STEAP1 (Six-transmembrane epithelial antigen of the prostate 1), initially discovered in prostate cancer, belongs to the STEAP family of proteins and is primarily expressed in prostate epithelial cells as well as various malignant tumor cells. Increasing research has demonstrated that STEAP1 exhibits high expression in multiple solid tumors, including prostate cancer, bladder cancer, colorectal cancer, breast cancer, and non-small cell lung cancer, and is associated with tumor progression and poor prognosis, making it a potential tumor target.

Structure and Function of STEAP1

STEAP1 is a six-transmembrane protein located on the cell membrane surface. The STEAP family also includes STEAP1B (a truncated homolog of STEAP1), STEAP2, STEAP3, and STEAP4, which are primarily involved in metal ion metabolism, particularly in the reduction of iron and copper. Unlike other members, STEAP1 lacks the N-terminal NADPH oxidoreductase (FNO) domain and cannot independently perform metal reduction reactions. Instead, it may indirectly participate in metal metabolism through interactions with STEAP2 or STEAP4. Additionally, the partial colocalization of STEAP1 with transferrin (Tf) and transferrin receptor 1 (TfR1) suggests its potential role in iron metabolism. Since STEAP1 is primarily localized at cell junctions of the cell membrane, it may function as a channel or transporter involved in intercellular signaling. Although the specific functions of STEAP1 are not fully understood, its potential roles in metal metabolism and cell communication make it an important research target.

The structures and physiological characteristics of STEAP1-4

The Dual Roles of STEAP1 in Different Cancers

STEAP1 exhibits dual roles in different cancers. In some cancers, it promotes tumor development, whereas in others, it may inhibit tumor growth.

Promote tumor progression

Prostate Cancer: STEAP1 is highly expressed in prostate cancer, especially in metastatic castration-resistant prostate cancer (mCRPC), and its expression level is closely related to disease progression. Knockdown of STEAP1 can induce cancer cell apoptosis and reduce their proliferation.

Lung Cancer: Through the JAK2/STAT3 signaling pathway, STEAP1 promotes cell migration and angiogenesis. Knockout of STEAP1 can significantly inhibit the proliferation, migration, and invasion of tumor cells.

Gastric Cancer: Upregulation of STEAP1 is closely associated with tumor proliferation, migration, and peritoneal metastasis. Knockdown of STEAP1 can effectively reduce these malignant processes.

Ovarian Cancer: STEAP1 can promote epithelial-mesenchymal transition (EMT), accelerate cell invasion and metastasis. Knockout of STEAP1 can inhibit cell proliferation and migration, and promote cell apoptosis.

Colorectal Cancer: STEAP1 is associated with reactive oxygen species (ROS) levels and affects ROS levels by regulating the NRF2 pathway. Knockdown of STEAP1 can reduce ROS production and promote cancer cell apoptosis.

Liver Cancer: Knockdown of STEAP1 can inhibit the expression of the oncogene c-Myc, causing tumor cells to arrest in the G1 phase and significantly inhibiting their proliferation.

Inhibit tumor progression

Breast Cancer: STEAP1 exhibits an inhibitory effect in breast cancer, and its reduced expression increases the invasiveness of cancer cells, accompanied by upregulation of EMT-related genes.

Endometrial Cancer: STEAP1 also plays an inhibitory role in endometrial cancer. Downregulation of STEAP1 can accelerate cancer cell proliferation, migration, invasion, and EMT progression.

The molecular mechanisms of STEAP1 in cancer

Targeted therapy for STEAP1

Antibody Therapy

Antibody-Drug Conjugates (ADCs) are currently one of the important strategies for targeting STEAP1. ABBV-969, an ADC targeting STEAP1, is currently in Phase I clinical trials primarily for the treatment of mCRPC. The focus of this study is to evaluate the safety, pharmacokinetics, and preliminary efficacy of ABBV-969, and to determine the optimal therapeutic dose through dose escalation.

Mechanism of ABBV-969

Furthermore, bispecific T-cell engager (TCE) therapy targeting STEAP1 is also gradually emerging as a promising approach. AMG 509 is a TCE drug that can simultaneously target STEAP1 on tumor cells and CD3 on T-cells, linking T-cells to tumor cells to promote T-cell activation and kill tumor cells with high expression of STEAP1. Early clinical studies have shown that AMG 509 has good potential as an immunotherapy for mCRPC.

Structure of AMG 509

CAR-T Therapy

STEAP1 CAR-T is a modified CAR-T cell that targets prostate tumors, while Enzalutamide is a drug that inhibits cancer cell growth by blocking the action of androgens. On January 9, 2024, Fred Hutchinson Cancer Research Center and PromiCell Therapeutics initiated a Phase I/II clinical trial in the United States to evaluate the efficacy of combining STEAP1 CAR-T with Enzalutamide in the treatment of mCRPC.

Illustration of STEAP1 CAR-T Cell

mRNA Vaccine Therapy

Furthermore, STEAP1 has been developed as a target for cancer vaccines. Ahvaz Jundishapur University of Medical Sciences is developing an mRNA vaccine for prostate cancer, which utilizes an RNA-liposome delivery system for intravenous injection. This candidate vaccine targets three antigens associated with prostate cancer: PSMA, STEAP1, and PAP. By delivering these antigen modules, it stimulates the patient's immune system, enabling T-cells to recognize and attack cancer cells, thereby generating an anti-tumor effect. Currently, Phase I clinical trials of the vaccine are ongoing, primarily to assess its safety and preliminary efficacy. It is hoped that this vaccine will provide a new immunotherapy option for prostate cancer patients.

Research and development pipeline of STEAP1

Data source: global data

Relying on FLAG, the technology platforms of multi-pass transmembrane proteins, ACROBiosystems has successfully developed full-length STEAP1 protein expressed in the HEK293 system. These products with native conformation and complete epitopes, and have been validated through ELISA/SPR to exhibit high biological activity, meeting the development of STEAP1-targeted drugs development.

Reference

1. Xu M, Evans L, Bizzaro C L, et al. STEAP1–4 (six-transmembrane epithelial antigen of the prostate 1–4) and their clinical implications for prostate cancer[J]. Cancers, 2022, 14(16): 4034. https://doi.org/10.3390/cancers14164034.

2. Chen W J, Wu H T, Li C L, et al. Regulatory roles of six-transmembrane epithelial antigen of the prostate family members in the occurrence and development of malignant tumors[J]. Frontiers in Cell and Developmental Biology, 2021, 9: 752426. https://doi.org/10.3389/fcell.2021.752426.

3. Nakamura H, Arihara Y, Takada K. Targeting STEAP1 as an anticancer strategy[J]. Frontiers in Oncology, 2023, 13: 1285661. https://doi.org/10.3389/fonc.2023.1285661.

4. Berger R, Tolcher A W, Dorff T B, et al. 1660TiP First-in-human study of ABBV-969, a dual variable antibody-drug conjugate (ADC), in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)[J]. Annals of Oncology, 2024, 35: S1000-S1001. https://doi.org/10.1016/j.annonc.2024.08.1741.

5.  Kelly W K, Danila D C, Lin C C, et al. Xaluritamig, a STEAP1× CD3 XmAb 2+ 1 immune therapy for metastatic castration-resistant prostate cancer: results from dose exploration in a first-in-human study[J]. Cancer Discovery, 2024, 14(1): 76-89. https://doi.org/10.1158/2159-8290.CD-23-0964.