Six-Transmembrane Epithelial Antigen of Prostate 1, or STEAP1, is a protein found on the surface of cells, known for its association with prostate cancer. This association makes STEAP1 an important area of research for understanding and potentially treating the disease.
The Biological Function of STEAP1 in Prostate Cancer
STEAP1 is a member of the STEAP protein family, known for their involvement in metal ion metabolism, specifically the reduction of iron and copper. While other STEAP family members directly reduce metals, STEAP1 may participate indirectly, potentially aiding iron uptake through interactions with other STEAP proteins. STEAP1 also facilitates intra- and intercellular communication by modulating the concentration of ions like sodium, calcium, and potassium, as well as small molecules.
In prostate cancer, STEAP1 expression is increased compared to healthy prostate tissue. This overexpression is observed in both primary prostate cancer and metastatic castration-resistant prostate cancer, including lesions in bone and lymph nodes. Elevated STEAP1 levels promote prostate tumor growth, and reducing its expression can inhibit cancer cell proliferation and induce cell death. It contributes to tumor progression by enhancing cell proliferation, invasion, and metastasis, and by influencing signaling pathways related to cell survival and communication within the tumor microenvironment.
Identifying STEAP1 in Prostate Cancer
STEAP1 holds promise as a biomarker for prostate cancer. Its high expression in prostate cancer cells and minimal presence in normal tissues make it an attractive target for diagnostic purposes. STEAP1 can help distinguish malignant prostate lesions from benign prostatic hyperplasia (BPH) with high sensitivity and specificity.
Beyond initial diagnosis, STEAP1 also demonstrates prognostic value, correlating with disease aggressiveness and patient outcomes. Higher levels of STEAP1 expression are associated with elevated Gleason scores, which indicate more aggressive tumors, and a worse prognosis. STEAP1 overexpression has been identified as an independent marker for biochemical recurrence, meaning its elevated presence can predict the return of cancer after initial treatment. STEAP1 can be assessed using methods such as immunohistochemistry on tissue biopsies. STEAP1 is found in extracellular vesicles, which are tiny sacs released by cells, and these STEAP1-positive vesicles in the bloodstream are being explored as a non-invasive circulating biomarker.
Therapeutic Strategies Involving STEAP1
STEAP1’s high presence on prostate cancer cells and limited expression on healthy tissues makes it an attractive target for therapeutic interventions. Several approaches are being developed to leverage STEAP1 for prostate cancer treatment, aiming to precisely deliver therapies to cancer cells while minimizing harm to normal cells.
One strategy involves antibody-drug conjugates (ADCs), which combine an antibody that binds to STEAP1 with an anti-cancer drug. Once the antibody binds to STEAP1 on the cancer cell surface, the ADC is internalized, releasing the drug directly into the tumor cell. While early ADCs like vandortuzumab vedotin showed limited efficacy and some toxicity in initial trials, newer ADCs such as ABBV-969 are currently undergoing Phase I clinical trials for metastatic castration-resistant prostate cancer (mCRPC).
Chimeric Antigen Receptor (CAR) T-cell therapies are another approach, where a patient’s own T-cells are engineered in the lab to recognize and attack STEAP1-expressing cancer cells. These modified T-cells, known as STEAP1 CAR T-cells, have shown anti-tumor activity in preclinical models and are being evaluated in Phase I/II clinical trials, sometimes in combination with other treatments. Bispecific T-cell engagers, such as xaluritamig (AMG 509), are being developed; these molecules are designed to bind simultaneously to STEAP1 on cancer cells and to CD3 on T-cells, thereby bringing T-cells to the tumor and triggering cancer cell destruction.
Vaccine-based strategies aim to harness the immune system against STEAP1. One such mRNA vaccine in Phase I clinical trials targets STEAP1 along with other prostate cancer antigens like PSMA and PAP. By delivering these antigen modules, the vaccine intends to activate the patient’s immune system, prompting T-cells to recognize and eliminate cancer cells.