TROP2, or trophoblast cell surface antigen 2, is a protein found on the surface of cells throughout the body. It has garnered attention due to its involvement in various cellular processes, making it important in health and disease.
What is TROP2?
TROP2 is a cell surface glycoprotein, a protein with attached sugar chains on the cell’s outer membrane. It is encoded by the TACSTD2 gene, located on chromosome 1p32.1. TROP2 is present in many normal tissues, though its expression levels can vary.
This protein plays a role in several normal physiological functions, including cell proliferation, cell adhesion, and cell signaling pathways. TROP2 acts as an intracellular calcium signal transducer, relaying signals into the cell. It is involved in regulating cell growth and self-renewal.
TROP2’s Role in Cancer
In cancerous conditions, TROP2 often becomes dysregulated, exhibiting overexpression in various tumor types compared to healthy tissues. This elevated expression contributes to cancer progression by promoting uncontrolled cell growth, enhancing cell migration and invasion, and influencing resistance to conventional therapies.
TROP2 overexpression has been observed in a range of cancers, including breast cancer (particularly triple-negative and hormone receptor-positive/HER2-negative), lung cancer (especially non-small cell lung cancer), and urothelial cancer. Its presence in these malignancies often correlates with more aggressive disease and a less favorable prognosis. The specific role of TROP2 can vary depending on the cancer and cell type involved.
Targeting TROP2 for Treatment
TROP2’s high expression on cancer cells and more limited expression on healthy cells make it an attractive target for therapeutic interventions. The primary method of targeting TROP2 involves Antibody-Drug Conjugates (ADCs). ADCs are engineered molecules that combine the specificity of an antibody with the potency of a cytotoxic drug.
An ADC consists of three main components: a monoclonal antibody that specifically binds to TROP2 on cancer cells, a potent cytotoxic payload (a chemotherapy drug), and a chemical linker connecting the antibody to the payload. When the ADC binds to TROP2, the complex is internalized. Once inside, the linker breaks down, releasing the cytotoxic payload directly into the cancer cell. This targeted delivery minimizes damage to healthy tissues, reducing side effects associated with traditional chemotherapy.
Current and Developing TROP2 Therapies
Sacituzumab govitecan (Trodelvy) is an approved Antibody-Drug Conjugate that targets TROP2. This therapy consists of an anti-TROP2 antibody conjugated to SN-38, an active metabolite of irinotecan, via a hydrolyzable linker. Sacituzumab govitecan has received FDA approval for treating metastatic triple-negative breast cancer, unresectable locally advanced or metastatic hormone receptor-positive/HER2-negative breast cancer, and metastatic urothelial cancer.
Other TROP2-targeted agents are in various stages of clinical trials, showing promise for additional cancer types. Datopotamab deruxtecan (Dato-DXd) is another investigational TROP2-directed ADC, comprising a humanized anti-TROP2 antibody linked to a topoisomerase I inhibitor payload called exatecan derivative (DXd). This ADC is being evaluated in over 20 trials for various cancers, including non-small cell lung cancer, triple-negative breast cancer, and hormone receptor-positive/HER2-low or negative breast cancer. Beyond ADCs, other approaches like bispecific antibodies, which can latch onto both TROP2 and a T-cell to destroy cancer cells, are also being explored.