PROJECT DEVELOPMENT
In the Western world, prostate cancer is the most common malignant tumour in males. The number of men affected by this form of cancer increases every year. For example, in 1990 it was estimated that one in 20 males would be diagnosed with prostate cancer; nowadays, the estimate is that, in some developed countries, it affects one in seven men. In the majority of these cases, the cancer is diagnosed as a localised disease, confined to the prostate, and can be cured with surgery and/or radiotherapy, although in some cases it will also be necessary to include hormone treatment. However, with these treatments, a significant number of patients with more aggressive tumours will be under-treated and will develop a recurrence of the disease, while a not insignificant proportion of patients will be over-treated if their tumours are more indolent than normal, and will receive more side-effects than benefits.
The Prostate Cancer Clinical Research Unit started its work in September 2012, with the main aim of translating new advances in prostate cancer research into improvements in patient care. To achieve this ambitious objective, our group is focused on the development of new treatments, the discovery of new targets and the identification of new disease markers that are reliably linked to the clinical progression of the disease. In order to focus on all aspects of research relating to the project: basic, translational and clinical, we are building a multidisciplinary team that includes biologists and doctors with proven experience in a variety of fields.
The two main challenges are:
− Firstly, to stratify the patients with localised disease more appropriately, based on the biological features of the tumour, and to study new treatments in those patients with a higher risk of failure with the current treatments.
− Secondly, to improve the prognosis of patients where the disease has spread beyond the prostate, and who are no longer responding to classic hormone treatments. Recent studies have allowed us to understand more accurately the mechanisms which control the acquisition of resistance to hormone treatments and, as a consequence, several new drugs have emerged to treat this condition. Unfortunately, these treatments fail to kill all cancer cells, limiting the benefit to some patients; further, their effects are limited in time. New markers, targets and drugs are needed to significantly increase the benefit to these patients.
The specific objectives of our translational research are:
− To study the ability of prostate cancer cells to repair genetic defects, and the connection between this ability and other cancer properties, such as growth, invasion, migration and resistance to treatment.
− To incorporate new techniques for the isolation of tumour cells or tumour material in the blood of patients where the disease is in an advanced stage. These cells and the material they produce can be used to study and understand the mechanisms which control the dissemination of cancer and its resistance to treatments.
− To grow prostate tumours from patients in mice, using tumour cells isolated from their blood or from biopsies. These cancer models, called mouse AVATARS, can be used to simultaneously analyse different treatments or combinations in the same tumour, thus learning about each patient’s disease more quickly.
− To design and perform early clinical trials to test new drugs or drug combinations against different phases of the disease where new advances are needed. Patients for these trials will be selected using new markers that can predict sensitivity and resistance to treatments at an early stage.
RESULTS
We began with the results of a study previously published in 2013, in which it was observed that patients carrying inherited mutations in BRCA genes suffered more aggressive tumours and died sooner. We discovered the primary genetic factor associated with prostate cancer prognosis. Carrier patients with localised tumours (that is, non-metastasised), irrespective of the treatment they received, had a worse response to current therapies than the non-carriers.
In the current study, more than 1,300 patients have been included, of which 67 are carriers of the BRCA mutation. These carrier patients who have undergone radiotherapy show a ten-year survival rate of 39%, compared with 80% for non-carriers. In patients undergoing surgery, the difference in the ten-year survival rate is less marked (91% vs. 67%; see table); the explanation for this smaller difference in survival rates between carriers and non-carriers undergoing surgery could be due to the fact that those patients would require a longer follow-up to establish conclusively whether or not the differences are significant.
A tool designed specifically for the destruction of tumour cells with BRCA mutations are the PARP inhibitors. These molecules, which are in the clinical trial phase for prostate cancer treatment, have been shown to be very effective in the treatment of breast and ovarian cancers with BRCA mutations. Moreover, tumours of the prostate with sporadic BRCA mutations (only present in the tumour, not inherited) also responded to these inhibitors, therefore opening up a new treatment option.
At 3 years At 5 years At 10 years
Non-carriers (surgery) 99 % 97 % 91 %
Carriers (surgery) 96 % 89 % 67 %
Non-carriers (radiotherapy) 96 % 91 % 80 %
Carriers (radiotherapy) 85 % 57 % 39 %