Lay Summary: Ovarian cancers have historically suffered from generic treatment and prevention approaches that do not account for biologic and clinical differences between subtypes and research conducted without consideration of histotype, making interpretation of results and knowledge translation challenging. Using this subtype-specific approach, one of the key areas of my research program is to prevent disease by studying precursor lesions of ovarian cancer.

Using genomic approaches, we are exploring the transformation events that lead to the transformation of endometriosis into clear cell and endometrioid cancers, the 2nd and 3rd most common ovarian cancer histotypes. The goal is to develop a risk model to identify women with endometriosis who are at increased risk of developing cancers. We are also studying the potential cells of origin for endometriosis-associated cancers through profiling the mutations found in ciliated and secretory cells of the endometrium.

Karnezis A, Cho R, Gilks B. Pearce CL, Huntsman DG .  The disparate origins of ovarian cancers: pathogenesis and prevention strategies.  Nature Reviews Cancer. 2017 Jan;17(1):65-74.  PMID 2788526

Lay summary: Accurate diagnosis forms the foundation of effective cancer care. A fundamental aspect of my research is to develop effective diagnostics to guide appropriate therapies for gynaecological cancers. We were one of the original advocates of studying and treating various histological subtypes of ovarian cancer as distinct diseases, both in research and clinically. Using this research, my laboratory discovered key mutations driving several ovarian cancers and rapidly translated these findings into clinical diagnostics.

Detailed Summary: In collaboration with the Proteomics Platform at the BC Cancer, we are using a proteomic-based strategy to develop and identify highly specific immunohistochemical markers to supplement standard pathology which can be more readily translated into global practice changes as compared to nucleic-acid based approaches. In particular, we are interested in studying the protein profiles to identify antibody targets that can discriminate between and accurately diagnose look-alike tumours, which will have an immediate positive impact on patient treatment.

The outcome for patients with advanced stage clear cell ovaria cancer (CCOC) has not changed in several decades. The inability to cure such advanced cancers is primarily due to resistance to platinum/taxane-based therapies of the disseminated disease. A lack of of understanding of the molecular mechanisms underlying recurrence and metastatic spread in these diseases is a major roadblock in the development of new effective treatment strategies. Therefore, there is an urgent need to identify and develop new therapeutics. In the proposed studies, the critical roles of a protein called CTH in CCOC spread, as well as the potential utility of its targeting will be determined. 

Metastatic dissemination of malignant cells is the hardest challenge facing clinicians treating cancer patients and it accounts for nearly ninety percent of cancer morality. Late stage clear cell ovarian cancer (CCOC) has a worse prognosis than other ovarian cancer histotypes, which is partially attributable to the more frequent metastasis of CCOC to distant organs compared to other types of epithelial ovarian cancer. Oxidative stress and perturbation in redox balance are common hallmarks of cancer progression. However, reactive oxygen species (ROS) must be kept under tight control to prevent ROS-induced toxicity. Alteration in redox-related genes is a hallmark of clear cell ovarian cancer (CCOC). Yet, it is unclear how CCOC adapts under oxidative stress and develops distant metastasis. CCOC, but not other subtypes of ovarian cancer, has been shown to express abundant levels of cystathionine γ-lyase (CTH), an enzyme required for the production of cysteine and glutathione, which is a key player in protecting against oxidative injury. Robust in vitro and new in vivo approaches will be used to investigate the role of CTH in conferring CCOC with aggressive behavior and its potential use as a therapeutic target in CCOC. This research could be the first to provide solid pre-clinical data on targeting CTH in CCOC. Furthermore, introducing new in vivo approaches to help understand the early steps of disease progression, and how stress adaptation confers metastatic advantage will provide a much-needed platform for future studies of targeting stress adaptive pathways in gynecological malignancies. This will eventually lead to improvements in cancer survival, improvements in patient quality of life, and ultimately resulting in alleviation of the economic burden imposed by such diseases.

Shah S, Köbel M, Senz J, Morin R, Wiegand K, Kalloger S, Sun M, Guiliany R, Yorida E, Swenerton K, Miller D, Clement P, Crane C, Madore J, Provencher D, Leung P, DeFazio A, Turashvili G, Zhao Y, Zeng T, Glover M, Vanderhyden B, Mes-Masson AM, Brenton J, Aparicio S, Boyd N, Hirst M, Gilks CB, Marra M and  Huntsman D. Mutation of FOXL2 in granulosa-cell tumors of the ovary. N Engl J Med. 2009; 360(26): 2719-29.  PMID: 19516027

Heravi-Moussavi A,  Anglesio MS,  Cheng SW,  Senz J,  Yang W,  Prentice L,  Fejes AP,  Chow C,  Tone A,  Kalloger SE,  Hamel N,  Roth A,  Ha G,  Wan AN,  Maines-Bandiera S,  Salamanca C,  Pasini B,  Clarke BA,  Lee AF,  Lee CH,  Zhao C,  Young RH,  Aparicio SA,  Sorensen PH,  Woo MM,  Boyd N,  Jones SJ,  Hirst M,  Marra MA,  Gilks B,  Shah SP,  Foulkes WD,  Morin GB,  Huntsman DG*.   Recurrent Somatic DICER1 Mutations in Nonepithelial Ovarian Cancers.  New England Journal of Medicine. 2012; 366(3): 234-42.  PMID: 22187960

McConechy MK, Färkkilä A, Horlings HM, Talhouk A, Unkila-Kallio L, van Meurs HS, Yang W, Rozenberg N, Andersson N, Zaby K, Bryk S, Bützow R, Halfwerk JB, Hooijer GK, van de Vijver MJ, Buist MR, Kenter GG, Brucker SY, Krämer B, Staebler A, Bleeker MC, Heikinheimo M, Kommoss S, Blake Gilks C, Anttonen M,  Huntsman DG.  Molecularly Defined Adult Granulosa Cell Tumor of the Ovary: The Clinical Phenotype.   J Natl Cancer Inst. 2016; 108(11) PMID:  27297428, PMCID: PMC5241905​

Cochrane, D. R., Tessier-Cloutier, B., Lawrence, K. M., Nazeran, T., Karnezis, A. N., Salamanca, C., Cheng, A. S., McAlpine, J. N., Hoang, L. N., Gilks, C. B., & Huntsman, D. G. (2017). Clear cell and endometrioid carcinomas: are their differences attributable to distinct cells of origin?. The Journal of pathology, 243(1), 26–36. https://doi.org/10.1002/path.4934

Ramos, P., Karnezis, A. N., Hendricks, W. P., Wang, Y., Tembe, W., Zismann, V. L., Legendre, C., Liang, W. S., Russell, M. L., Craig, D. W., Farley, J. H., Monk, B. J., Anthony, S. P., Sekulic, A., Cunliffe, H. E., Huntsman, D. G., & Trent, J. M. (2014). Loss of the tumor suppressor SMARCA4 in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). Rare diseases (Austin, Tex.), 2(1), e967148. https://doi.org/10.4161/2167549X.2014.967148