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Developmental signaling pathways, such as those controlled by Wnt and Sonic Hedgehog (Shh), play pivotal roles in the initiation, progression, and chemotherapeutic resistance of many cancers. As such, their dysregulation affects the mortality and morbidity of large numbers of such patients. Despite being commonly studied, few therapeutic agents against these highly cancer-relevant signaling pathways are in clinical use.
Our current focus is on understanding the role Wnt signaling plays in colorectal cancer and the role Shh signaling plays in brain tumors. The ultimate goal of our work is to identify novel therapeutic agents for cancer patients harboring tumors dependent on these developmental signaling pathways. Thus, the work in our lab spans the spectrum from basic mechanism to preclinical/translational relevance.
Project 1: Wnt signaling in colorectal cancers
Elucidate mechanisms underlying Wnt-driven colorectal carcinogenesis.
Identify novel, druggable targets in Wnt-driven colorectal cancers.
Figure 1: A schematic of the Wnt signaling.
Figure 2: A CK1α activator, SSTC3, attenuates Wnt-driven CRC growth without disturbing normal intestinal homeostasis. A. SW403 xenograft growth in mice treated with SSTC3 or TANKi for the indicated days (n = 7 in each group) is shown. * p value < 0.05. B. Representative H&E staining of mouse intestines after treatment as described in A is shown. V, villi; C, crypt. Yellow and white arrows indicate crypt base columnar and paneth cells, respectively (Li B et al. Science Signaling, 2017).
Figure 3: Mechanisms depicting the importance of CK1α upon Wnt pathway activation. A. Differential abundance of CK1α provides selectivity for pharmacological CK1α activators to target WNT-dependent tumors (Li B et al. Science Signaling, 2017). B. The E3 ubiquitin ligase component, Cereblon (CRBN), targets CK1α for degradation upon Wnt activation, representing a mechanism of differential abundance of CK1α driven by Wnt signaling in cells (Shen C et al. Nature Communications, 2021).
Project 2: Sonic hedgehog signaling in brain tumors
Elucidate mechanisms underlying the genesis of Shh-driven medulloblastoma.
Identify novel, druggable targets in Shh-driven medulloblastoma.
Figure 1. A schematic of the Sonic Hedgehog signaling pathway
Figure 2: A CK1α activator, SSTC3, and a BET inhibitor, I-BET151, attenuate the growth of Shh-driven medulloblastoma. A. Mice carrying an orthotopically implanted medulloblastoma PDX, TB-14-7196, were treated with vehicle or SSTC3 (10 mg/kg i.p in DMSO) every other day for 30 days and medulloblastoma symptom-free survival monitored (n = 10) (Rodriguez-Blanco J et al. Clin Cancer Res, 2019). B. Ptch1+/−medulloblastoma tissue was subcutaneously implanted into immunodeficient mice (n = 5 for vehicle group and n = 6 for experimental group). When the tumor size reached ∼200 mm3, the mice were treated with 30 mg/kg of I-BET151 or DMSO. Tumor volume was measured daily (Long J et al. J Biol Chem, 2014). * p value < 0.05.
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