Abstract LB-189: Novel bone morphogenetic protein receptor inhibitor JL5 suppresses tumor cell survival signaling and induces regression of human lung cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-07, Vol.78 (13_Supplement), p.LB-189-LB-189
• Main Authors: Newman, Jenna H., NeMoyer, Rachel E., Augeri, David, Malhotra, Jyoti, Langenfeld, Elaine, Chesson, Charles B., Lee, Micheal J., Tarabichi, Saeed, Jhawar, Sachin R., Bommareddy, Praveen K., Marshall, Sh'rae, Sadimin, Evita T., Kerrigan, John E., Goedken, Michael, Minerowicz, Christine, Jabbour, Salma K., Li, Shengguo, Dobias, Natalie, Carayannopolous, Mary O., Zloza, Andrew, Langenfeld, John
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2018-LB-189

Purpose: Studies have shown that bone morphogenetic protein (BMP) signaling is aberrantly expressed in lung and other carcinoma leading to pro-oncogenic effects on tumor growth. The BMP receptor inhibitor DMH2 induces death of lung cancer cells through the downregulation of anti-apoptotic proteins XIAP, TAK1, and Id1-Id3. Since DMH2 does not downregulate BMP signaling in vivo because of metabolic instability and poor pharmacokinetics better BMP inhibitors are needed. Experimental Design: Here, we identified a site of metabolic instability of DMH2 and designed a novel BMP receptor inhibitor, JL5. We examined the effects of JL5 to downregulate BMP signaling and induce cell death of lung cancer cells in vitro and in vivo. We also queried the The Cancer Genome Atlas (TCGA) to assess if genetic alterations in lung cancer would affect drug targetability of the BMP receptors. Results: We show that JL5 has improved pharmacokinetic profile compared to DMH2. JL5 suppresses BMP signaling in lung cancer cells in vitro and in tumor xenografts. Moreover, we demonstrate JL5-induced tumor cell death and tumor regression in xenograft mouse models without immune cells and humanized with adoptively transferred human immune cells. In humanized mice, JL5 additionally induces the infiltration of immune cells within the tumor microenvironment. The TCBA database analysis suggests that genetic alterations in the BMP signaling cascade will not limit targeting with small molecule inhibitors. Conclusion: Our studies show that the BMP signaling pathway is targetable and BMP receptor inhibitors should be developed as a therapeutic to treat lung and other cancer patients. Citation Format: Jenna H. Newman, Rachel E. NeMoyer, David Augeri, Jyoti Malhotra, Elaine Langenfeld, Charles B. Chesson, Micheal J. Lee, Saeed Tarabichi, Sachin R. Jhawar, Praveen K. Bommareddy, Sh'rae Marshall, Evita T. Sadimin, John E. Kerrigan, Michael Goedken, Christine Minerowicz, Salma K. Jabbour, Shengguo Li, Natalie Dobias, Mary O. Carayannopolous, Andrew Zloza, John Langenfeld. Novel bone morphogenetic protein receptor inhibitor JL5 suppresses tumor cell survival signaling and induces regression of human lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-189.