites in the body. Our investigation, studying the biological impacts of the translocation, contributes to the understanding of ACC development benefiting patients suffering from this rare form of cancer at different primary sites.
Most of the workload of SALMYB involved developing methods to induce the production of the fusion protein by normal cells. To achieve this we designed a vector containing the sequence of the most common chromosomal translocation of MYB and NFIB. The literature shows that the fusion protein triggers MYB activity, but in this study we were interested in identifying if there were differences between wild-type (normal) MYB and the new fusion protein. The specific gene sequences for MYB-NFIB and full-length MYB were inserted into vectors expressing a green-fluorescent protein (a vehicle to artificially insert a foreign nucleic sequence) for transfer into a human salivary gland cell. We used a vector expressing a green fluorescent protein as this allows us to monitor the efficiency of the transfer of new DNA by fluorescent microscopy and also use this to further select the cells that are expressing the sequence, through fluorescence-activated cell sorting (FACS). We have been able to successfully induce the production of MYB and MYB-NFIB in embryonic cells, with detectable protein levels, and are now working on achieving this in normal salivary gland and breast cells.
Also during the fellowship tissue from a cohort of patients diagnosed with ACC was retrieved from our tissue banks alongside key information such as clinical stage at diagnosis, presence of invasion of the nerves by cancer cells, and appearance under the microscope; factors known to be associated with lower survival times. We are now looking to expand the number of cases to further evaluate the presence of the translocation in our cohort. As we also have information on follow-up, such as presence of recurrence or the time the patients survived after diagnosis, we will be able to establish correlations between the molecular status and pathological and clinical aspects.
The preliminary results of SALMYB have not yet been published. A broad review on the subject has been conducted and was published in the journal Critical Reviews in Oncology/Hematology. A second review paper on the current status of clinical trials in ACC has very recently been accepted for publication and will be available online soon. Both articles are published under an open access licence.
Dr Petersen Wagner has shared her journey, experience in applying for the MSCA and some advice for early career researchers, in two interviews that can be accessed using the links:
https://drive.google.com/file/d/1I5kN1AmSe6DVVDfw37cP54WE-Sk7iMmi/view(si apre in una nuova finestra)
https://www.euraxess.org.uk/united-kingdom/news/meet-scientist-vivian-petersen-wagner(si apre in una nuova finestra)
Also during the fellowship tissue from a cohort of patients diagnosed with ACC was retrieved from our tissue banks alongside key information such as clinical stage at diagnosis, presence of invasion of the nerves by cancer cells, and appearance under the microscope; factors known to be associated with lower survival times. We are now looking to expand the number of cases to further evaluate the presence of the translocation in our cohort. As we also have information on follow-up, such as presence of recurrence or the time the patients survived after diagnosis, we will be able to establish correlations between the molecular status and pathological and clinical aspects.
The preliminary results of SALMYB have not yet been published. A broad review on the subject has been conducted and was published in the journal Critical Reviews in Oncology/Hematology. A second review paper on the current status of clinical trials in ACC has very recently been accepted for publication and will be available online soon. Both articles are published under an open access licence.
Dr Petersen Wagner has shared her journey, experience in applying for the MSCA and some advice for early career researchers, in two interviews that can be accessed using the links:
https://drive.google.com/file/d/1I5kN1AmSe6DVVDfw37cP54WE-Sk7iMmi/view(si apre in una nuova finestra)
https://www.euraxess.org.uk/united-kingdom/news/meet-scientist-vivian-petersen-wagner(si apre in una nuova finestra)
The expected findings of SALMYB, as a basic-research project, can be used for further studies seeking more effective drugs to treat ACC. Most of the advances that have been achieved for the treatment of salivary gland cancers are currently based on using the molecular deregulations as a target. Our ultimate aim is to contribute to an improvement in patients’ quality of life and survival time. Impacts on healthcare from social, cultural and economic perspectives are end-user aims of our research. Moreover, our results could be transposed to other types of cancer that harbour MYB rearrangements (such as leukaemia and colon cancer), and the methods used in further studies assessing other tumours characterised by chromosome translocations, such as prostate, colorectal and non-small-cell lung cancer.