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Research  > Australian National University John Curtin School  > Our Sarcoma Research

RESEARCH PROGRAMS

Sarah-Grace Sarcoma Foundation Research:

Researchers: Professor Christopher R Parish and Dr Lucy Coupland

Cancer and Vascular Biology Group

Department of Immunology

John Curtin School of Medical Research

The Cancer and Vascular Biology Group (CVBG) is a world leader in the fields of immunology and cancer biology and carries out cancer research with the following long term aims:

  • The delineation of key molecules that control tumour angiogenesis (new blood vessel growth) and metastasis (cancer spread).
  • The development of new anti-cancer drugs based on our basic research findings, that are resistant to tumour evasion and have minimal side effects.
  • The development of immunotherapeutic cancer vaccines.

Track Record of the Cancer and Vascular Biology Group: The CVBG has a very strong track record in carrying out basic cancer research and translating these research findings into the clinic. For example:

  • The CVBG identified heparanase as a key enzyme involved in tumour metastasis and angiogenesis. The Group then developed, in collaboration with Progen Pharmaceuticals, a novel anti-cancer drug (PI-88, Muparfostat) that inhibits heparanase and also interferes with the action of angiogenic growth factors. Muparfostat has now entered Phase III clinical trials in primary liver cancer patients, the drug reducing cancer recurrence after surgery by 40%.
  • The CVBG has also developed a novel immunotherapeutic vaccine for melanoma (Lipovaxin) that targets dendritic cells, key cells involved in the initiation of immunity, and induces potent anti-tumour immunity. In collaboration with a new Biotech company, Lipotek, the vaccine is currently undergoing Phase I clinical trials in advanced melanoma patients.

Sarcoma Research

A notorious feature of soft tissue sarcomas (the vast majority of sarcomas) is that at an early stage of tumour development they metastasise by directly entering the blood stream (hematogenous metastasis). This is unlike most other solid cancers that have a predilection to metastasise via the lymphatics system and usually metastasise at a later stage of development. Thus, with soft tissue sarcomas ~10% of patients already have metastatic disease when their cancer is first diagnosed and almost one quarter of patients with localised disease eventually develop metastases. The situation is even worse with high-grade sarcomas where 70% develop metastatic disease.

In this context it should be emphasised that the primary tumour rarely kills the patient, it is the metastases that are truly life threatening. Based on these clinical observations a major unanswered question is why sarcomasmetastasise by preferentially entering the blood stream. Also, does the unique behaviour of these tumours provide novel strategies for treatment?Recent studies by the CVBG, soon to be submitted for publication, may provide an explanation for this paradox. The Group has discovered that platelets, blood borne cellular fragments that initiate clotting, can play unexpected roles in tumourmetastasis.

 Our studies indicate that platelets can dramatically enhance metastasis by (i) adhering to tumour cells within a tumour and inducing the expression of cell invasion genes; and (ii) promoting adhesion of blood borne tumour cells to the blood vessel wall of target tissues. The importance of platelets in promoting lung metastasis of melanoma and breast cancer cells by aiding their lodgement in the lung is illustrated in Figure 1 below. We would anticipate that platelets not only aid the lodgement of metastasising sarcoma cells in the lung but, unlike melanoma and breast cancer, also play a key role in the escape of the tumour cells from the primary sarcoma into the blood stream (see Figure 2). We already have some clues as to themolecular basis of platelet-induced escape of tumour cells from the primary tumour.For example, we have identified in vitro ~100 candidate genes induced by platelets in tumour cells that are potentially involved in tumour metastasis, with ~10 representing feasible drug targets. We also have some evidence that a platelet-expressed molecule called P-selectin is involved in the platelet-induced induction of invasion genes.

These studies need to be extended, particularly to establish that sarcomas are very effective at using platelets for blood borne spread and that some of the candidate molecules identified can be used as drug targets for the treatment of sarcomas.

Figure 1. The importance of platelets in aiding the metastasis of melanoma and breast cancer by enhancing the lodgement of tumour cells in the lung. In these experiments tumour cells were injected directly into the circulation and the effect of platelet depletion on lung metastasis determined.

Research Personnel Involved

We are particularly fortunate that a PhD student in my laboratory, Lucy Coupland, has just completed her PhD on the role of platelets in tumour metastasis. She wishes to continue as a postdoctoral fellow in my laboratory and is ideally placed to undertake the proposed studies.

Figure 2. Stages in the hematogenous (blood borne) metastasis of tumour cells. The upper panel depicts direct entry of tumour cells into the bloodstream by passage through the blood vessel wall. Sarcomas are particularly effective at using this pathway of metastatic spread whereas most other solid cancers (e.g., melanoma, breast cancer) favour metastasis via the lymphatics. The lower panel depicts the platelet-assisted lodgement of tumour cells within the blood vessels of a distant organ(often the lung).