# Targeting chemotherapy resistant high grade serous ovarian cancer

> **NIH NIH F99** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $36,300

## Abstract

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 antiangiogen...

## Key facts

- **NIH application ID:** 10908705
- **Project number:** 5F99CA284284-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Behnam Ebrahimi
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $36,300
- **Award type:** 5
- **Project period:** 2023-08-16 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908705

## Citation

> US National Institutes of Health, RePORTER application 10908705, Targeting chemotherapy resistant high grade serous ovarian cancer (5F99CA284284-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10908705. Licensed CC0.

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