Periodic Reporting for period 4 - SPICE (Synthetic Lethal Phenotype Identification through Cancer Evolution Analysis)
Reporting period: 2020-04-01 to 2021-03-31
The project was designed to address specific clinical questions in the setting of lethal prostate cancers, a genetically and clinically heterogeneous disease with high incidence in the population. While advances in targeted therapy have recently led to more effective management of metastatic disease, prostate cancer still results in the second cause of cancer death in men. Significant effort was also dedicated to chemotherapy-resistant urothelial carcinoma. From a technical perspective, the project aimed at the development of computational approaches to be applicable across cancer, both for the refined analysis of genomic lesions and the inference of tumor evolution and disease progression biomarker identification, and for the nomination of potential synthetic lethal combinations. These approaches together with the results of the large-scale computations performed on thousands of tumors across more than twenty-five tumor types have been made available to the research community.
Furthermore, through the application of those approaches, we provided major contributions to the clinically-relevant definition of common and aggressive tumor types. Specifically, we were able to describe the landscape of clonal evolution of chemotherapy-resistant urothelial carcinoma and the genomic and epigenetics features characteristic of prostate cancer trans-differentiation from adenocarcinoma to neuroendocrine disease. In this specific disease setting, through our well-established collaborative network, we provided major contributions to the field by suggesting neuroendocrine biomarkers relevant both for tissue and liquid biopsy based assays and by studying the profiles of human derived organoids in pre-clinical studies. All the above-mentioned results have been published and the relevant material made available to the research community. In the context of synthetic lethality, we coupled the agnostic search of genomic lesion combination results with extensive experimental work using ad hoc engineered single clones of prostate and of bladder cancer cells. This work led to the novel identification of a prostate cancer phenotype with therapeutic potential and to the nomination of drugs with higher sensitivity in the presence of a common genomic loss in bladder cancer. These lines of work are in their final stages and will soon be submitted for publication. Further, we contributed to the development of two innovative strategies to increase the specificity of genome editing systems (Hit and go strategy and evoCas9 strategy). Although at a limited rate due to the 2020 pandemic, dissemination of results has been pursued throughout the SPICE project through presentations at conferences and international collaborative meetings, including as part of AACR conferences, of World Congress of the International union of Physiological Sciences, and of Scientific Foundations Symposia.