Guest lecture by Kirsi Ketola
Ph.D. Kirsi Ketola has trained in systems biology and medical biotechnology as well as in biochemistry and drug discovery. The title of her talk is 'Tumour cell plasticity and cancer stem cell - neuroendocrine transdifferentiation as a resistance mechanism and therapeutic target in advanced prostate cancer'.
Kirsi Ketola (Photo: private)
Kirsi Ketola is a Postdoctoral Fellow at the University of British Columbia, Vancouver Prostate Centre. Her current research interests include utilizing the knowledge of the “-omics” in designing novel treatment options for cancer and the use of state-of-the-art high-throughput technologies to identify novel targets and to repurpose old drugs for cancer treatment. A goal is also to find better ways to utilize current genome-wide technologies in designing personalized treatment options.
Prostate cancer is the second leading cause of cancer death in Western world due to the wide development of resistance even on the era of second-line antiandrogenic therapies like Enzalutamide (ENZ). Thus, the rapid recurrence underscores the need for improved therapies. Resistance to castration and ENZ has been described to occur via reactivation of androgen receptor (AR) signalling via overexpression or mutation of AR. However, heterogeneity in resistance is seen and there are no targetable pathways identified in non-AR mediated resistance to ENZ. Recent evidence suggests that continued androgen-deprivation therapy may promote the emergence of more aggressive tumor cell types, including stem cells (CSC) or neuroendocrine (NE)-like cells. The survival time for prostate cancer patients with NE disease is less than 12 months.
We generated xenograft models of ENZ resistance in our laboratory and explored master regulators activated and enriched gene sets to identify genome-wide changes and novel targetable pathways and inhibitors for non-AR mediated ENZ resistance. The systems biology results obtained were validated by qRT-PCR, flow cytometric analysis, protein expression levels in vitro and in vivo as well as in prostate cancer patient tumors. The results revealed FOXM1 as a major pathway activated in ENZ resistant cells. Moreover, Hedgehog-Gli1 and Wnt developmental pathways, which govern stemness as well as NE differentiation markers were upregulated in non-AR driven cells suggesting these pathways may regulate phenotypic plasticity that emerges during treatment resistance. Targeting FOXM1 with a novel FOXM1 binding agent reduced the pathway activity and cancer stem cell properties that were identified as upregulated in ENZ resistant cells in vitro and in vivo. FOXM1 pathway was seen particularly upregulated in prostate cancer patients with high Gleason score and low androgen response suggesting FOXM1 targeting as a potent way to target high-risk disease. Furthermore, upregulated pathways included Brn2 and EZH2 that were validated as drivers of neuroendocrine transdifferentiation in prostate cancer.
Taken together, our data indicates that ENZ resistant cells are associated with phenotypic plasticity leading to activation of pluripotency and NE differentiation programs in subsets of cancer cells that promote progression of resistant disease. The results revealed FOXM1 pathway as a novel target in a subset of non-AR mediated ENZ resistant prostate cancer cells displaying cancer stem cell features and targeting FOXM1 pathway reduced cancer stem cell phenotype in vitro and in vivo. In conclusion, the results revealed that elucidating the molecular mechanisms that govern aggressive cell phenotypes, and establishing their importance in prostate disease progression, may guide clinical evaluation of compounds targeting cellular phenotypic plasticity associated with ENZ and castration resistant prostate cancer to improve current standard of care.