COMPOSITIONS AND METHODS FOR MODULATING LEFTY AND BMP PROTEINS

COMPOSITIONS AND METHODS FOR MODULATING LEFTY AND BMP PROTEINS

Researchers at Stanford, funded in part by the Chan Zuckerberg Biohub, have surprisingly found that LEFTY1 suppresses not only the SMAD2/3 signaling pathway (a pathway activated by Nodal signaling) but also the SMAD1/5/8 signaling pathway (a pathway activated by BMP proteins, including BMP7).

Left-right differentiation factors (LEFTYs) are members of the TGF-b superfamily of growth factors. Dysregulation of TGF-b superfamily pathways often results in neoplastic transformation. Therefore, there is a need to characterize the roles of pathway members in adult tissue homeostasis and disease models. The LEFTY1/BMP7 pathway is newly identified in the present invention and is highly relevant to neoplastic disease. BMP7 acts as a tumor suppressor in multiple cancer types by inducing differentiation of tumorigenic cancer cells. Surprisingly, the inventors found that LEFTY1 promotes long-term proliferation of cells and inhibits differentiation-promoting pathways mediated by BMP7 in breast cancer cell lines. Moreover, LEFTY is amplified in a substantial number of breast cancer patients.

Stage of Research

The inventors have demonstrated that LEFTY1 antagonizes BMP7-dependent signaling by binding a receptor for BMP7 - the bone morphogenetic protein type 2 receptor (BMPR2) - preventing BMP7 from binding the receptor and activating the receptor’s downstream signaling pathway. The inventors have further shown that inhibition of LEFTY1 expression or activity in cancer models can significantly impair tumor growth.

Applications

Methods of treating a cancer by administering a therapeutic amount of an agent that antagonizes the expression or activity of LEFTY.
Methods for diagnosing a cancer by detecting a genomic amplification of a LEFTY gene or expression of a LEFTY mRNA or protein

Advantages

Target tumor-initiating cells responsible for cancer recurrence
RNAi, antibody or blocking peptide inhibitors

Stage of Development

Research-in vitro

Publication

Zabala M, Lobo NA, Antony J, Heitink, LS, Gulati GS, Lam J, Parashurama N, Sanchez K, Adorno M, Sikandar SS, Kuo AH, Qian D, Kalisky T, Sim S, Li. L, Dirbas. FM, Somlo G, Newman A, Quake SR, Clarke MF. LEFTY1 Is a Dual-SMAD Inhibitor that Promotes Mammary Progenitor Growth and Tumorigenesis. Cell Stem Cell 27(2):284-299 (2020)

PCT publication WO2019/200397