Development of a novel drug targeting MRCK and ROCKII for the treatment of invasive and/or metastatic cancer.

Around one in three people will be diagnosed with cancer, and many of these will go on to suffer and die from their disease. At present, the best chance of cure comes from removal of the initial tumour before it has had a chance to spread elsewhere in the body. Once it has spread, the disease is incurable for most patients. Currently used anti-cancer drugs work primarily by stopping or slowing cancer growth, but their effects are usually only temporary and so the benefits are small. However, cancer growth is only one part of the disease process, and a well-tolerated drug which prevents cancer from spreading has the potential to reduce an enormous amount suffering and death. At present, no such drugs are in routine use.

MRCK and ROCKII are molecules that are important in the process by which cancer moves from one part of the body to another, so a drug which stops these molecules from working may stop cancer spreading.

The proposed research aims to make a drug that will do this. The approach that will be taken involves first discovering chemicals which block MRCK and ROCKII activity and then changing these chemicals to make them safe and suitable for use in humans. An important part of this process is to ensure that the chemicals do not block other molecules that are required for the body's normal functions, as this might lead to unacceptable side effects.

The vast majority of deaths from cancer directly result from the metastatic spread of the disease; however, currently there are no drugs available that specifically combat this process. The structurally related Rho kinases (ROCK) and Myotonic dystrophy kinase-related Cdc42-binding kinases (MRCK), key effectors in Rho GTPase signalling pathways that control the actomyosin cytoskeleton, have emerged as attractive therapeutic targets for the treatment of metastasis. Our pre-clinical evaluation indicates that whilst targeting either kinase alone reduces the ability of tumour cells to invade, a strategy targeting the inhibition of both ROCKII and MRCK should have a significantly greater effect on inhibiting the invasive processes that contribute to metastasis. We propose to develop candidate small molecule MRCK/ROCKII and/or MRCK inhibitors for further pre-clinical/clinical evaluation as anti-metastatic or anti-invasive agents.

Most carcinomas evolve in a step-wise fashion from normal tissue, progressing through non-invasive, pre-malignant changes, followed by local invasion of the basement membrane, then metastatic spread. Most morbidity and mortality from cancer is a direct result of metastatic disease. The greatest opportunity to minimise this is to intervene prior to invasion into local tissue and the formation of symptomatic metastases. At present, the mainstay of treatment is eradication, usually surgical, of the primary, invasive tumour if identified before metastasis has occurred. However, even with a greater trend towards early detection, many cancers treated in this way relapse due to occult micrometastases or residual locally invasive cancer cells. Current drug therapy, which essentially targets cancer cell growth, has a limited role in palliating symptoms and delaying death in patients with advanced disease. Although the goal of peri-operative chemotherapy is to reduce the likelihood of future distant failure, in most common tumours the impact is modest.

Thus a drug that can inhibit cancer cell invasion may have benefits in a number of clinical scenarios:

i. Preventing the progression from pre-invasive disease stages. For example, patients with carcinoma in situ of the bladder have approximately 20% chance of developing muscle invasive (life-threatening) bladder cancer within 2 years.

ii. Reducing the morbidity that results directly from local invasion (for example in glioblastoma). Although these tumours rarely metastasise, due to their anatomical location and biological characteristics tumours may not be resectable. If resected, residual invasive cancer cells almost inevitably lead to local failure and death.

iii. Preventing secondary spread from established, irresectable primary cancer.

iv. Preventing progression of micrometastatic disease to overt, invasive secondary tumours. It is clearly described that many patients with breast (and other) cancers have residual cancer cells present in the bone marrow at the time of surgical resection, and that these cells may persist for several years even in the absence of distant disease failure. The presence of these cells is a poor prognostic feature, but the events that trigger the switch from dormancy to overt disease are unknown. However, when the disease progresses, it displays the hallmarks of invasion. For this group of patients an anti-invasive drug may preserve the dormant disease state.

iv. Reducing morbidity from established metastatic disease. Many of the symptoms arising from metastases are a direct consequence of invasion into the surrounding tissue. For example, bone pain in metastatic prostate cancer. Thus an inhibitor of tumour invasion may delay symptomatic progression. This may be a particularly effective strategy following a cytoreductive approach - for example after optimal disease control by castration therapy in metastatic prostate cancer - where the minimum residual disease state presents an opportunity to allow normal tissue recovery without ongoing cancer cell invasion.

Current data suggest that ROCK II and MRCK are important in a wide variety of common solid tumours, including testicular, bladder, pancreatic and breast cancer. However it is envisaged that the benefits of this approach are likely to be limited to a molecularly defined subset of patients.

It is likely that the ultimate niche for a drug such as this will be during early stages of cancer progression - stages associated with few symptoms and high quality, productive life. It is therefore a prerequisite that such a drug is simple to take with minimal toxicity in order that this quality can be maintained in the longer term. It is also important that any new therapeutic approach is affordable: it is likely that a drug which maintains high quality life and prevents morbidity and mortality would be valued by society as a whole and that it could be delivered in a cost-effective manner.