Squamous cell carcinomas of the skin and oral cavity are among the most common cancers afflicting humankind. Osteosarcomas are the most common primary bone malignancy afflicting children.
Current Laboratory Members
Associate Professor Nicholas Saunders: Dr Liliana Endo-Munoz, Dr Alex Guminski, Ms Alison Dahler, Mrs Lilia Merida de Long, Mr Andrew Cumming, Mrs Mehlika Rethinam, Ms Orla Gannon, Ms Sarina Cameron, Ms Kim Hanchard.
Understanding the molecular basis for cancer formation and metastasis is essential if we are to develop new therapies to treat cancer. Our group has identified specific factors in cells of the skin, bone and oral cavity that contribute to cancer formation and cancer spread. We are now pursuing projects that target these genes selectively as a possible means of treating these cancers.
Current Research Projects
Development of E2F inhibitors as novel therapies for treating squamous cell carcinoma
The E2F family of transcription factors are pleiotropic factors involved in controlling proliferation and differentiation of keratinocytes. We have previously shown that a dominant/negative form of E2F was able to reinstate a program of squamous differentiation in differentiation-resistant squamous cell carcinoma cells. This provided proof-of-concept for the notion that the E2F complex could be a viable target for treating squamous cell carcinomas. More recently, a new member of the E2F family was identified, E2F7, that is able to inhibit normal E2F functions.
We have now shown that E2F7 is able to inhibit proliferation, inhibit apoptosis and stimulate differentiation in keratinocytes. More importantly, we have shown that E2F7 is overexpressed in human cancers and that inhibiting E2F7 sensitises cancer cells to chemotherapeutic agents. Based on these data we propose that E2F7 may play an important role in the development of cutaneous squamous cell carcinomas. Our working model is that UV exposure causes mutational changes leading to the disruption of the E2F:Rb axis. This in turn results in the deregulated overexpression of E2F1 and E2F7 which in turn results in the disruption of growth, differentiation and apoptosis control (Fig. 1). Based on this model we would predict that E2F7 inhibition would lead to the reinstatement of E2F1-mediiated apoptosis.
Figure 1: Disrupted E2F1/E2F7 axis may contribute to squamous cell carcinomas formation.
The role of osteoclast loss in the development of life threatening lung metastasis in patients with osteosarcoma
Osteosarcoma is the most common primary bone malignancy afflicting children. Unfortunately, 40% of patients with osteosarcoma will die as a consequence of pulmonary metastases. We have recently shown that the development of pulmonary metastases is preceded by the loss of osteoclasts at the site of the primary lesion in the bone (Fig. 2). In fact, the loss of osteoclasts predicts with 90% accuracy whether a patient will develop pulmonary metastases. We are now conducting studies to see whether the loss of osteoclasts is responsible for the development of pulmonary metastases. In this regard, we have found that metastatic osteosarcoma cells are able to inhibit osteoclastogenesis and that osteoclasts are able to inhibit osteosarcoma cell migration. It is our aim to identify the factors responsible for osteoclast loss and to exploit this in the development of anti-metastases therapies.
Figure 2: Tumours from osteosarcoma patients who develop lung metastases (left panel) show loss of osteoclasts (brown staining) compared to tumours from patients that do not develop metastases (right panel).
What is the molecular basis for the initiation of squamous differentiation?
The initiation of squamous differentiation involves the inhibition of E2F activity and the irreversible withdrawal of keratinocytes from the cell cycle. Once growth arrested the keratinocytes are sensitised to the induction of differentiation. These events are not simply of academic interest since we know that squamous cell carcinoma cells are able to undergo a reversible growth arrest yet are unable to initiate squamous differentiation. Hence, understanding the molecular requirements for the initiation of squamous differentiation will provide insight into the molecular basis of squamous cell carcinoma formation. We are currently using a number of models in which we can manipulate squamous differentiation to try to identify specific molecules that control squamous differentiation.
The value of a combination of a histone deacetylase inhibitor plus AKT inhibitor in treating patients with head and neck squamous cell carcinomas
Our previous studies indicated that histone deacetylase inhibitors may have anticancer activity against head and neck squamous cell carcinomas. We have now tested an histone deacetylase inhibitor, valproate, as a monotherapy in patients and found that whilst it showed some promise as an anticancer therapy it was unlikely to be useful as a curative monotherapy. In this regard, we have found that the anticancer activity of the histone deacetylase inhibitors is greatly enhanced when combined with an AKT inhibitor. Therefore, we are undertaking preclinical testing of this combination with a view to starting a clinical trial in head and neck patients within 18 months.
Associate Professor Saunders is currently offering postgraduate projects in his laboratory. Click here for more information.