Project Portugal 2030

Summary

Triple-negative breast cancer (TNBC), representing about 15% of all breast cancers, has a highly aggressive clinical course, with earlier age of onset and greater metastatic potential. The standard therapy for advanced TNBC includes neoadjuvant chemotherapy, adjuvant radiotherapy (RT) and immunotherapy, but responses are often short-lived, and patients have a median overall survival of 12 to 18 months. The lack of therapeutic targets and limited treatment options confer to TNBC patients the poorest prognosis, with high rate of relapse. Among the myriad challenges in managing TNBC, radioresistance stands out as a critical factor that highly impacts treatment outcome. RT is a cornerstone in the TNBC treatment, serving as an effective strategy to eliminate residual cancer cells following surgery and to target inoperable tumors at the time of diagnosis. However, TNBC's aggressive nature and propensity for early metastasis often result in a suboptimal response to RT, leading to higher rates of locoregional recurrence and distant metastasis. Unraveling the mechanisms underpinning TNBC radioresistance is essential for devising tailored therapeutic approaches to overcome its aggressive nature. Recently, attention has turned toward the emerging role of exosomes in mediating cancer progression and therapy resistance (Ni et al., 2019). In TNBC, it is known that breast cancer cells-derived exosomes promote proliferation and drug resistance in non-tumorigenic cancer cells (Ozawa et al., 2018). Recently, exosomes derived from radioresistant breast cancer cells promote therapeutic resistance in radiosensitive cells (Payton et al., 2021). This prompts a closer examination to the mechanisms underlying exosomes-mediated TNBC radioresistance and to their potential as putative biomarkers and prognosticators in TNBC treatment. Hence, our hypothesis posits that TNBC patients who have undergone RT and, afterwards developed locoregional or distant disease, exhibit a unique blood exosome transcriptomic and proteomic profile compared with the ones that do not relapse. This distinctive profile my serve as potential SIGNATURE OF RADIORESISTANCE and a predictive factor of RT response and/or relapse, and could identify novel targets for pharmacological intervention, either as alternative treatments or in combination with RT. To address this question, we will take advantage of the 3D preclinical breast cancer model established in our lab, TNBC immune-spheroids, to identify the exosomes-derived signature of radioresistance, through advanced transcriptomic/proteomic studies (AIM1), functional assays (AIM2) and clinical validation in human samples (AIM3). The specific aims will accomplish: (AIM1)- the identification of a multi-omics exosome-derived radioresistance signature in TNBC, identifying potential biomarkers and/or therapeutic molecules, using a 3D biomimetic model of TNBC; (AIM2)– the establishment of the proof-of-concept, that one or more molecules identified in AIM1 drive radioresistance in TNBC immune-spheroids; (AIM3)– the validation of the identified exosome-derived radioresistance signature in the blood of TNBC patients. Gathering a multidisciplinary and international team, E-MAGIC aims to establish the groundwork for harnessing the prognostic potential of exosomes and identifying novel targets for pharmacological intervention. E-MAGIC impact will extend beyond its immediate scope, holding significant implications for other radioresistant cancers.