Inhibition of Ly6K and Ly6E enhances anti PDL1/PDL2 Therapy Response

Categories:  “Cancer Therapeutics“

Reference #: 2015-030

OTC Contact: Ruchika Nijhara, Ph.D., MBA, CLP (Directory Information | Send a Message)

Description

Targeted immunotherapy for the treatment of triple negative breast cancer (TNBC) that uses Ly6K and Ly6E
inhibition for anti-TGFβ and for inhibition of PD-L1 expression.

Recent discoveries in triple negative breast cancer suggest that the immune checkpoint protein PD-L1 is increased in TNBC and that its increased expression contributes to tumor immune escape. TGFβ signaling represents another key hub in cancer that activates both immune and non-immune associated pathways of tumor progression. The widespread expression and essential function of TGFβ signaling and PD-L1 in many normal tissues make them problematic targets for therapeutic intervention.

Georgetown researchers identified the cell surface protein Ly6K as a potent activator of TGFβ signaling and epithelial to mesenchymal transition required for in vivo tumor growth. Ly6K is also required for IFNg induced overexpression of PD-L1 in cancer cells. The researchers found that the knockdown or pharmacological inhibition of Ly6K inhibits PD-L1 expression in TNBC cells and have identified small molecule binders of Ly6K potentially leading to this outcome. Importantly, an antibody targeted approach would also be suitable to target Ly6K.

Applications

• Enhances the efficacy of immunotherapy against anti PDL1/PDL2. Can potentially help the body's natural killer cells fight cancer cells and prevent tumor escape.

Advantages

• Ly6K and Ly6E are surface proteins which can be easily targeted for cancer therapy, in contrast with intracellular targets which are notoriously difficult to reach.
• Can be used in place of hormone therapy or anti-Her2 therapies that do not work for TNBC

Stage of Development

Validated in mice xenograft models.

Relevant Publications

• AlHossiny M, Luo L, Frazier WR, Steiner N, Gusev Y, Kallakury B, Glasgow E, Creswell K, Kumar R, Upadhyay G. "Ly6E/K signaling to TGF-ß promotes breast cancer progression, immune escape and drug resistance." Cancer Research (2016).
• Luo L, McGarvey P, Madhavan S, Kumar R, Gusev Y, Upadhyay G. "Distinct lymphocyte antigens 6 (Ly6) family

  members Ly6D, Ly6E, Ly6K and Ly6H drive tumorigenesis and clinical outcome.." Oncotarget 7.10 (2016).

Inventors

Geeta Upadhyay