Rescigno, Pasquale (2020) New predictive and prognostic biomarkers in metastatic prostate cancer. [Tesi di dottorato]

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Abstract

In this thesis, I discuss the identification of new prognostic and predictive biomarkers in lethal prostate cancers (PCs), derived from studies focused on molecular characterisation as a key element for detection of aberrant pathways in this disease. This approach allows the refinement of patient stratification and delivers more precise and individually tailored clinical care. Since the discovery of the usefulness of castration in the treatment of PC during the early decades of the last century, therapeutic strategies for treating this disease have improved and now involve the suppression of androgenic signalling, with several hormonal agents currently available, including enzalutamide, abiraterone, apalutamide and darolutamide. This has led researchers to focus their work on mechanisms of resistance to available hormonal manipulations, including androgen receptor (AR) splicing variant expression, AR amplification, and mutations. Here, I explored the importance of interrogating the serum level of prostate-specific antigen (PSA) as early as 4 weeks post-treatment as a biomarker of responses to second generation hormonal agents (SGHAs) and its correlation with overall survival. I also discovered that AR splicing variant 7 (AR-V7) expression, which is negligible in hormone-naïve PC, increases as patients progress into metastatic castration-resistant PC (mCRPC), and that this is correlated with prognosis and can also explain resistance to SGHAs. Using data gathered from several assays, including sequencing platforms, as well as immunohistochemistry (IHC) and immune-phenotyping assays, I also studied the impact of key tumour suppressor gene aberrations on outcomes of mCRPCs and present this work here as well. I have demonstrated, using IHC, the role of PTEN loss as a biomarker of poor response to abiraterone and investigated its role in docetaxel-treated cancers and in the context of a prospective, randomised, phase I/II trial of enzalutamide with or without the AKT inhibitor, capivasertib. I have also demonstrated the extreme importance of defects in the mechanism of DNA repair, such as homologous recombination as a sensitizer to PARP inhibition in the context of synthetic lethality. Finally, I have shown that in mCRPC, mismatch repair defects are associated with worse outcomes and increased likelihood of PD-L1 expression and lymphocyte infiltration, suggesting that these cancers are an ideal subset for immunotherapies. The work I have presented here, therefore, has shown that the molecular stratification of PC is feasible and can be used to identify new prognostic biomarkers for mCRPCs, as well as identifying predictive biomarkers for both standard and novel therapeutic strategies, offering more precisely targeted and effective care regimens.

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