Cancer Stem Cells
 Prof Tom Gonda
Cancer Research Unit, Diamantina Institute
Identification and Characterisation of Cancer Stem Cells in Chronic Lymphocytic Leukaemia
Leukaemia is a cancer of the blood and while treatments have improved over the years the most common adult form of leukaemia, CLL, remains incurable. One reason this disease has been difficult to develop better treatments for is the lack of any laboratory tools typically used to research cancer. The main problem is there are no cell lines or animal models with which to work. A team of physicians and scientists here at the PA Hospital have formed a collaboration to address this issue. We intend to try and find the cells that promote and cause this disease, the cancer stem cell.
We hypothesise that:
- CLL arises from the clonal expansion of a stem cell that has undergone cancerous cellular changes
- The stem cell resides in the bone marrow compartment, and
- It is able to be engrafted into nude mice to allow cell survival and recapitulate the disease.
To do this we are going to take cancer cells from CLL patient bone marrow and place them into a special mouse that lacks a normal immune system, thereby allowing the cancer cells to grow. We will follow the cancer cells progress in these mice and see if they survive or cause disease.
If we could find which cell was starting the CLL this would be a major breakthrough in this area and allow us to begin to find novel treatments for this incurable disease.
Identification and Characterisation of Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma
Squamous cell carcinoma of the head and neck region (HNSCC) is amongst the top 10 most prevalent cancers. It is a life threatening cancer that is associated with a mortality rate of approximately 40%. Whilst most patients are treated with a combination of surgery, radiation and chemotherapy a significant fraction of patients relapse and eventually succumb to the cancer.
The molecular basis for relapse in these patients is still unknown. One possible explanation for treatment failure is the notion that the cancer contains biologically distinct subtypes of cancer cells. Some of these cells may respond to therapy whilst a small fraction of cells may not. If this small fraction of resistant cells were able to divide and repopulate the tissue then this would provide an explanation for relapse in these patients. However, as yet no such data has been available to support this argument. Most recently, studies with another cancer called acute myeloid leukaemia has shown that they do contain a small subtype of cancer cells that are resistant to therapy and can regenerate the disease in patients. These cells have been called "tumour initiating cells" (TIC).
In this application we will use patient tumour samples to try to isolate TICs from HNSCC. We will first determine whether these TICs exist and whether they express markers of normal human stem cells. We will also test whether these TICs are more resistant to chemotherapeutics or radiation than the rest of the tumour cells. In addition we will enrich for these TICs and identify new protein markers that could be used to test patient samples before or after treatment.
This would be of considerable assistance in making decisions about treatment choice or prognosis. Since TICs have not been reported in HNSCC previously their identification would lead to a considerable advance in our understanding of how these tumours form.
Targeting Cancer Stem Cells in Acute Myeloid Leukaemia
Acute myeloid leukaemia (AML) is a particularly difficult form of leukaemia to treat successfully and so new drugs are needed. Very rare cells (less than 1% of the total) called “cancer stem cells” (CSC) are responsible for initiating AML and probably relapse of the disease; thus a cure for AML requires killing of these cells, not just the bulk of AML cells.
This project aims, firstly, to establish in our laboratories recently-described methods for isolating AML CSCs. Following this, we will investigate the actions of new classes of drugs on AML CSCs. One class targets a family of “transcription factors” (molecules that switch genes on and off) called NF-?B, which acts to maintain the growth and survival of AML cells. Because AML cells seem much more dependent on NF-?B for survival than normal cells, drugs that target NF-?B could kill AML cells while sparing normal cells.
Another class is called “histone deacetylase inhibitors”. These drugs also seem to affect the regulation of groups of genes involved in cancer cell growth and survival, by preventing particular chemical modifications to transcription factors. In each case we will monitor the effects of the drugs on the numbers of AML CSCs compared to the bulk of the AML cells, initially in cultured cells and subsequently in immunocompromised mice in which human leukaemia cells will grow. It is planned to eventually extend this approach to monitoring AML CSC in patients participating in clinical trials.
Together, these studies may not only identify drugs with the potential of suppressing or eliminating AML CSCs but should also yield significant insights into the clinical importance of CSCs.
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