Advances in Personalized Oncology

Abstract

Advances in next-generation sequencing (NGS) have catalyzed a paradigm shift in cancer treatment, steering the focus from conventional, organ-specific protocols to precision medicine. Emerging targeted therapies offer a cutting-edge approach to cancer treatment, while companion diagnostics play an essential role in aligning therapeutic choices with specific molecular changes identified through NGS. Despite these advances, interpreting the clinical implications of a rapidly expanding catalog of genetic mutations remains a challenge. The selection of therapies in the presence of multiple mutations requires careful clinical judgment, supported by quality-centric genomic testing that emphasizes actionable mutations. Molecular tumor boards can play an increasing role in assimilating genomic data into clinical trials, thereby refining personalized treatment approaches and improving patient outcomes.

Keywords: driver mutations; oncogenic alterations; oncogenic drivers; personalized medicine; precision medicine; precision oncology.

Figure 1

Therapeutic targets and mechanisms of action in precision medicine. Made with BioRender. 1. Antibodies (in red) bind to specific receptors on the cell membrane, initiating or inhibiting various signaling pathways. 2. Cell death mechanisms: (a) The antibody is linked to a drug conjugate, which can be a chemotherapeutic agent, a radioactive substance, or a toxin. The conjugation allows the drug to be delivered directly to the target cells. (b) Antibody binding to certain receptors can lead to programmed cell death (apoptosis). 3. Small molecules, such as tyrosine kinase inhibitors, can inhibit the activation of proliferative signaling pathways such as the PI3K/Akt/mTOR and RAS/RAF/MEK/ERK pathways. 4. Activation of the PI3K/Akt/mTOR and RAS/RAF/MEK/ERK pathways leads to the expression of Cyclin D1, which forms a complex with CDK4/6 (cyclin-dependent kinase 4/6), regulating cell cycle progression. CDK4/6 inhibitors are currently used as the standard of care in breast tumors. 5. Histones are modified by acetylation (Ac) and methylation (Me3), influencing gene transcription. To compensate for identified chromatin modifier mutations, the potential of targeting enzymes like DNA methyltransferases and histone deacetylases is currently being evaluated. 6. PARP (Poly(ADP-ribose) polymerase), involved in DNA repair in response to damage, is targeted by PARP inhibitors. 7. The PROTAC strategy: proteins marked for degradation are directed to the proteasome, where they are broken down into peptides.

Figure 2

Therapeutic targets and corresponding drugs used in precision oncology. Receptor tyrosine kinases (RTKs) are crucial in cancer cell proliferation and survival. Each receptor is depicted on the cell membrane with associated therapeutic agents shown either as antibodies or small molecule inhibitors. ROS: ROS proto-oncogene 1; FGFR: fibroblast growth factor receptor; EGFR: epidermal growth factor receptor; MET: mesenchymal-epithelial transition factor; VEGFR: vascular endothelial growth factor receptor; HER: human epidermal growth factor receptor; KIT: Kit proto-oncogene receptor tyrosine kinase; ALK: anaplastic lymphoma kinase; RET: rearranged during transfection.