TACC3 as a target in tumour stem cells and brain tumourigenesis

We aim to validate the biological role of a molecule that potentially drives brain cancer. This molecule is called TACC3 and appears to be particularly active in so called glioblastoma multiforme (GBM) tumours that represent the most aggressive form of brain cancer. Patients presenting with this disease have a median survival time of only approximately 12-24 months, which is due to resistance of GBM to currently available treatments including chemotherapy and radiation therapy. GBM tumours are diffuse and invade the normal brain tissue, which makes it impossible to completely remove the cancer via surgery. Tumour residues after surgery often lead to quick relapse due to re-growth of the tumour. Importantly, this recurrent tumour growth has been recently attributed to a specific fraction of cells within the tumor mass that are able to evade standard therapies. These so called brain tumour stem cells (BTSCs) are at the root of an organ-like tumour organization feeding tumour growth during the whole course of the disease. Therefore, specific treatments targeting BTSCs are expected to improve the efficiency of brain cancer therapy and a better understanding of BTSC biology, including appropriate 'drugable' target molecules, is urgently needed. Our focus is on the molecule TACC3 because previous studies and preliminary work link TACC3 function to BTSC and we aim to inhibit TACC3 with specific gene silencing and our drug-like small molecule that inhibits TACC3. Utilizing these research tools, we will reveal which role TACC3 plays in BTSCs and how it promotes their malignant behaviour in cell cultures of GBM-derived BTSCs and in valid in vivo models of BTSC-driven brain tumour development. Our recent work has also implicated TACC3 in the biology of normal brain stem cells that exist in distinct brain areas and that can become a source of brain cancer due to abnormal gene modifications. Strikingly, TACC3 is abnormally elevated in GBM and in GBM-derived BTSCs and we aim to investigate whether and how TACC3 can transform non-cancerous brain stem cells into BTSCs, and how the regulation of genes is differently controlled by TACC3 in BTSCs compared with normal brain stem cells. Overall, our proposed study will provide new insights into the mechanisms that maintain the malignant program of BTSCs and into TACC3 as a candidate driver of GBM development and a potential anti-tumour drug target. Ultimately, our goal is to accelerate the development of more effective treatment strategies against malignant brain cancers.

Brain tumour growth and recurrence have been attributed to so called brain tumour stem cells (BTSCs) and targeting BTSCs is expected to improve the efficiency of anti-brain cancer therapies. However, this approach is hampered by a poor understanding of the genes and pathways that promote BTSC-driven growth.
Recent evidence including our studies and preliminary data suggest that TACC3 is a potential brain tumour-driving factor. We demonstrated thatTACC3 downregulation, either by RNAi or a novel small molecule inhibitor significantly decreases neural stem cell (NSC) self-renewal via NSC differentiation.
Accordingly, the important questions arise as to whether TACC3 promotes the BTSC phenotype, whether TACC3 is functionally relevant for brain tumourigenesis (potentially causing malignant transformation of NSCs into BTSCs), and what downstream pathways mediate TACC3 function in BTSCs compared to NSCs.
To this end, we will use our established biological tools (including patient-derived BTSCs and adult NSCs) and biological readouts for self-renewal and differentiation in vitro plus xenograft tumour formation in vivo. Our BTSC models in combination with loss-of-function (RNAi or chemical inhibitor) and gain of function (cDNA overexpression) studies will allow us to investigate the link between aberrant TACC3 levels and resulting cellular phenotypes. In addition, we will use gene expression analysis and mass spectrometry-based proteomics to reveal the critical molecular components and networks downstream of TACC3 in BTSCs as compared to NSCs. These synergistic approaches will examine TACC3 as driver of brain tumour development and progression and explore 'normal' versus 'malignant' stem cell growth. Our research will validate TACC3 as potential therapeutic target in BTSC-driven brain tumours and is of relevance for neural stem cell/ cancer stem biology and cancers with TACC3 alterations, and may ultimately be exploited for drug development and anti-cancer therapies.

We are studying the interrelated biology of brain tumour stem cells (BTSCs), adult neural stem cells, and brain cancers. Here, we aim to validate the biological relevance of the potential oncogene TACC3 in brain cancer and its role as a drug target in BTSCs. We also aim to elucidate key molecular mediators downstream of the TACC3-dependent stem cell growth control. In addition to academia, the expected beneficiary groups are:
1) General Public/Cancer Patients: Brain tumours cause ~3400 deaths in the UK, and ~13.000 deaths in the USA per year. Aggressive brain cancer has a severe impact on individuals and their families because most patients suffer from seizures and have an average life expectancy of only 1-2 years after diagnosis. Contributing towards a better understanding of brain tumour and (cancer) stem cell biology, we hope to provide a basis for the development of new treatment options against malignant stem cell/BTSC growth that represents the root cause of several cancer types and also hampers the use of stem cells for regeneration therapy. For example, elucidating key molecular players regulating the normal compared to the malignant stem cell growth control may also help to inform patients with neurodegenerative diseases about possibilities and risks associated with neural stem cell-based therapy.
2) Charities:. Brain cancer is an understudied research field in the UK and little research funding is dedicated to this devastating disease. We will keep several brain tumour support groups informed about our findings/publications, for example local charities (YCR, Andreas gift etc.) that can advocate research outcomes effectively to raise public awareness.
3) Business/Industry: our research builds on previous work that we conducted in an international research environment that links academic inquiry with industrial resources. I have experience with high-throughput applications and target identification/validation programs used in the private sector. This experience will help me to forge collaborations with industrial partners in the future and our research could potentially serve as a basis for a MRC industry collaborative award application. Our target validation efforts may also lead to opportunities for patenting, for example novel anti-cancer agents and/or treatment modalities against aggressive brain cancer.

Our research is designed to potentially have both academic and societal impact. Primarily, our studies should provide important new insight into interrelated aspects of stem cell and cancer biology and the members of the research team are expected to directly benefit from the interdisciplinary nature of the project. The PI will benefit from team building and team management efforts and has excellent support from his immediate environment at Leeds (direct mentors, career development programs). Team members (postdoctoral student, research associate) will profit from improving their technical, networking, and scientific dissemination skills and will broaden their scientific horizons to identify and work towards their own career goals supported by the PI and research environment. Our research builds on biological, genetic and chemical tools that we use in a state-of-the-art research environment that fosters translational science (http://www.bhrc.ac.uk/). Therefore, we believe that our findings have strong potential for knowledge transfer activities including drug development approaches, for example chemical improvement of a drug-like tool compound and/or development of targeted therapies against BTSCs. Aspects of our research may be suitable for clinical translation, including development of prognostic indicators and/or treatment modalities based on optimized pharmacological agents. Our ultimate goal is to inform clinical trial design that potentially has a direct impact on the health/well-being of patients with stem cell-driven cancers, particularly incurable brain tumours.