Dimitrios Iliopoulos, PhD, MBA

Senior Scientific Advisor & Board Member

135
Academic Publications

Lysine methyltransferase 2D regulates pancreatic carcinogenesis through metabolic reprogramming. Gut 68(7):1271-1286, 2019.

Summary:
We define a new antitumorous function of the histone lysine (K)-specific methyltransferase 2D (KMT2D) in pancreatic cancer. KMT2D is transcriptionally repressed in human pancreatic tumours through DNA methylation. Clinically, lower levels of this methyltransferase associate with poor prognosis and significant weight alterations. RNAi-based genetic inactivation of KMT2D promotes tumour growth and results in loss of H3K4me3 mark. In addition, KMT2D inhibition increases aerobic glycolysis and alters the lipidomic profiles of pancreatic cancer cells. Further analysis of this phenomenon identified the glucose transporter SLC2A3 as a mediator of KMT2D-induced changes in cellular, metabolic and proliferative rates.

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The IBD interactome: an integrated view of aetiology, pathogenesis and therapy.  Nat Rev Gastroenterol Hepatol. 14(12):739-749, 2017.

Summary:
Crohn’s disease and ulcerative colitis are prototypical complex diseases characterized by chronic and heterogeneous manifestations, induced by interacting environmental, genomic, microbial and immunological factors. These interactions result in an overwhelming complexity that cannot be tackled by studying the totality of each pathological component (an ‘-ome’) in isolation without consideration of the interaction among all relevant -omes that yield an overall ‘network effect’. The outcome of this effect is the ‘IBD interactome’, defined as a disease network in which dysregulation of individual -omes causes intestinal inflammation mediated by dysfunctional molecular modules. To define the IBD interactome, new concepts and tools are needed to implement a systems approach; an unbiased data-driven integration strategy that reveals key players of the system, pinpoints the central drivers of inflammation and enables development of targeted therapies. Powerful bioinformatics tools able to query and integrate multiple -omes are available, enabling the integration of genomic, epigenomic, transcriptomic, proteomic, metabolomic and microbiome information to build a comprehensive molecular map of IBD. This approach will enable identification of IBD molecular subtypes, correlations with clinical phenotypes and elucidation of the central hubs of the IBD interactome that will aid discovery of compounds that can specifically target the hubs that control the disease.

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Results of the Seventh Scientific Workshop of ECCO: Precision medicine in IBD – what, why, and how. J Crohns Colitis. jjab051, 2021.

Summary:
Many diseases that affect modern humans fall in the category of complex diseases, thus called because they result from a combination of multiple aetiological and pathogenic factors. Regardless of the organ or system affected, complex diseases present major challenges in diagnosis, classification, and management. Current forms of therapy are usually applied in an indiscriminate fashion based on clinical information, but even the most advanced drugs only benefit a limited number of patients and to a variable and unpredictable degree. This ‘one measure does not fit all’ situation has spurred the notion that therapy for complex disease should be tailored to individual patients or groups of patients, giving rise to the notion of ‘precision medicine’ [PM]. Inflammatory bowel disease [IBD] is a prototypical complex disease where the need for PM has become increasingly clear. This prompted the European Crohn’s and Colitis Organisation to focus the 7 th Scientific Workshop on this emerging theme. The articles in this special issue of the Journal address the various complementary aspects of PM in IBD, including what is PM; why it is needed and how it can be used; how PM can contribute to prediction and prevention of IBD; how IBD PM can aid in prognosis and improve response to therapy; and the challenges and future directions of PM in IBD. This first article of this series is structured on three simple concepts [what, why, and how] and addresses the definition of PM, discusses the rationale for the need of PM in IBD, and outlines the methodology required to implement PM in IBD in a correct and clinically meaningful way.

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Assessment of Circulating MicroRNAs for the Diagnosis and Disease Activity Evaluation in Patients with Ulcerative Colitis by Using the Nanostring Technology. Inflamm Bowel Dis 21(11):2533-9, 2015.

Summary:

We have identified a signature of 12 circulating microRNAs that differentiate patients with UC from control subjects. Moreover, 6 of these microRNAs significantly correlated with UC disease activity. Importantly, a set of 4 microRNAs (hsa-miR-4454, hsa-miR-223-3p, hsa-miR-23a-3p, and hsa-miR-320e), which correlated with UC disease activity were found to have higher sensitivity and specificity values than C-reactive protein. Circulating microRNAs provide a novel diagnostic and prognostic marker for patients with UC. The use of an FDA-approved platform could accelerate the application of microRNA screening in a gastrointenstinal clinical setting. When used in combination with current diagnostic and disease activity assessment modalities, microRNAs could improve both IBD screening and care management.

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MicroRNA-124 regulates STAT3 expression and is down-regulated in colon tissues of pediatric patients with ulcerative colitis. Gastroenterology 145(4):842-52.e2, 2013.

Summary:
miR-124 appears to regulate the expression of STAT3. Reduced levels of miR-124 in colon tissues of children with active UC appear to increase expression and activity of STAT3, which could promote inflammation and the pathogenesis of UC in children. Thus, the activation of miR-124 could have a therapeutic potential in IBD patients.

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Weiqi Sun, PhD

Vice President of AI Research

18
Academic Publications

Unfreeze with Care: Space-Efficient Fine-Tuning of Semantic Parsing Models

 

Summary:

Semantic parsing is a key NLP task that maps natural language to structured meaning representations. As in many other NLP tasks, SOTA performance in semantic parsing is now attained by fine-tuning a large pretrained language model (PLM). While effective, this approach is inefficient in the presence of multiple downstream tasks, as a new set of values for all parameters of the PLM needs to be stored for each task separately. Recent work has explored methods for adapting PLMs to downstream tasks while keeping most (or all) of their parameters frozen. We examine two such promising techniques, prefix tuning and bias-term tuning, specifically on semantic parsing. We compare them against each other on two different semantic parsing datasets, and we also compare them against full and partial fine-tuning, both in few-shot and conventional data settings. While prefix tuning is shown to do poorly for semantic parsing tasks off the shelf, we modify it by adding special token embeddings, which results in very strong performance without compromising parameter savings.

 

 

Compositional Task-Oriented Parsing as Abstractive Question Answering

 

Summary:

Task-oriented parsing (TOP) aims to convert natural language into machine-readable representations of specific tasks, such as setting an alarm. A popular approach to TOP is to apply seq2seq models to generate linearized parse trees. A more recent line of work argues that pretrained seq2seq2 models are better at generating outputs that are themselves natural language, so they replace linearized parse trees with canonical natural-language paraphrases that can then be easily translated into parse trees, resulting in so-called naturalized parsers. In this work we continue to explore naturalized semantic parsing by presenting a general reduction of TOP to abstractive question answering that overcomes some limitations of canonical paraphrasing. Experimental results show that our QA-based technique outperforms state-of-the-art methods in full-data settings while achieving dramatic improvements in few-shot settings.

Allan J. Pantuck, MD

Senior Medical Advisor

268
Academic Publications

Carbonic anhydrase-IX score is a novel biomarker that predicts recurrence and survival for high-risk, nonmetastatic renal cell carcinoma: Data from the phase III ARISER clinical trial. Urol Oncol 33(5):204.e25-33, 2015.

Summary: 

The largest, multicenter, prospective analysis of patients with high-risk nonmetastatic ccRCC demonstrates the utility of CAIX score as a statistically significant prognostic biomarker for survival. It recommends that CAIX score be quantified for all patients with high-risk disease after nephrectomy.

 

Clinical, molecular, and genetic correlates of lymphatic spread in clear cell renal cell carcinoma. Eur Urol. 61(5):888-95, 2012.

Summary:

predictive model consisting of smoking history (p=0.040), T stage (p<0.0001), Fuhrman grade (p<0.0001), Eastern Cooperative Oncology Group performance status (p<0.0001), and microvascular invasion (p<0.0001) was independently associated with lymphatic spread. After adjustment with these clinical variables, low carbonic anhydrase IX (CAIX) (p=0.043) and high epithelial vascular endothelial growth factor receptor 2 (p=0.033) protein expression were associated with a higher risk of lymphatic spread, and loss of chromosome 3p (p<0.0001) with a lower risk.

 

Smoking negatively impacts renal cell carcinoma overall and cancer-specific survival. Cancer. 1;118(7):1795-802, 2012. 

Summary:

In patients with RCC, a history of smoking was associated with worse pathologic features and survival outcomes and with an increased risk of having mutated p53. Further investigation of the genetic and molecular mechanisms associated with decreased CSS in patients with RCC who have a history of smoking is indicated.

 

Carbonic anhydrase IX in bladder cancer: a diagnostic, prognostic, and therapeutic molecular marker. Cancer, 115(7):1448-58, 2009.

Summary:

CAIX was expressed differentially in noninvasive versus invasive tumors, in low-grade versus high-grade bladder cancer, and in primary tumors versus metastases. The current results indicated that CAIX is a strong predictor of recurrence, progression, and overall survival of patients with bladder cancer; and the integration of CAIX expression into conventional prognostic models significantly improved their predictive accuracy. The data suggest a tripartite role of CAIX as a diagnostic, prognostic, and therapeutic molecular marker in bladder cancer.

 

Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. N Engl J Med,375(23):2246-2254, 2016. 

Summary:

Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic events.

Athanasios Papatsoris, MD PhD

Senior Medical Advisor

203
Academic Publications

An up-to-date evaluation of darolutamide for the treatment of prostate cancer. Expert Opin Pharmacother. 22(4):397-402, 2021.

Summary:

The unique structure of darolutamide is characterized by a high affinity for androgen receptors and detainment of antagonist activity in mutant isoforms of androgen receptors. In clinical practice, this is the main reason that makes darolutamide exceptional in terms of safety and efficacy compared to other drugs in this category. Darolutamide is considered to have the lowest probability for adverse events (AEs) compared to apalutamide and enzalutamide. Future studies, along with real-world clinical data are warranted to improve personalized treatment strategies as well as sequencing treatment between approved novel drugs.

 

Risk for Venous Thromboembolic Events in Patients With Advanced Urinary Tract Cancer Treated With First-Line Chemotherapy. Clin Genitourin Cancer. 18(4):e457-e472,  2020.

Summary:

Development of tumor-specific algorithms for the risk of VTEs is advisable. Patients with aUTC and a history of vascular events are at high risk for VTE development, and prophylaxis should be prospectively studied in this group. 

 

Perspectives on the current and emerging chemical androgen receptor antagonists for the treatment of prostate cancer. Expert Opin Pharmacother. 20(2):163-172, 2019.

Summary:

Prostate cancer is the most common cancer in men. Regardless of the initial treatment of localized disease, almost all patients develop castration resistant prostate cancer (CRPC). A better understanding of the molecular mechanisms behind castration resistance has led to the approval of novel oral androgen receptor (AR) antagonists, such as enzalutamide and apalutamide. Indeed, research has accelerated with numerous agents being studied for the management of CRPC. Areas covered: Herein, the authors present currently used and emerging AR antagonists for the treatment of CRPC. Emerging agents include darolutamide, EZN-4176, AZD-3514, and AZD-5312, apatorsen, galeterone, ODM-2014, TRC-253, BMS-641988, and proxalutamide. Expert opinion: Further understanding of the mechanisms leading to castration resistance in prostate cancer can reveal potential targets for the development of novel AR antagonists. Current novel agents are associated with modest clinical and survival benefit, while acquired resistance and safety issues are under continuous evaluation. The combination of AR antagonists used and ideal sequencing strategies are key tasks ahead, along with the investigation of molecular biomarkers for future personalized targeted therapies. In the future, the challenge will be to determine an AR antagonist with the best combination of outcome and tolerability.

 

Expression and prognostic significance of VEGF and mTOR pathway proteins in metastatic renal cell carcinoma patients: a prognostic immunohistochemical profile for kidney cancer patients. World J Urol 35(3):411-419, 2017.

Summary:

The aim of the study was to identify prognostic molecular profiles in patients with mRCC treated with sunitinib, we performed immunohistochemical analysis for VEGF and PI3K/Akt/mTOR pathway components. Immunohistochemistry for VEGF and p-mTOR proteins may discriminate patients refractory to first-line sunitinib with poor prognosis.

 

Phase I and II therapies targeting the androgen receptor for the treatment of castration resistant prostate cancer. Expert Opin Investig Drugs 25(6):697-707, 2016. 

Summary:

Further understanding of the mechanisms leading to castration resistance in prostate cancer can reveal potential targets for the development of novel anti-cancer agents. Except for the development of novel antiandrogens and CYP-17 modulators, bipolar androgen therapy is an interesting therapeutic approach. The combinations of the novel agents tested in Phase I and II studies with established agents is another field of interest. The real challenge is to distinguish a novel anti-cancer agent with acceptable tolerability and the best outcome.