Technology and knowledge connecting university and business
Issue 17 | Year 7 | NOVEMBRE 2017


Studying experimental prostate tumour models to find increasingly personalised treatments

Versione stampabile
by Andrea Lunardi and Francesco Cambuli
Andrea Lunardi is a professor and P.I. at the Armenise-Harvard Laboratory of Cancer Biology & Genetics, CIBIO. Francesco Cambuli is an Umberto Veronesi Foundation research fellow and post-doc at the Armenise-Harvard Laboratory of Cancer Biology & Genetis.
The generation of increasingly accurate models will improve our understanding of the oncogenic mechanisms responsible for the progression, aggressiveness, and therapeutic response of the prostate tumour and will help to identify new biomarkers and more efficacious oncological strategies.

Prostate cancer is the most commonly diagnosed cancer in men over 60. From a clinical point of view, the procedure for a confined tumor is to surgically remove the whole prostate (prostatectomy) or, alternatively, to use radiotherapy.  If the tumour is metastatic, inhibition of the androgen signalling pathway is the treatment of choice.  Although almost 90% of patients respond positively to hormone deprivation, with latency periods that range from a few months to several years depending on the patient, the cancer inevitably becomes resistant to the treatment.  Two of the mechanisms that have been identified, for which drugs are currently being trialled, are mutations that activate the androgen receptor in the absence of the hormone, and the neo-synthesis of androgen by the tumour cells themselves, through the activation of specific metabolic pathways. The increasingly accurate identification of both the mechanisms underlying the initiation and metastatic progresson of prostate tumours, and those underlying the response to radiotherapy and hormonal therapy will therefore have a fundamental impact on the development of precision medicine based on more effective and long lasting treatment strategies, which are targeted at the molecular alterations that characterise the tumour of the individual patient.

Understanding how specific genetic alterations can influence the aggressiveness of the disease and the response to specific treatments, by altering specific cellular mechanisms, will allow on the one hand better stratification of patients into appropriate therapeutic regimes, and on the other the identification of new therapies to complement the existing therapies, thus improving their efficacy.  

We have demonstrated, along with other research groups and thanks to the use of genetically engineered models, that the genetics of the prostate tumour determine how aggressive the disease is, that different tumour genetics lead to different mechanisms of resistance to the same therapeutic approach, and that the pharmacological modulation of these mechanisms can make the tumour regain its sensitivity to the therapy. 

The use of genetically engineered murine models that develop prostate tumours due to specific alterations in their genetic makeup has led to a fundamental improvement in our knowledge of some of the basic mechanisms of the tumorigenic process of the prostate, and recently, of some of the forms of resistance to specific therapies, with important implications for clinical practice.

The genetic complexity of the human prostate tumour inevitably requires the development of increasingly sophisticated models. 

Because of this, we are developing a new strategy for generating and studying experimental models of prostate tumours through an ex-vivo/in vitro/in vivo method. Primary prostate cells are kept in three-dimensional cultures following a recently-published protocol.  Inside hydrogels, and with the addition of a cocktail of growth factors that we are developing,  the primary prostate cells form ‘organoids’, tissue structures that recapitulate various key characteristics of the prostate tissue that they originate from.  These avatars of the prostate tissue will allow us to understand in more depth the physiology of the epithelium of the prostate, to identify and study the stem cell niches that regulate its homeostasis, and to gain a much more detailed understanding of the molecular mechanisms that maintain the state and function of the epithelium.  

This knowledge is fundamental in order to correctly interpret oncological processes, and consequently, to identify the treatment strategies that are most efficacious, as they are personalised.  We have developed a panel of viral vectors to genetically engineer the organoids so that they recapitulate specific genetic lesions and molecular deregulations that are typical of the human prostate tumour.  These engineered organoids will be studied in vitro to identify new tumour mechanisms responsible both for the progression of the tumour and for the resistance to specific therapeutic approaches.  

We expect these studies to identify new concepts in the field of prostate cancer as, unlike traditional studies on human metastatic tumour lines that were isolated decades ago and maintained in bidimensional cultures, the cellular model used will have a correct genetic makeup, the normal physiology of a prostate cell, and the correct epithelial context, being part of the three-dimensional organoid. Finally, given the role that the tumoral microenvironment plays in both the progression of the tumour and its response to therapy, the in vitro analyses will be implemented in studies in vivo. The tumorigenic process and the response to innovative therapeutic approaches, defined through the in vitro studies, will be followed using in vivo imaging techniques,  similarly to the clinical approach used to treat patients.  

In conclusion, the generation of models that recapitulate fundamental aspects of the human tumour with increasing accuracy will improve our knowledge of the oncogenic processes responsible for the progression, aggressiveness, and therapeutic response of the prostate tumour. It will also enable the definition of new biomarkers for a better stratification of tumours (into indolent or aggressive) as well as the identification of more efficacious oncological strategies, through targeted therapies and precision medicine.