The Christie Lab seeks to understand how ovarian and endometrial cancers evolve to become resistant to treatment, develop biomarkers of treatment response and identify treatments that can overcome resistance.
Acquired treatment resistance, whereby patients respond well to primary treatment but eventually develop drug resistance, is common across a range of cancer types. It is particularly problematic in the most common form of ovarian cancer, high-grade serous ovarian cancer, and high-risk endometrial cancer.
The Christie Lab seeks to:
- Identify the mechanisms of acquired treatment resistance that arise in high-grade serous ovarian cancer and high-risk endometrial cancer.
- Identify treatments that can overcome resistance.
- Develop tumour-based and circulating tumour DNA biomarkers of resistance.
- Understand the metastatic processes that occur in high-grade serous ovarian cancer.
Research projects
Understanding acquired resistance, disease evolution, and tumour heterogeneity
Through genomic analysis of recurrent and end-stage tumour samples from high-grade serous ovarian cancer patients, we have identified a number of acquired resistance mechanisms that arise. However, we have not yet identified resistance mechanisms in all of the samples we have studied, and many of the resistance mechanisms are subclonal, meaning there are cells within the tumour that do not have a resistance mechanism. This project involves further molecular analysis of tumour samples to identify additional mechanisms of resistance, to evaluate interactions of cells with different resistance mechanisms within the tumour, and to understand how the tumour evolves under the selective pressure of treatment. Using functional genomics, we are also investigating treatment strategies to overcome the different resistance mechanisms we identify.
Developing biomarkers of resistance in ovarian and endometrial cancer
Using our molecular data from primary and recurrent tumour samples, we are investigating biomarkers that may be used to guide treatment in ovarian and endometrial cancer. Additionally, we are examining blood-based biomarkers, in particular circulating tumour DNA (ctDNA), to determine if detection of resistance-causing mutations can be used as a biomarker to track the emergence of resistance which may also be useful for personalising therapy in recurrent disease. We are evaluating a unique cohort of serially collected blood samples to compare detection of mutations in ctDNA to tumour burden and response to different treatments.
Understanding metastatic spread in ovarian cancer
Metastasis is the process of cancer cells spreading to different parts of the body through the bloodstream. High-grade serous ovarian cancer primarily spreads to organs within the abdomen without entering the circulation. Even when a patient with high-grade serous ovarian cancer has extensive disease, metastasis via the bloodstream to distant organs, such as the lungs or brain, is uncommon. This is a unique feature of high-grade serous ovarian cancer and is in contrast to other cancers, such as breast or colorectal cancer, where metastatic spread to distant organs such as the liver, lung, brain or bone is frequently seen. We are seeking to understand why some patients with high-grade serous ovarian cancer will develop distant metastatic disease, as these patients have a poorer prognosis than those with abdominally confined disease.
People
Key publications
Pishas KI, Cowley KJ, Pandey A, Hoang T, Beach JA, Luu J, Vary R, Smith LK, Shembrey CE, Rashoo N, White MO, Simpson KJ, Bild A, Griffiths JI, Cheasley D, Campbell I, Bowtell DDL, Christie EL. Phenotypic consequences of SLC25A40-ABCB1 fusions beyond drug resistance in high-grade serous ovarian cancer. Cancers (Basel). 2021 Nov 11;13(22):5644.
Christie EL, Pattnaik S, Beach J, Copeland A, Rashoo N, Fereday S, Hendley J, Alsop K, Brady SL, Lamb G, Pandey A, deFazio A, Thorne H, Bild A, Bowtell DDL. Multiple ABCB1 transcriptional fusions in drug resistant high-grade serous ovarian and breast cancer. Nat Commun. 2019 Mar 20;10(1):1295.
Christie EL, Fereday S, Doig K, Pattnaik S, Dawson SJ, Bowtell DDL. Reversion of BRCA1/2 germline mutations detected in circulating tumor DNA from patients with high-grade serous ovarian cancer. J Clin Oncol. 2017 Apr 20;35(12):1274-1280.
Patch AM, Christie EL, Etemadmoghadam D, Garsed DW, George J, Fereday S, Nones K, Cowin P, Alsop K, Bailey PJ, Kassahn KS, Newell F, Quinn MC, Kazakoff S, Quek K, Wilhelm-Benartzi C, Curry E, Leong HS; Australian Ovarian Cancer Study Group, Hamilton A, Mileshkin L, Au-Yeung G, Kennedy C, Hung J, Chiew YE, Harnett P, Friedlander M, Quinn M, Pyman J, Cordner S, O'Brien P, Leditschke J, Young G, Strachan K, Waring P, Azar W, Mitchell C, Traficante N, Hendley J, Thorne H, Shackleton M, Miller DK, Arnau GM, Tothill RW, Holloway TP, Semple T, Harliwong I, Nourse C, Nourbakhsh E, Manning S, Idrisoglu S, Bruxner TJ, Christ AN, Poudel B, Holmes O, Anderson M, Leonard C, Lonie A, Hall N, Wood S, Taylor DF, Xu Q, Fink JL, Waddell N, Drapkin R, Stronach E, Gabra H, Brown R, Jewell A, Nagaraj SH, Markham E, Wilson PJ, Ellul J, McNally O, Doyle MA, Vedururu R, Stewart C, Lengyel E, Pearson JV, Waddell N, deFazio A, Grimmond SM, Bowtell DD. Whole-genome characterization of chemoresistant ovarian cancer. Nature. 2015 May 28;521(7553):489-94. Erratum in: Nature. 2015 Nov 19;527(7578):398.
