Targeting Cancer Stem Cells with a Novel Glycolytic Inhibitor to Overcome Metastasis and Chemoresistance in Small Cell Lung Cancer
Abstract
We will address the critical topic area "understand susceptibility or resistance to chemotherapy" in patients with small cell lung cancer (SCLC). Most patients with SCLC succumb to their disease within about 2 years. Although initially responsive to chemotherapy with cisplatin alone or in combination with either etoposide or irinotecan, almost all patients develop highly metastatic disease, which is thought to arise from cancer stem cells (CSC), also contributing to chemoresistance; patients typically recur within 6-12 months. Cancer is now considered as a stem cell disease. Determining the role of CSC metabolism in carcinogenesis has become a leading focus in cancer research, and substantial efforts are directed to explore new clinical targets. However, conventional chemotherapy alone has little effect in eradicating the CSC population. To date, there are no reports on the effects of targeting the glycolytic pathway on CSC in SCLC. Thus, we believe a better understanding of the properties and mechanisms underlying CSC resistance is imperative. A promising approach to improving patient survival is to identify novel drugs that target CSC markers and/or associated signaling pathways in order to eradicate SCLC. In this regard, recent studies have shown that PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 , PFK2), a critical enzyme in the glycolytic pathway where cancer cells consume glucose to generate energy in the form of ATP, is overexpressed in several tumor types. Increased expression of PFKFB3 has been shown to be present in a cancer stem cell compartment in the tumors. PFK158 (PFKi), a novel glycolytic inhibitor that specifically targets PFKFB3, is currently in Phase 1 clinical trials (Clinical Trias.gov Identifier: NCT02044861). We have generated preliminary data that targeting H1048 SCLC cell line with PFKi leads to downregulation of several CSC markers, CD133, CD44, and SOX-2, including the active form of PFKFB3, namely p-PFKFB3. The amplification of SOX2 in SCLC has an important role as a "lineage-specific oncogene" and targeting SOX-2 with this novel glycolytic inhibitor may reverse chemoresistance in SCLC. There are very few targeted therapies being tested in SCLC clinical trials. Given the importance of CSC in chemoresistance and metastasis, new CSC-targeting compounds appear to be a promising strategy to prevent cancer recurrence and metastasis. We hypothesize that treatment of SCLC with PFKi alone, as well as in combination with platinum-based drugs, will result in better response rates via targeting the CSC population. We have proposed to test the effect of this drug using various molecular approaches both in the tissue culture setting and in a preclinical mouse model. We believe that the successful completion and validation of our work on downregulation of CSC markers in vivo will further provide us with biomarkers of response to PFKi alone and in combination with standard chemotherapy to be tested in future clinical trials that will ultimately lead to improving patient outcomes. There is an indisputable link between all three factors, cigarette smoking, carbon nanotubes inhalation (which poses the same health risks as asbestos exposure and is currently heavily used in the production of tablets, phones, and solar panels), and radon exposure to CSC induction and SCLC development. All three factors are relevant to military personnel who are exposed to radon and environmental pollution and carbon nanotubes inhalation. While the US national average for smoking in civilians is only 19.4%, it is up to 32.2% for military personnel. Deployment results in further increase in smoking. US troops in Iraq and Afghanistan have been reported to smoke at a rate two times higher than the average American citizen. These statistics illustrate how much greater the risk is of developing SCLC among the military population (https://smokingjacketmagazine.com). Our proposed experiments to test the effe
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810504
Entities
People
- Vijayalakshmi Shridhar
Organizations
- Mayo Clinic
- United States Army