Home » Research Paper » Cancer Research: Antibody-Mediated Targeting of Secretory Protein SCUBE3 Suppresses Cancer Progression by Inhibiting Oncogenic Signaling and Inducing Anti-tumor Immunity (Rao, Zhou, Hromas, Sung, Chen, et al)
Cancer Research: Antibody-Mediated Targeting of Secretory Protein SCUBE3 Suppresses Cancer Progression by Inhibiting Oncogenic Signaling and Inducing Anti-tumor Immunity (Rao, Zhou, Hromas, Sung, Chen, et al)
Approaches targeting factors that simultaneously promote tumor growth and progression, induce therapy resistance, and inhibit anti-tumor immunity offer clear benefits over therapies targeting only one of these tumor-promoting processes. Through comprehensive loss-of-function genomic screening, we identified SCUBE3 as a pivotal factor that supports survival and therapy resistance and also orchestrates an immunosuppressive tumor microenvironment. Secretory SCUBE3 supported oncogenic activity through interactions with key oncogenic cell surface receptor proteins, including EGFR, mutant CALR, and TGFβRI/II. These interactions activated the transcription factors FOXR2 and c-Myc, promoting cancer cell proliferation and therapy resistance by enhancing DNA damage repair. Additionally, the SCUBE3-FOXR2 axis created an immunosuppressive tumor microenvironment by facilitating recruitment of the DNMT1 epigenetic repressor complex to the transcription regulator IRF1, thereby inhibiting the expression of MHC-I and MHC-II genes. A first-in-class neutralizing antibody targeting SCUBE3, developed using a sophisticated antibody discovery platform and engineered with specific mutations in the heavy chain to enhance specificity and efficacy, demonstrated profound therapeutic potential across various cancer types in preclinical models, including breast and ovarian cancer patient-derived xenografts. This discovery advances efforts to develop a targeted therapy for cancers characterized by hyperactive SCUBE3-associated signaling pathways.
Since 2004, UT Health San Antonio, Greehey Children’s Cancer Research Institute’s (Greehey CCRI) mission has been to advance scientific knowledge relevant to childhood cancer, contribute to the understanding of its causes, and accelerate the translation of knowledge into novel therapies. Through the discovery, development, and dissemination of new scientific knowledge, Greehey CCRI strives to have a national and global impact on childhood cancer. Our mission consists of three key areas: research, clinical, and education.
