Casein Kinase-1 Epsilon as a Novel Therapeutic Target Against Small Cell Lung Cancer
Abstract
The Area(s) of Emphasis are to understand the molecular mechanisms of initiation and progression to lung cancer and identify innovative strategies for the treatment of lung cancer. Lung cancer is the second most common cancer in humans. Among different subtypes of lung cancers, small cell lung cancer (SCLC) is the most aggressive subtypes, defined by rapid growth, high rate of metastasis, and resistance to existing therapies. Due to very limited therapeutic options available and a high chance of recurrence, the death rate is very high in SCLC patients compared to other subtypes of lung cancer. Although chemotherapy treatment shrinks the tumor at first, the residual tumor often regrows with acquired resistance to chemotherapies. A minor sub-population of tumor cells in SCLC, known as cancer stem cells (CSCs), are resistant to chemotherapy. Therefore, novel therapeutic strategies capable of targeting CSCs might act in synergy to chemotherapy and regress tumors. A recent study has shown that Casein Kinase-1 epsilon (CK1e) is specifically upregulated in intestinal stem cells and is required for the maintenance of these cells. CK1e is also a well-established positive regulator of Wnt/ß-Catenin signaling pathway. Activation of Wnt and ß-Catenin proteins accelerates tumor progression and CSCs’ activity in different cancers, including SCLC. Our initial data show that levels of CK1e are specifically higher in SCLC patient tumors compared to other type of lung cancers and normal lungs. In this proposal, we will define the role of CK1e in SCLC progression using genetically engineered cell lines expressing more CK1e and analyzing them for rate of cell growth in a petri dish or inside a mouse. We will also evaluate whether chemical inhibitor of CK1e umbralisib alone or in combination with chemotherapy treatment inhibits the growth of SCLC tumors spontaneously developed or implanted into the mice. Umbralisib is safe for human use, well tolerated, and FDA-approved for the treatment of lymphoma. We will further evaluate the effect of umbralisib on inhibiting Wnt/ß-Catenin-mediated molecular mechanisms to suppress the CSCs’ activities. In the short term, these studies will provide the novel information about the role of CK1e in SCLC growth and progression. These studies will also define the preclinical potential of CK1e inhibitor alone or in combination with chemotherapy against SCLC. In the long term, these studies will provide valuable insight for the development of innovative combination therapy regimes against chemotherapy refractory SCLC. The use of FDA-approved umbralisib will help in its quick transition from laboratory to clinics. Due to exposure of environmental carcinogens and tobacco smoking, lung cancer incidence is higher and survival rate is lower in military personnel compared to civilians. SCLC tends to recur earlier with acquired resistance to chemotherapy, resulting in the shortest survival among different lung cancer subtypes. These studies will have a short-term as well as long-term effect for military personnel and beneficiaries by overcoming drug resistance observed in deadly SCLC disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210001
Entities
People
- Dinesh Ahirwar
Organizations
- Indian Institute of Technology Jodhpur
- United States Army