Process flow of identification of potential compounds for oral cancer treatment.

<p>Process flow of identification of potential compounds for oral cancer treatment.</p

Compound structures of potential compounds with supporting evidences about their activity against oral cancer.

<p>The name of compound with natural origin is distinctly highlighted with green color.</p

Potential Compounds for Oral Cancer Treatment: Resveratrol, Nimbolide, Lovastatin, Bortezomib, Vorinostat, Berberine, Pterostilbene, Deguelin, Andrographolide, and Colchicine

<div><p>Oral cancer is one of the main causes of cancer-related deaths in South-Asian countries. There are very limited treatment options available for oral cancer. Research endeavors focused on discovery and development of novel therapies for oral cancer, is necessary to control the ever rising oral cancer related mortalities. We mined the large pool of compounds from the publicly available compound databases, to identify potential therapeutic compounds for oral cancer. Over 84 million compounds were screened for the possible anti-cancer activity by custom build SVM classifier. The molecular targets of the predicted anti-cancer compounds were mined from reliable sources like experimental bioassays studies associated with the compound, and from protein-compound interaction databases. Therapeutic compounds from DrugBank, and a list of natural anti-cancer compounds derived from literature mining of published studies, were used for building partial least squares regression model. The regression model thus built, was used for the estimation of oral cancer specific weights based on the molecular targets. These weights were used to compute scores for screening the predicted anti-cancer compounds for their potential to treat oral cancer. The list of potential compounds was annotated with corresponding physicochemical properties, cancer specific bioactivity evidences, and literature evidences. In all, 288 compounds with the potential to treat oral cancer were identified in the current study. The majority of the compounds in this list are natural products, which are well-tolerated and have minimal side-effects compared to the synthetic counterparts. Some of the potential therapeutic compounds identified in the current study are resveratrol, nimbolide, lovastatin, bortezomib, vorinostat, berberine, pterostilbene, deguelin, andrographolide, and colchicine.</p></div

Potential Therapeutic Targets for Oral Cancer: ADM, TP53, EGFR, LYN, CTLA4, SKIL, CTGF, CD70

<div><p>In India, oral cancer has consistently ranked among top three causes of cancer-related deaths, and it has emerged as a top cause for the cancer-related deaths among men. Lack of effective therapeutic options is one of the main challenges in clinical management of oral cancer patients. We interrogated large pool of samples from oral cancer gene expression studies to identify potential therapeutic targets that are involved in multiple cancer hallmark events. Therapeutic strategies directed towards such targets can be expected to effectively control cancer cells. Datasets from different gene expression studies were integrated by removing batch-effects and was used for downstream analyses, including differential expression analysis. Dependency network analysis was done to identify genes that undergo marked topological changes in oral cancer samples when compared with control samples. Causal reasoning analysis was carried out to identify significant hypotheses, which can explain gene expression profiles observed in oral cancer samples. Text-mining based approach was used to detect cancer hallmarks associated with genes significantly expressed in oral cancer. In all, 2365 genes were detected to be differentially expressed genes, which includes some of the highly differentially expressed genes like matrix metalloproteinases (MMP-1/3/10/13), chemokine (C-X-C motif) ligands (IL8, CXCL-10/-11), PTHLH, SERPINE1, NELL2, S100A7A, MAL, CRNN, TGM3, CLCA4, keratins (KRT-3/4/13/76/78), SERPINB11 and serine peptidase inhibitors (SPINK-5/7). XIST, TCEAL2, NRAS and FGFR2 are some of the important genes detected by dependency and causal network analysis. Literature mining analysis annotated 1014 genes, out of which 841 genes were statistically significantly annotated. The integration of output of various analyses, resulted in the list of potential therapeutic targets for oral cancer, which included targets such as ADM, TP53, EGFR, LYN, CTLA4, SKIL, CTGF and CD70.</p></div

Coarse Grid Search for <i>C</i> and γ for parameter estimation.

<p>Coarse Grid Search for <i>C</i> and γ for parameter estimation.</p

List of potential therapeutic targets for oral cancer.

<p>The right sign ‘✓’ represents significant publication evidence to support association of concerned target gene with a cancer hallmark mentioned in a concerned column, and ‘’ represents absence of such association between gene and cancer hallmark. The ‘’ sign represents significant overexpression of the gene, and ‘’ represents significant under-expression of the gene, observed in oral cancer in study dataset. ‘CausalNet Degree’ is the no. of causally connected genes to the particular target gene. ‘Diff’ is difference in the no. of connections in dependency network, under cancer and control condition for the concerned target gene. ‘MN’ means that annotations for the concerned target gene was inferred from articles related with mouth neoplasm or oral cancer, whereas ‘C’ means that annotations are not specific to oral cancer and were inferred using generic term ‘neoplasms’ or cancer.</p

Fine Grid Search for <i>C</i> and γ for parameter estimation.

<p>Fine Grid Search for <i>C</i> and γ for parameter estimation.</p

Details about potential compounds for oral cancer treatment identified in current study.

<p>Details about potential compounds for oral cancer treatment identified in current study.</p

Distribution of oral cancer specific statistic ‘OC_Score’.

<p>Box-plots depicting score distribution of compounds belonging to different groups, compared with those identified as potential compounds for oral cancer treatment. Horizontal line indicates the cutoff used in the current study to select potential compounds.</p

Comparison of Prediction Results.

<p>Comparison of Prediction Results.</p