Arrow-HCC Phd Scholarships

Alexander Martyn

Alexander Martyn - Arrow / HCC PhD scholarship recipient

PhD student at the School of Chemistry, University of Wollongong


PhD Project summary:

VLA-4 Antagonist Hybrids

Novel strategies and therapeutics for treating haematological malignancies and preventing disease recurrence are highly sought after in the cancer arena. One approach is to block VLA-4/VCAM-1 interactions with VLA-4 antagonists which cause rapid mobilisation of malignant early haemopoietic stem and progenitor cells (HSPCs) into the peripheral blood. These cells are normally protected in the bone marrow from chemotherapy drugs; an effect known as Environment Mediated Drug Resistance (EMDR). It is postulated that mobilisation of these cells would make them more vulnerable to chemotherapy, and thus reducing the chance of recurrence.

Thioridazine, a discontinued anti-psychotic drug, was recently shown to possess multiple potentially useful activities against haematological malignancies. The compound acts as an allosteric antagonist of VLA-4 leading to HSPC mobilization and can selectively induce apoptosis and differentiation in malignant early HSPCs. Given these recent findings it is of interest to explore novel multi-action compounds which combine a known VLA-4 antagonist and thioridazine into a hybrid molecule and explore their potential as new agents for treating haematological malignancies.

 

Michael Papadimitrious

Michael Papadimitrious - Arrow / HCC PhD scholarship recipient

PhD scholarship student at the University of Sydney


PhD Project summary:

CMRF 56+ dendritic cell immune therapy for the treatment of multiple myeloma

Each year 1,200 elderly patients are diagnosed with the incurable plasma cell malignancy, Multiple Myeloma. Current therapeutic options include chemotherapy and haematopoietic stem cell transplantation. Although these treatments are effective, each has adverse effects including malignant (and healthy) cell toxicity and Graft versus Host Disease. One approach for the treatment of Multiple Myeloma is cellular therapy. Cellular therapy uses cells from the patient's own immune system to treat the disease.

My project uses isolated blood dendritic cells loaded with Multiple Myeloma tumour mRNA. With these cells, I will train the patient's immune system to recognise the tumour and generate an anti-tumour immune response. I will do this by 1) assessing the expression of various dendritic cell co-stimulatory molecules and activation markers post introduction of tumour mRNA, 2) detection of secreted cytokines from dendritic cells loaded with tumour mRNA, 3) tracking cells migrated to lymph nodes and 4) generate a T cell anti-tumour immune response. Once optimised, the same methodology may be applied to other haematological malignancies. These results will lead to the development of a cellular therapy that will drive the patient in to remission and improve the wellbeing of the patient.

 

Dario Gerace

Dario Gerace - Arrow / HCC PhD scholarship recipient

Dario Gerace, a PhD student at the University of Technology, Sydney.


PhD Project summary:

Pancreatic β-cells are destroyed by an autoimmune process in Type I diabetes (T1D), so a replacement cell therapy which is either resistant to recurrent autoimmune reactions, or able to modulate the immune system to induce tolerance, is required.

We have already shown that we can successfully engineer artificial beta cells from hepatocytes and liver cell lines; so this study aims to determine the possibility of engineering glucose-responsive insulin-secreting cells from adult bone marrow derived mesenchymal stem cells (BMSC). This would provide proof-of-principle to formulate a Phase I safety trial using BMSC therapy for T1D.

I completed the first year of my PhD project at the end of 2012, with the aim being to utilise bone marrow-derived mesenchymal stem cells (BMSCs) for the production of "artificial" β-cells as a potential cure for Type 1 Diabetes. Native BMSCs express some β-cell genes and are thusly predisposed to differentiate into β-cells. This differentiation process can be enhanced when the BMSCs are engineered to express β-cell transcription factor genes. After one year of my PhD project, I have successfully isolated, sorted and expanded BMSCs from our chosen animal model (Non-obese diabetic mice). These cells are ready for nucleofection with our therapeutic vector which was also constructed during 2012, however prior to any genetic manipulation of the BMSCs it is imperative that safety studies are performed to ensure that the BMSCs behave as expected and have not undergone transformation. As a result, the year 2013 will involve performing these safety studies, followed by the expression of our therapeutic vector in BMSCs and subsequently evaluating the functional capacities of the engineered cells, specifically observing whether the engineered cells have developed insulin granules and secrete insulin in a glucose-dependent manner.

 

Marcus Lefebure Arrow / HCC PhD scholarship recipient

Marcus Lefebure

Marcus Lefebure, a PhD scholarship student at the Peter MacCallum Cancer Centre Melbourne Australia.


PhD project outline:

Lymphomas are comprised of a broad spectrum of diseases that are linked to normal cellular counterparts in the haematopoetic and lymphoid compartments. As a group, lymphomas account for the 5th most common disease cohort in Australia and they affect all age groups without prejudice. My PhD, which began in late 2011, is aimed at defining critical mutations in cells that allow normal lymphoid cells to become cancerous lymphoid cells.

By understanding and defining the critical mutations and pathways that are activated during the development of lymphoma, we arm ourselves with a new arsenal of information to aid in diagnosing and treating lymphomas based on which mutation(s) they are driven by. Such improvements would hopefully lead to improved therapies that can minimise side effects and, resultantly, improve patient quality of life.

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