Sunday, May 18, 2025
5/18/2025
Identifying Mechanisms of Resistance to SLC6AB Inhibition in CRC Liver Metastasis - Project Summary Of all gynecologic cancers, ovarian cancer (OCa) has the highest mortality rate in the US. Patients with serous OCa respond to current treatments, including cytotoxic therapy and surgery. But about 90% of patients have recurrence, and they inevitably pass away from a disease that is chemoresistant. Leukemia inhibitory factor (LIF), a cytokine that belongs to the interleukin-6 family, and it signals through the glycoprotein 130 (gp130) and LIFR complex. My preliminary research using tumor online data bases revealed that LIF is strongly expressed in OCa compared to normal tissues, and expression levels of LIF and LIFR were significantly greater in chemotherapy non-responders as compared to responders. Further, my analyses of conditioned medium and cell lysates collected form 18 different OCa cells confirmed existence of autocrine loops of LIF and LIFR in OCa. However, the mechanisms and therapeutic utility of targeting LIFR axis to treat chemotherapy resistance remain unknown, representing a major knowledge gap and this premise will be tested in F99 phase. In F99 phase, I will test the hypothesis that disruption of LIF/LIFR signaling will sensitize resistant cells to chemotherapy, and maintenance therapy with LIFR inhibitor will delay chemotherapy resistance. Specifically, I will establish the significance and mechanisms of LIFR axis in promoting chemotherapy resistance in serous OCa cells using CRISPR KO and global genomic approaches. I will test the utility of LIFR inhibitor EC359 in treating/preventing development of chemotherapy resistance using patient derived organoid (PDO) and xenograft (PDX) models. The hypoxic circumstances that bigger tumors experience decrease chemotherapy response and are exacerbated by ascites. Hypoxia inducible factors (HIFs) are activated by cancer cells to stimulate vasculogenesis, control cell metabolism, and promote cell growth as a defense mechanism against hypoxic stress. Moreover, hypoxia transactivates two functional hypoxia responsive elements within LIF promoter and induces LIF expression. There is a relationship between OCa Stem Cells (CSCs) and tumor chemoresistance and recurrence. Antiangiogenic treatment resistance and chemoresistance of ovarian CSCs are both influenced by hypoxia. Together, these recent findings imply that the hypoxic tumor microenvironment increases the expression of HIFs, LIF, and efflux transporters, as well as development of chemoresistance in CSCs. In the K00 phase, I will expand my training into the area of hypoxia mediated stemness, epithelial mesenchymal transition (EMT) and therapy resistance. Specifically, I will define the mechanisms by which hypoxia and LIF/LIFR axis induce EMT and stemness and establish the significance of hypoxia-LIF/LIFR axis in the development of OCa resistance to targeted therapy. The proposed research in F99/K00 is clinically important because it will define the significance of LIFR axis in OCa progression, chemotherapy and antiangiogenic therapy resistance and establish LIFR as a novel therapeutic target for the treatment of OCa.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).