Trophoblast cell surface antigen 2, or TROP2, is a protein found on the exterior of various cells throughout the body. It plays a part in a range of normal biological processes.
Understanding TROP2
TROP2 is a type I transmembrane glycoprotein, meaning it spans the cell membrane with a part of the protein extending outside the cell and another part inside. It is encoded by the TACSTD2 gene and is also known by other names like tumor-associated calcium signal transducer 2 or epithelial glycoprotein 1. This protein is found on the surface of various healthy epithelial cells, which line the surfaces of organs and structures throughout the body, including the skin, kidney, liver, and breast.
The normal physiological functions of TROP2 involve several cellular activities, such as cell adhesion, where cells stick to each other or to their surroundings. It also influences cell growth and differentiation, processes by which cells mature into specialized types. TROP2 has a significant role in embryonic development, contributing to processes like embryo implantation and the formation of placental tissue. Furthermore, it helps maintain the proliferation of embryonic stem cells and supports organ development.
TROP2 acts as a transducer for intracellular calcium signaling, affecting pathways that govern cell self-renewal and transformation. It can also modulate cell adhesion to fibronectin, a protein involved in tissue structure, through interactions with specific protein complexes.
TROP2’s Role in Cancer Progression
In various cancers, TROP2 expression and activity become dysregulated. High levels of TROP2 are observed in numerous malignant tumors, including those of the breast, lung, ovarian, gastric, pancreatic, and colorectal systems. This overexpression is often linked to the initiation and growth of tumors.
TROP2 contributes to tumor progression by influencing several intracellular signaling pathways. It can activate pathways like ERK/MAPK and PI3K/AKT, which are deeply involved in cancer cell proliferation, migration, invasion, and survival. This signaling can accelerate the cancer cell cycle and stimulate tumor growth.
The protein’s dysregulation also plays a part in metastasis, which is the spread of cancer cells from the primary tumor to other parts of the body. High TROP2 expression has been associated with an increased risk of metastasis in many cancer types. Additionally, TROP2 expression in cancer cells has been correlated with resistance to various chemotherapy drugs.
Targeting TROP2 in Cancer Treatment
TROP2 has emerged as a promising target for cancer therapy due to its high expression on cancer cells and lower expression on most healthy tissues. This allows for the development of treatments that selectively target malignant cells. The internalization of TROP2 upon antibody binding makes it particularly suitable for therapies that deliver drugs directly into cancer cells.
One of the main strategies for targeting TROP2 involves antibody-drug conjugates (ADCs). ADCs are engineered molecules that combine the specificity of an antibody with the potency of a chemotherapy drug. The antibody component of the ADC specifically binds to TROP2 on the cancer cell surface. Once bound, the ADC-TROP2 complex is internalized into the cell through a process called endocytosis.
Inside the cancer cell, the linker connecting the antibody and the chemotherapy payload is designed to break down under specific cellular conditions, such as acidic environments or the presence of certain enzymes. This breakdown releases the chemotherapy drug directly into the tumor cell, where it exerts cytotoxic effects. This targeted delivery enhances the drug’s efficacy while reducing systemic exposure and side effects on healthy tissues.
An example of a TROP2-targeting ADC is sacituzumab govitecan (Trodelvy). This drug consists of a humanized anti-TROP2 antibody linked to SN-38, an active metabolite of the chemotherapy drug irinotecan. Sacituzumab govitecan has demonstrated significant antitumor activity in various cancers and is approved for use in certain metastatic breast cancers, particularly triple-negative breast cancer, and metastatic urothelial cancer. Other TROP2-targeted ADCs, such as datopotamab deruxtecan, are also being investigated for their potential in different cancer types, including breast cancer.
Looking Ahead: The Future of TROP2-Targeted Therapies
Research into TROP2-targeted therapies is evolving to enhance treatment outcomes and expand their application. Beyond antibody-drug conjugates, scientists are investigating other TROP2-targeting agents, including bispecific antibodies and CAR T-cells. Bispecific antibodies are designed to bind to both TROP2 on cancer cells and another target, such as a molecule on immune cells, to redirect the body’s own defenses against the tumor.
Combination therapies are also a significant area of focus, where TROP2-targeted agents are used alongside other treatment modalities. This includes combining ADCs with traditional chemotherapy, immunotherapy, or other targeted therapies like PARP inhibitors. Such combinations aim to improve anti-tumor effects, potentially overcome resistance mechanisms, and reduce overall drug toxicity by leveraging different therapeutic approaches.
The role of TROP2 as a biomarker for patient selection is being explored to identify which patients are most likely to benefit from these targeted treatments. This can lead to more personalized therapeutic strategies. Ongoing studies are also addressing potential challenges such as managing side effects and overcoming mechanisms by which cancer cells might develop resistance to TROP2-targeted therapies.