There are two main areas that are the focus of my research

Salivary Gland Cancer

Salivary Gland Cancers are a rare Head and Neck Cancer with significant unmet need. Our knowledge of the biology of these cancers is behind most other cancers. With few exceptions, treatment options have not changed for over 50 years. The initial focus of my Laboratory Research is understanding the biology of salivary gland cancers to enable new treatment to be developed. 

Personalised Medicine

Once new treatments are developed, it is clear that all patients do not gain the same benefit. My second research focus is applying the discoveries around the biology of cancer to enable personalised medicine. Although I focus on Salivary Gland Cancer and other Head and Neck Cancers, this is applicable across all of Cancer Medicine. 

Unique salivary gland cancer tumour bank

As I see two to four new patients and around 10 to 20 patients on follow up each week with Salivary Gland Cancer, through the generosity of these patients, we have developed a unique collection of patient tumour and blood samples. This is a globally unique resource which provides that start point for research studies into the biology of salivary gland cancers.

Because biobanks deal with sensitive information and human samples, they are subject to strict ethical, legal, and regulatory requirements to ensure that the rights of donors are protected and that the samples are used for legitimate research purposes.

Laboratory research at the CRUK Manchester Institute/University of Manchester

I am establishing my own independent Head and Neck Cancer Research Lab in the University of Manchester Cancer with the guidance and expertise of the large and successful Clinical and Experimental Pharmacology Lab led by Prof Caroline Dive CBE and the Immunology expertise of Prof Tracy Hussell, the current President of the British Society for Immunology. The initial focus of my laboratory research is on genomic changes driving adenoid cystic carcinoma and how that impacts on the body’s immune system.

Adenoid cystic carcinoma

Adenoid cystic carcinoma (ACC) is a rare type of cancer that can arise in various locations in the body, including the salivary glands, lacrimal glands, and other secretory glands. The genetic changes that occur in ACC can vary depending on the location and stage of the tumor, but some common genetic alterations have been identified through research studies.

One of the most common genetic alterations in ACC is a chromosomal translocation between chromosomes 6 and 9, which creates a fusion gene called MYB-NFIB. This fusion gene produces a protein that plays a role in regulating cell growth and division, and its overexpression has been implicated in the development and progression of ACC. The MYB-NFIB fusion gene is present in about 50-60% of cases of ACC and can be used as a diagnostic marker for the disease.

Other genetic alterations that have been associated with ACC include mutations in genes such as TP53, PTEN, and PIK3CA, which are involved in the regulation of cell cycle and signaling pathways. These mutations can lead to abnormal cell growth and survival and contribute to the development and progression of ACC.

More recently, studies have identified other potential genetic changes in ACC, such as alterations in the chromatin remodeling complex genes, including ARID1A and ARID1B, and mutations in the MAPK signaling pathway genes, such as BRAF and HRAS.

The identification of these genetic changes has helped to improve our understanding of the molecular mechanisms underlying ACC and may lead to the development of targeted therapies for this challenging disease.

What does MYB do in ACC?

MYB is a transcription factor that regulates the expression of genes by binding to specific DNA sequences and controlling the rate of transcription, which is the process by which DNA is copied into RNA. MYB plays important roles in various cellular processes, including cell growth, differentiation, and survival.

The MYB protein consists of three functional domains: an N-terminal DNA-binding domain, a central transcriptional activation domain, and a C-terminal negative regulatory domain. The DNA-binding domain recognizes specific DNA sequences, called MYB recognition sites, and binds to them to regulate gene expression.

MYB can function as a transcriptional activator or repressor depending on the context and the genes it regulates. As an activator, MYB can recruit other transcriptional coactivators and modify chromatin structure to promote the binding of RNA polymerase and increase transcriptional output. As a repressor, MYB can interact with other transcriptional corepressors and inhibit the binding of RNA polymerase to reduce transcriptional output.

The MYB protein also interacts with other cellular proteins and signaling pathways to modulate gene expression and cellular functions. For example, MYB can interact with members of the Notch signaling pathway and the Wnt signaling pathway to regulate cell fate determination and differentiation. MYB also interacts with cell cycle regulators, such as cyclin-dependent kinases, to control cell proliferation and apoptosis.

In adenoid cystic carcinoma (ACC), the MYB-NFIB fusion gene creates a chimeric protein that retains the DNA-binding and transcriptional activation domains of MYB but replaces the negative regulatory domain with NFIB. This fusion protein can promote the abnormal growth and survival of ACC cells by deregulating the expression of target genes involved in cell cycle, apoptosis, and other cellular processes.

What is MYB super-enhancer translocation?

The MYB super-enhancer translocation is a genetic abnormality that occurs in some cases of adenoid cystic carcinoma (ACC). It involves a rearrangement of genetic material that leads to the fusion of the MYB gene with another nearby gene, resulting in the production of a chimeric protein that promotes the growth and survival of cancer cells.

Specifically, the translocation involves a break in the DNA near the MYB gene, which contains a regulatory region known as a super-enhancer. This super-enhancer controls the expression of MYB and other genes by promoting the binding of transcription factors and other regulatory proteins to the DNA.

In ACC, the translocation causes the super-enhancer to become attached to a nearby gene, NFIB, resulting in the creation of a fusion gene called MYB-NFIB. This fusion gene produces a chimeric protein that retains the DNA-binding and transcriptional activation domains of MYB but replaces the negative regulatory domain with NFIB. This altered protein can promote the abnormal growth and survival of ACC cells by deregulating the expression of target genes involved in cell cycle, apoptosis, and other cellular processes.

The MYB super-enhancer translocation is thought to play a key role in the development and progression of ACC and may be a potential target for new therapeutic approaches.

How does MYB promote cancer?

MYB overexpression can also occur in other types of cancer, such as breast cancer, leukemia, and colorectal cancer. In these cases, MYB can be activated by various signaling pathways, such as the Wnt and Notch pathways, or by mutations in other genes that regulate MYB expression.

MYB overexpression can promote cancer growth by several mechanisms, including:

• Activating genes involved in cell cycle progression, such as cyclins and cyclin-dependent kinases (CDKs), and inhibiting genes involved in cell cycle arrest, such as p21 and p27.

• Inhibiting genes involved in apoptosis, such as BAX and BAD, and activating genes involved in cell survival, such as BCL2 and MCL1.

• Regulating genes involved in cell differentiation, such as MYC and RUNX1, and promoting the development of undifferentiated, aggressive cancer cells.

Targeting MYB overexpression may be a promising strategy for developing new cancer therapies, particularly for ACC and other cancers with MYB-driven pathways.

How can we target the MYB fusion?

MYB fusion results in neoantigens. A neoantigen, also known as a neoepitope, is a type of antigen that is generated from a mutation or alteration in a person's own DNA. Specifically, it is a protein fragment, or peptide, that is derived from a mutated gene or from a fusion of two genes that are not normally connected. These neoantigens are not present in healthy cells, but are expressed on the surface of tumor cells or infected cells, making them unique targets for the immune system to recognize and attack. Because they are specific to the individual, neoantigens hold great promise as potential targets for personalized cancer immunotherapy.

how does the immune system normally respond to neoantigens?

The immune system is constantly on the lookout for foreign substances, including abnormal or mutated cells, and it can recognize and respond to neoantigens in a similar way as it does to other types of antigens. When a cell becomes cancerous or infected, it can produce neoantigens that are not present in healthy cells. These neoantigens can be presented on the surface of the cancer or infected cell by major histocompatibility complex (MHC) molecules, which act as markers that alert the immune system to the presence of a potential threat.

T cells, a type of immune cell, can recognize these neoantigens through their T cell receptors (TCRs). Once a T cell recognizes a neoantigen, it can initiate an immune response to eliminate the cancer or infected cells. This process involves the activation of other immune cells, such as killer T cells and helper T cells, that can directly attack the cancer or infected cells or support the immune response by producing cytokines and other signaling molecules.

However, some tumors can develop ways to evade the immune system, including by reducing the expression of neoantigens or by suppressing the immune response. This is why research is ongoing to better understand how the immune system recognizes and responds to neoantigens, and how to harness this response for cancer immunotherapy.

Can we exploit differences in macrophages in patients To develop new treatments?

We have identified unique populations of macrophages in ACC Patients in our current studies on patient blood and tumour samples.

Macrophages are a type of immune cell that play an important role in controlling the immune response to neoantigens. When macrophages encounter a cancer cell or infected cell that displays neoantigens on its surface, they can phagocytose (engulf and ingest) the abnormal cell and present the neoantigens to other immune cells, such as T cells.

Macrophages can also secrete cytokines, which are signaling molecules that can influence the immune response. For example, macrophages can secrete cytokines that promote inflammation, which can recruit other immune cells to the site of infection or cancer. In addition, macrophages can secrete cytokines that promote the activation and proliferation of T cells, which can help to mount a more effective immune response to the neoantigens.

However, macrophages can also play a role in suppressing the immune response. For example, they can secrete cytokines that inhibit the activation of T cells, or they can interact with regulatory T cells (Tregs) to promote immune tolerance and prevent autoimmune reactions.

Overall, the role of macrophages in controlling the immune response to neoantigens is complex and context-dependent, and ongoing research is needed to better understand the mechanisms involved and to develop strategies to modulate macrophage function for therapeutic purposes.

Cancer therapies that target macrophages

There are several cancer drugs that target macrophages, which are important immune cells that play a role in cancer growth and progression. These drugs work by either inhibiting the activity of macrophages or altering their function to enhance their ability to fight cancer cells.

Some examples of cancer drugs that target macrophages include:

1. CSF1R inhibitors: These drugs target the colony-stimulating factor 1 receptor (CSF1R) on macrophages, which is essential for their survival and function. By blocking CSF1R, these drugs can reduce the number of macrophages in the tumor microenvironment and limit their ability to promote cancer growth.

2. CD47 inhibitors: CD47 is a protein that is overexpressed on many cancer cells, and it interacts with a receptor on macrophages called SIRPα to inhibit their ability to engulf and destroy cancer cells. CD47 inhibitors block this interaction, allowing macrophages to recognize and eliminate cancer cells more effectively.

3. TLR agonists: Toll-like receptors (TLRs) are a type of receptor on macrophages that recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) on cancer cells. TLR agonists can activate macrophages to attack cancer cells and stimulate the immune system to fight cancer.

4. Immunomodulatory drugs: Some drugs that modulate the immune system, such as thalidomide and lenalidomide, can also affect the activity of macrophages. These drugs can enhance the ability of macrophages to engulf and destroy cancer cells and stimulate the immune system to fight cancer.

Overall, cancer drugs that target macrophages are an important area of research and development in oncology, as they hold promise for improving the effectiveness of cancer treatment and reducing the risk of cancer recurrence.

Personalised T cell therapies

Personalized CAR T cells are being studied as an approach to exploiting our understanding of neoantigens. They are a type of immunotherapy that involves genetically modifying a patient's own T cells to recognize and attack their cancer cells. CAR T cells, or chimeric antigen receptor T cells, are created by taking T cells from a patient's blood and modifying them in a laboratory to express a chimeric antigen receptor (CAR) on their surface.

The CAR is designed to recognize a specific protein, or antigen, on the surface of the patient's cancer cells. Once the CAR T cells are infused back into the patient's body, they can recognize and attack the cancer cells, leading to their destruction.

Personalized CAR T cells are unique to each patient because they are created using their own T cells and are designed to target the specific antigen on their cancer cells. This approach has shown promising results in treating certain types of blood cancers, such as acute lymphoblastic leukemia and non-Hodgkin's lymphoma and is still an active research area in salivary cancers.