Study level

  • PhD

Faculty/School

Faculty of Health

School of Biomedical Sciences

Topic status

We're looking for students to study this topic.

Research centre

Supervisors

Professor Tony Kenna
Position
Professor
Division / Faculty
Faculty of Health
Associate Professor Pamela Pollock
Position
Associate Professor
Division / Faculty
Faculty of Health

External supervisors

  • Dr Nic Waddell (QIMR)
  • Dr David Gallego-Ortega (Garvin)

Overview

FGFR2 encodes two alternatively spliced isoforms that differ in their ligand binding domain and the combination of tissue specific expression of these isoforms and tissue specific expression of the FGF ligands is the foundation of normal paracrine signalling. Isoform switching from FGFR2b (inclusion of exon 8) to FGFR2c (inclusion of exon 9) occurs in tumorigenesis as it establishes an autocrine loop in epithelial cancer cells. Our lab has reported that FGFR2 activation by mutations or isoform switching is associated with aggressive clinical features and decreased survival in endometrial cancer (EC) [1]. Activated FGFR2 signalling has also been reported to orchestrate an immunosuppressive tumour microenvironment (TME) and FGFRi in combination with PD-1 inhibition (PD-1i) has led to marked tumour regressions and improved long term survival compared to either treatment alone in a transgenic mouse lung cancer model [2].

References:

1. Sengal, et al., FGFR2c mesenchymal isoform expression is associated with poor prognosis and further refines risk stratification within endometrial cancer molecular subtypes. 2020. Clin Cancer Res, doi:10.1158/1078-0432.CCR-19-4088.

2. Palakurthi, et al., The Combined Effect of FGFR Inhibition and PD-1 Blockade Promotes Tumor-Intrinsic Induction of Antitumor Immunity. 2019. Cancer Immunol Res, 7: 1457-1471.

Aims and hypotheses

We hypothesise that 1) in addition to driving EC cell proliferation and survival, FGFR2 activation modulates the expression of downstream cytokines that increase the number, migration or activation status of myeloid derived cell types and 2) that the combination of FGFR inhibition (FGFRi) and PD-1 inhibitors will be more effective than either alone.

  1. Demonstrate FGFR2c+ PDX models are sensitive to FGFRi in vivo in hu-mice and perform immunophenotyping by scRNA-seq to identify immune cell changes after FGFRi
  2. Validate the combination of FGFRi with PD-1i in a FGFR2c PDX model in hu-mice leads to deeper and more durable tumour regression and improved survival.

Approaches/skills and techniques

  • Establishing, measuring and drugging in vivo patient derived xenograft models.
  • Single cell RNA sequencing.
  • Collaboration with bioinformatic experts.
  • Immunoprofiling using FACs and multiplex IHC.
  • Data management and presentation.
  • Statistical analysis.
  • Written and oral communication skills.

Expected outcomes

We expect to see significant changes in tumour size and longer survival in hu-mice receiving an FGFR inhibitor and we expect to see changes in multiple myeloid derived cell types. From Aim 2, we expect highly significant results regarding the improved efficacy of FGFRi + PD-1i compared to FGFRi alone. This project is highly translational and will provide essential preclinical data to support a biomarker driven clinical trial of an FGFRi and a PD-1/PD-L1i in endometrial cancer.

Keywords

Contact

pamela.pollock@qut.edu.au