University of California

Johns Hopkins University

Other

The University of Texas System

Yale University

Duojia Pan

Gerald M Rubin

Jenny Rooke

Reza Yavari

Tian Xu

Drew M Pardoll

Hongbing Zhang

Fan Pan

Joseph Barbi

Juan Fu

Ying Zheng

Andriana Lebid

Benjamin Park

The present invention relates to compositions and methods for treating cancer by targeting the Activin signaling pathway. In certain embodiments, combining Activin blockade with immunomodulation alters regulatory T (Treg) cell-mediated immune regulation and treats cancer.

Compositions and methods for targeting activin signaling to treat cancer

Yes-associated protein (Yap), a downstream co-activator of the Hippo pathway, is highly expressed in the Treg cell subset, and is critical to maintain its suppressive activity. Originally discovered in, the Hippo signaling pathway is a major regulator of cellular growth and proliferation in mammals. Loss of Yap expression in Treg cells can lead to superior anti-tumor immune responses, and thus, Yap is an important immunotherapeutic target for cancer.

Inhibition of YAP for breaking tumor immune tolerance

Tumor suppressor genes (TSGs) play a major role in the pathogenesis of human cancers. Here, a new TSG designated hippo (hpo) is described, and the human homolog mst2 is identified as an additional TSG. hpo as a gene that regulates both cell proliferation and cell death in, and encodes a Ste-20 family protein kinase that binds to and phosphorylates the tumor suppressor protein Salvador (Sav), which is known to interact with the Warts (Wts) protein kinase. Loss of hpo results in elevated transcription of the cell cycle regulator cyclin E and the cell-death inhibitor diap1, leading to increased proliferation and reduced apoptosis. Further, hpo, sav, and wts define a pathway that regulates diap1 at the transcriptional level. A human homolog of hpo completely rescues the overgrowth phenotype ofhpomutants.

Tumor suppressor designated Hippo

The invention provides methods and compositions relating to Kuz involvement in angiogenesis. In various embodiments, the invention provides methods for modulating angiogenesis by specifically modulating the activity of Kuz in a vertebrate animal predetermined to have a pathogenic angiogenesis; methods for modulating angiogenesis by specifically modulating the activity of Kuz in a vertebrate animal and subsequently detecting a resultant angiogenic modulation in the animal; methods for specifically detecting Kuz activity in a vertebrate animal predetermined to have a pathogenic angiogenesis; methods for specifically detecting a pathogenic angiogenesis in a vertebrate animal having a predetermined Kuz activity; and methods for identifying a modulator of angiogenesis by (a) contacting an angiogenic assay system comprising a predetermined amount of Kuz with a candidate agent, under conditions whereby but for the presence of the agent, the system provides a reference angiogenesis; and (b) detecting an agent-biased angiogenesis of the system.

Modulating angiogenesis

Members of a novel family of polypeptides, the KUZ family, are metalloproteases involved in neuronal partitioning and neuronal development. The invention provides KUZ poylpeptides, antibodies that bind the KUZ polypeptides, KUZ encoding nucleic acids, methods for identifying cells expressing the KUZ polypeptides, methods of identifying ligands that bind to the subject proteins and methods of blocking KUZ polypeptide/ligand interactions.

KUZ, a novel family of metalloproteases

Members of a novel family of polypeptides, the KUZ family, are metalloproteases involved in neuronal partitioning and neuronal development. The invention provides KUZ poylpeptides, antibodies that bind the KUZ polypeptides, KUZ encoding nucleic acids, methods for identifying cells expressing the KUZ polypeptides, methods of identifying ligands that bind to the subject proteins and methods of blocking KUZ polypeptide/ligand interactions

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Dallas, TX, United States of America

Duojia Pan