Thesis

EGFR/SHP2-targeted nanomedicines for colorectal cancer theranostic

• Call:

  ProtoTera Call 2023/1

• Academic Year:

  2023

• Supervisor:

  Célia Fernandes

• Co-Supervisor:

  Marta Martins

• Host Institution:

  C2TN - Centro de Ciências e Tecnologias Nucleares

• Granting Degree Institution:

  Instituto Superior Técnico (Universidade de Lisboa)

• Typology:

  National

• Abstract:

  Colorectal cancer (CRC) is the third most frequent cancer worldwide and the second leading cause of cancer-related death. Monoclonal antibodies (mAb) such as cetuximab target the epidermal growth factor receptor (EGFR) in RAS wild-type metastatic CRC (mCRC). However, these therapies result in high levels of resistance. Recent studies have found that antibodies targeting EGFR in combination with SHP2 inhibitors showed a synergistic effect bypassing resistance but this systemic co-treatment is associated with high toxicity. Nanomedicines can deliver drugs at higher doses with lower side effects. Among them, polymeric micelles (PM) may encapsulate a wide variety of bioactive molecules, be functionalized with ligand moieties targeting specific receptors and conjugate therapeutic and/or imaging agents, improving therapeutic efficacy and reducing systemic toxicity. Nuclear tools are particularly suited to explore a theranostic approach of cancer, profiting from the possible use of diagnostic and/or therapeutic radionuclides in the same molecular/nano entity. Thus, the main goal of this PhD project is to generate and validate new multifunctional targeted drug delivery platforms to explore the synergistic effect of targeted radionuclide therapy (TRT) combined with EGFR/SHP2-targeted therapy aiming to provide safe and selective drug delivery and ultimately to improve therapeutic efficacy and overcome resistance in the treatment of mCRC. Towards this goal, this PhD project proposes the development of PMs, carrying: i) anti-EGFR antibody to confer specificity and therapeutic effect; ii) specific SHP2-inhibitors to overcome drug resistance; iii) a chelator to stabilize trivalent radiometals for imaging (111In) or therapy (161Tb/177Lu) envisaging a nanotheranostic approach. This proposal expects to unravel the usefulness of this nanotheranostic approach with a simultaneous delivery of imaging/therapeutic radionuclides and EGFR/SHP2-targeted therapy to mCRC.