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Biology subjects

Gilks, C. B.

Publications and source records attributed to Gilks, C. B..

3 recordsLinked to original sources

Synthesis of diagnostic quality cancer pathology images

Deep learning-based computer vision methods have recently made remarkable breakthroughs in the analysis and classification of cancer pathology images. However, there has been relatively little investigation of the utility of deep neural networks to synthesize medical images. In this study, we evaluated the efficacy of generative adversarial networks (GANs) to synthesize high resolution pathology images of ten histological types of cancer, including five cancer types from The Cancer Genome Atlas (TCGA) and the five major histological subtypes of ovarian carcinoma. The quality of these images was assessed using a comprehensive survey of board-certified pathologists (n = 9) and pathology trainees (n = 6). Our results show that the real and synthetic images are classified by histotype with comparable accuracies, and the synthetic images are visually indistinguishable from real images. Furthermore, we trained deep convolutional neural networks (CNNs) to diagnose the different cancer types and determined that the synthetic images perform as well as additional real images when used to supplement a small training set. These findings have important applications in proficiency testing of medical practitioners and quality assurance in clinical laboratories. Furthermore, training of computer-aided diagnostic systems can benefit from synthetic images where labeled datasets are limited (e.g., rare cancers). We have created a publicly available website where clinicians and researchers can attempt questions from the image survey at http://gan.aimlab.ca/.

bioinformatics↗

Arginine depletion through ADI-PEG20 to treat argininosuccinate synthase deficient ovarian cancer, including small cell carcinoma of the ovary, hypercalcemic type

PurposeMany rare ovarian cancer subtypes such as small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) have poor prognosis due to their aggressive nature and resistance to standard platinum and taxane based chemotherapy. The development of effective therapeutics has been hindered by the rarity of such tumors. We sought to identify targetable vulnerabilities in rare ovarian cancer subtypes. Experimental DesignWe compared the global proteomic landscape of six cases each of endometrioid ovarian cancer (ENOC), clear cell ovarian cancer (CCOC), and SCCOHT to the most common subtype high grade serous ovarian cancer (HGSC) to identify potential therapeutic targets. Immunohistochemistry of tissue microarrays were used as validation of ASS1 deficiency. The efficacy of arginine-depriving therapeutic ADI-PEG20 was assessed in vitro using cell lines and patient derived xenograft mouse models representing SCCOHT. ResultsGlobal proteomic analysis identified low ASS1 expression in ENOC, CCOC, and SCCOHT compared to HGSC. Low ASS1 levels were validated through IHC in a large patient cohort. The lowest levels of ASS1 were observed in SCCOHT, where ASS1 was absent in 2/15 cases, and expressed in less than 5% of the tumor cells in 8/15 cases. ASS1 deficient ovarian cancer cells were sensitive to ADI-PEG20 treatment regardless of subtype in vitro. Furthermore, in two cell line mouse xenograft models and one patient derived mouse xenograft model of SCCOHT, once a week treatment of ADI-PEG20 (30mg/kg and 15mg/kg) inhibited tumor growth in vivo. ConclusionsPreclinical in vitro and in vivo studies identified ADI-PEG20 as a potential therapy for patients with rare ovarian cancers including SCCOHT. Translational relevanceMany rare ovarian cancers lack effective management strategies and are resistant to the standard platinum- and taxane-based chemotherapy. Thus, for a rare ovarian cancer subtype like small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) - an aggressive malignancy affecting young women in their twenties, effective targeted therapeutics are urgently needed. We used global proteomics to identify a deficiency in arginosuccinate synthase (ASS1) as a common feature among some rare ovarian cancer subtypes. Using in-vitro and in-vivo models, we demonstrated that the arginine-depriving investigational agent ADI-PEG20 effectively inhibited cell growth in ASS1 deficient ovarian cancers including SCCOHT, establishing it as a potential therapeutic agent for rare ovarian cancer subtypes deficient in ASS1. Further clinical investigation is warranted.

cancer biology↗

The interface of malignant and immunologic clonal dynamics in high-grade serous ovarian cancer

High-grade serous ovarian cancer exhibits extensive intratumoral heterogeneity coupled with widespread intraperitoneal disease. Despite this, metastatic spread of tumor clones is non-random, implying the existence of local microenvironmental factors that shape tumor progression. We interrogated the molecular interface between tumor-infiltrating lymphocytes (TIL) and cancer cells in 143 samples from 21 patients using whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T- and B-cell receptor sequencing. We identify 3 immunologic response categories, which frequently co-exist within individual patients. Furthermore, epithelial CD8+ TIL were inversely associated with malignant cell diversity, evidenced by subclonal neoepitope elimination and spatial tracking between tumor and T-cell clones. Intersecting mutational signatures and immune analysis showed that foldback inversion genomic aberrations lead to worse outcomes even in the presence of cytotoxic TIL (n=433). Thus, regional variation in immune contexture mirrors the pattern of intraperitoneal malignant spread, provoking new perspectives for treatment of this challenging disease.

cancer biology↗