Metastasis is the most common cause of cancer-related mortality, yet there are currently no therapeutic options that can be used to stop the spread of malignant cells. Recently, two members of the Transforming Growth Factor-? family, the secreted ligands Nodal and Bone Morphogenetic Protein-4 (BMP-4), have been linked with increased metastasis in breast and other cancers. These cytokines activate stem cell programs in cancers that enable malignant cells to leave the primary tumor and colonize distant organs. Inhibitors of Nodal or BMP-4 are therefore potential therapeutics for some metastatic cancers, however to date none have been developed. We have produced a novel inhibitor of Nodal and BMP-4 termed Cerberus- Fc. This protein-based inhibitor is a variant of the embryonic Nodal/BMP antagonist, Cerberus, fused to IgG1- Fc. We previously found Cerberus-Fc binds both Nodal and BMP-4 with high affinity, abrogates Nodal and BMP-4 signaling, and profoundly suppresses migration, invasion, and colony formation of two triple negative breast cancer cell lines that express these ligands. Additionally, in human breast cancer patients high Cerberus expression is strongly associated with increased relapse-free survival rates. Taken together, these findings suggest that Cerberus-Fc could inhibit metastasis of breast and potentially, other cancers. We envision this therapeutic could 1) treat or prevent metastasis, 2) be used in combination with existing cancer therapies that target the primary tumor or immune response, or 3) be used in conjunction with surgical removal of the primary tumor to help prevent spread of cancer cells that may lead to metastasis. In this phase 1 project, we will focus on breast cancer metastasis, using an orthotopic, patient derived xenograft (PDX) mouse model of breast cancer to demonstrate the in vivo activity of Cerberus-Fc on spontaneous metastasis to the lung and liver, as well as tumor burden. We will additionally verify acceptable pharmacokinetic behavior of the construct. If successful, these studies will provide proof of concept for the efficacy of Cerberus-Fc in the treatment of breast cancer metastasis and pave the way for more thorough pre- clinical development, including testing on additional PDX mouse models of breast and other cancers that express varying levels of Nodal and/or BMP-4. This project is a collaboration between Talapo Therapeutics and Dr. Erik Martinez-Hackert, Assistant Professor at Michigan State University and the discoverer of Cerberus-Fc's inhibiting functions.
Public Health Relevance Statement: Metastatic disease is the most lethal and least treatable facet of cancer. We have developed a novel agent, termed Cerberus-Fc, that inhibits breast cancer metastasis-like programs in vitro. This project will employ a preclinical model of breast cancer to establish Cerberus-Fc's utility in inhibiting metastasis in vivo.
Project Terms: Affinity; base; behavioral construct; Binding; Biological Sciences; bone morphogenetic protein 4; Breast; Breast Cancer cell line; Breast cancer metastasis; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Treatment; cancer cell; Cancer Etiology; Cancer Model; cell motility; Cell surface; Cessation of life; Collaborations; cytokine; Disease; Disseminated Malignant Neoplasm; Distant; Drug Kinetics; Drug Targeting; Embryo; Excision; experience; Family; Gene Targeting; Goals; Health; Human; human model; IgG1; Immune response; In Vitro; in vivo; inhibitor/antagonist; Lead; Legal patent; Ligands; Link; Liver; malignant breast neoplasm; Malignant Neoplasms; member; Metastatic Neoplasm to the Lung; metastatic process; Michigan; migration; Modeling; mortality; mouse model; Neoplasm Metastasis; Nodal; novel; novel therapeutics; Nuclear Translocation; Operative Surgical Procedures; Organ; Pathway interactions; patient population; Patients; Phase; Phosphorylation; Pre-Clinical Model; preclinical development; prevent; Primary Neoplasm; professor; programs; Proteins; receptor; receptor binding; Relapse; Rights; Scientist; Signal Transduction; Signaling Molecule; Stem cells; success; Survival Rate; targeted cancer therapy; Testing; Therapeutic; therapeutic development; transcription factor; Transforming Growth Factors; triple-negative invasive breast carcinoma; tumor; Tumor Burden; tumor growth; Universities; Variant; Xenograft Model; Xenograft procedure
