Periodic Reporting for period 2 - PDX-PC (Elucidation of tumour cell plasticity mechanisms associated to treatment in metastatic prostate cancer)
Período documentado: 2020-09-16 hasta 2021-09-15
Prostate cancer (PC) is the second most commonly diagnosed malignancy in the world and the fifth leading cause of cancer mortality in men. In patients with earlier stages the disease can be mild and curable but unfortunately, when it spreads throughout the body it ends in a fatal outcome. PC is a highly heterogeneous disease. This means that despite the wide spectrum of drugs available nowadays, not all patients respond to these treatments in the same manner. Furthermore, PC is plastic, which implies that not only time but also the administration of some treatments are responsible for generating molecular changes that limit the effectiveness of the subsequent therapies. This is why understanding the altered biological pathways behind such plasticity processes is crucial and would contribute to establishing optimal sequential treatment strategies that might result in better overall clinical outcomes at advanced stages of the disease.
This project aims to elucidate the molecular mechanisms responsible for tumour cell plasticity associated with treatment in metastatic PC by using patient-derived xenografts (PDX) in vivo models. In contrast to other pre-clinical models in PC, PDX preserve the molecular heterogeneity and therapeutic responses observed in clinical settings, thus providing a close-to-reality approach to address the goals of this project.
This project aims to elucidate the molecular mechanisms responsible for tumour cell plasticity associated with treatment in metastatic PC by using patient-derived xenografts (PDX) in vivo models. In contrast to other pre-clinical models in PC, PDX preserve the molecular heterogeneity and therapeutic responses observed in clinical settings, thus providing a close-to-reality approach to address the goals of this project.
PC consists of two well-established phases, an initial hormono-sensitive phase followed by a castration-resistant one, so different models to represent both contexts were selected. To contextualize castration-resistant PC we used a PDX line coming from a brain metastasis collected during the patient autopsy. This model represents an aggressive form of the disease as by the time the sample was collected the patient had become resistant to different previous treatments. Additionally, since hormone-sensitive PDX models are complex to grow in in vivo models, we explored the hormone-sensitive context by using organoids coming from a PDX line originating from a primary tumour in a metastatic patient in the hormono-sensitive phase of the disease. Both castration-resistant and hormone-sensitive pre-clinical models were submitted to different sequential treatment strategies simulating frequent treatment sequences administered in clinical practice. Interestingly, so far we have observed that in the castration-resistant model one of the therapeutic sequences caused a significant remission of the tumour volume, indicating that this tumour, even while being in a highly advanced stage, was still sensitive to that specific treatment option. In the hormono-sensitive context, viability analysis after treatment exposure was also performed revealing a variety of sensitivities to different agents, including drugs that belong to the same group of medicine.
The molecular analysis of treated organoids and PDX samples and its validation in patients’ samples have provided us with more specific information about treatment-leaded changes under different regimens. Metabolism has resulted a crucial process in tumor cell survival, which is strongly modulated by regimens that include cabazitaxel. Altogether, results reveal the efficacy of cabazitaxel treatment, alone or under sequential regimens, in an aggressive tumor context. Targeting metabolic pathways together with cabazitaxel treatment could be a potential strategy in order to overcome taxane resistance and to increase treatment efficacy in advanced PC.
These results were submitted and selected as an oral presentation to the European congress ESUR21. They have also resulted in a publication in the journal Cancers. A second manuscript is in preparation.
The molecular analysis of treated organoids and PDX samples and its validation in patients’ samples have provided us with more specific information about treatment-leaded changes under different regimens. Metabolism has resulted a crucial process in tumor cell survival, which is strongly modulated by regimens that include cabazitaxel. Altogether, results reveal the efficacy of cabazitaxel treatment, alone or under sequential regimens, in an aggressive tumor context. Targeting metabolic pathways together with cabazitaxel treatment could be a potential strategy in order to overcome taxane resistance and to increase treatment efficacy in advanced PC.
These results were submitted and selected as an oral presentation to the European congress ESUR21. They have also resulted in a publication in the journal Cancers. A second manuscript is in preparation.
The high prevalence of PC in the world makes it a public health burden in terms of follow-ups and treatment requirements. Furthermore, its heterogeneity at origin - together with its ability to be transformed as a result of tumor plasticity, triggered by evolution and treatment pressure - impair the management of the disease at clinical practice, reducing patients’ longevity. Fortunately, there is a wide landscape of treatment options although their administration needs to be optimized in order to best exploit clinical resources. It is in this field where this project hopes to add to existing knowledge. This project seeks the administration of more personalized strategies in order to prevent unnecessary side effects for advanced PC patients and costly therapies to the health system. In the absence of reliable predictive biomarkers in clinical practice, this project has provided insights about the biology behind of treatment in PC, although further research becomes essential in order to optimize sequential treatments, at least in patients with a specific molecular background. The use of models that reflect patients’ heterogeneity has given to this project a realistic context. The results obtained so far have confirmed that some sequential treatment strategies work better than others. We have also observed that metabolism is strongly modulated by treatment, and it becomes crucial for tumors growth and expansion, becoming a potential field to focus our attention when choosing the right treatment. The socio-economic impact of deeper understanding of tumor biology leading to the administration of more personalized treatments is huge. First, it will imply a reduction in the cost to the National Health country of treatments that are not beneficial enough for patients with specific subtypes of tumours. Second, giving the right treatment to the right patient will enlarge their overall survival. Third, patient’s quality of live will be improved, as they won’t experience secondary effects from treatments that won’t target their specific disease. Limited therapies against metabolism are nowadays in the market addressing PC or other tumours. Thus, further investigation on targeted therapies against metabolic pathways is mandatory after the knowledge provided by this project.