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A study was presented in which sarcomas were microinjected simultaneously with several drugs to study the pharmacodynamic response after resection. This platform may represent a future way of probing efficacy of anticancer agents in the relevant model system: human tumors. See related article by Gundle et al., p. 3958

Highlights • This report shows very rare cases of small cell carcinoma of the ovary, hypercalcemic type and pulmonary type. • Their chemo sensitivity is quite different. These two cases followed opposite clinical courses. • The first case (SCOHT) progressed rapidly, and showed resistance to chemotherapy and radiotherapy. • The second case (SCOPT) showed sensitivity to chemotherapy and radiotherapy although recurrence was repeated.

Triple negative breast cancer (TNBC), which is characterized by lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor type 2 (HER2), is frequently associated with aggressive behavior and adverse patient outcomes and comprises a heterogeneous subgroup of tumors of diverse genomic features. Currently, TNBC patients are managed with only a few approved therapies and treatment strategies, including taxane-anthracycline chemotherapy. However, there is a subgroup of women with TNBC whose tumors are extremely sensitive to chemotherapy, but there are many women for whom chemotherapy is of uncertain benefit (1). To identify candidate therapeutic treatments for chemo-resistant patients of TNBC, we combined TNBC causal network modeling and chemo-response associated genes. We detected the differentially expressed genes according to chemo-responses by investigating expression profiles of TNBC samples with annotated information about responses to neoadjuvant chemotherapy(2), and constructed TNBC causal molecular network modeling by integrating epigenetic data with genetic, genomic, and transcriptomic data available for the Cancer Genome Atlas (TCGA) data(3). We leveraged the global causal network with genes associated with chemo-responses and detected highly connected chemo-sensitive subnetwork, which are enriched for Extracellular Matrix related pathways. The chemo-sensitive subnetwork was used to identify potential treatments to enhance chemosensitivity in two ways: 1) to identify key drivers that perturb genes within subnetwork based on number of directed connections, and 2) to identify repurposed therapeutics by comparing our chemo-sensitive subnetwork to the transcriptomic response to drug treatment(4). We identified the activity of microRNA let-7g was the most upstream key regulator that perturbs several collagen genes, suggesting the potential mechanism of chemosensitivity involved the extracellular matrix pathway. Additionally, we predicted candidate drugs including Genistein to modulate chemo-sensitivity, which was experimentally validated in TNBC cell lines. Taken together, the results demonstrated that our novel integrative approach of multi-omics data is useful to identify potential therapeutic targets to treat chemo-resistant TNBC patients by modulating chemo-sensitivity. 1. Bianchini, G., Balko, J.M., Mayer, I.A., Sanders, M.E. and Gianni, L. (2016) Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nature reviews. Clinical oncology. 2. Hatzis, C., Pusztai, L., Valero, V., Booser, D.J., Esserman, L., Lluch, A., Vidaurre, T., Holmes, F., Souchon, E., Wang, H. et al. (2011) A genomic predictor of response and survival following taxane-anthracycline chemotherapy for invasive breast cancer. Jama, 305, 1873-1881. 3. Cancer Genome Atlas, N. (2012) Comprehensive molecular portraits of human breast tumours. Nature, 490, 61-70. 4. Lamb, J., Crawford, E.D., Peck, D., Modell, J.W., Blat, I.C., Wrobel, M.J., Lerner, J., Brunet, J.P., Subramanian, A., Ross, K.N. et al. (2006) The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science, 313, 1929-1935. Citation Format: Lee E, Ito K, Irie HY, Zhu J. Identify key regulators to modulate chemo-sensitivity of triple negative breast cancer by integrative analysis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-08-02.

Introduction: Multiple myeloma (MM) is characterized by the clonal expansion of plasma cells in the bone marrow resulting in end-organ damage. Despite an extensive increase in the five-year survival rate in recent years, MM is still considered an incurable disease as patients will repeatedly relapse and develop resistance to current chemotherapies. A key focus for the personalization of myeloma therapy is understanding the biological mechanisms of drug resistance and identifying clinically useful biomarkers of therapeutic response. Highly efficient techniques for the enrichment of phosphorylated peptides followed by high resolution mass spectrometry facilitates the quantitation of thousands of site-specific phosphorylation events. Here, we have performed a phosphoproteomic analysis on MM cell lysates stratified based on their ex vivo drug response profiles to advance our understanding of drug resistance mechanisms. Materials and Methods: CD138 + plasma cells were isolated from 20 adult MM patient bone marrow aspirates at diagnosis (n=7) or relapse (n=13). Samples were grouped based on ex vivo drug sensitivity and resistance testing (DSRT) as follows: highly sensitive (Group I), sensitive (Group II), resistant (Group III), highly resistant (Group IV) [1]. For the phosphoproteomic analysis, peptides were generated and purified using the filter aided sample preparation (FASP) protocol. Peptide tandem mass tag (TMT) labelling, Fe 3+ immobilized metal ion affinity chromatography (IMAC), synchronous precursor selection (SPS), and triple stage tandem mass spectrometry (MS3) was performed. Nonenriched peptides were used for proteomic analysis. Resulting data was analysed using MaxQuant, followed by normalization of phosphosite intensities using the internal reference scale (IRS) method, and statistical analysis using Perseus. Functional enrichment and kinase enrichment analyses were performed on significant phosphoproteins using g:profiler and KEA2, respectively. Results: Our quantitative MS-based phosphoproteomic analysis identified 2,945 phosphorylation sites on 2,232 phosphopeptides from 690 phosphoproteins. Of these phosphorylation sites, 176 were significantly changed between all four DSRT groups and 267 were significantly changed between Group I and Group IV (False Discovery Rate (FDR) < 0.05). Hierarchical clustering was performed to highlight the distinct phosphoproteomic profiles associated with each DSRT group, of which the very sensitive (Group I) and very resistant (Group IV) subgroups demonstrated a well-defined separation (Fig. 1A, 1B). KEGG pathway analysis and gene ontology (GO) analysis of significantly increased phosphorylated proteins in Group IV compared to Group I MM patients demonstrated an increased phosphorylation of proteins associated with tight junctions, the Rap1 signalling pathway and the phosphatidylinositol signalling system; indicating an upregulation of cell adhesion associated processes in drug resistant MM. Phosphoproteins increased in abundance in Group I compared to Group IV MM patients revealed an increased phosphorylation of proteins involved in translation and RNA processing including the spliceosome, RNA transport and RNA binding pathways (Fig. 1C). We identified filamin A serine 2152, RAS guanyl-releasing protein 2 serine 576 and proto-oncogene tyrosine-protein kinase Src serine 17 as increased in Group IV MM, and nuclease-sensitive element-binding protein 1 (YBX1) serine 165, CD44 serine 697 and Bcl2-associated agonist of cell death (BAD) serine 99 as increased in Group I MM. KEA of the upregulated phosphoproteome in Group IV revealed an enrichment of cyclin dependent kinase 1 (CDK1) and ribosomal s6 kinases (RPS6K) whereas casein kinase 2 (CK2) and the glycolysis-associated kinases were enriched in Group I (Fig. 1D). Conclusion: Our study has generated a phosphoproteomic dataset demonstrating distinct phosphorylation signatures associated with drug sensitivity in clinical MM plasma cells. The identification of phosphorylation events associated with drug resistance provides a basis for further exploration of these events and associated signalling pathways to further understand drug resistance mechanisms in MM and identify potential biomarkers of therapeutic response and targets for drug re-sensitization in MM. References: [1] M. M. Majumder et al., Oncotarget 8(34), 56338 (2017) Figure 1 Figure 1. Disclosures Heckman: Novartis: Research Funding; Orion Pharma: Research Funding; Celgene/BMS: Research Funding; Oncopeptides: Consultancy, Research Funding; Kronos Bio, Inc.: Research Funding.

Background: Non-small-cell lung cancer (NSCLC) is a deadly cancer with high mortality rate. Drug resistance represents a main obstacle in NSCLC treatment. High mobility group box-1 (HMGB1) protein promotes drug resistance in NSCLC cells by activating protective autophagy. Methods: In the current study, we investigated the regulatory role of microRNA-142-3p (miR-142-3p) in HMGB1-mediated autophagy of NSCLC cells and its impact on drug resistance of NSCLC in vitro and in vivo. HMGB1 was identified as a putative target gene of miR-142-3p by in silico analysis. Our luciferase reporter assay results confirmed that miR-142-3p directly targets the 3’-UTR of HMGB1 in NSCLC cells. Results: MiR-142-3p overexpression suppressed while miR-142-3p knockdown increased HMGB1 mRNA and protein expression. Starvation induced HMGB1 expression and activated autophagy in NSCLC cells. The starvation-induced autophagy was inhibited by miR-142-3p overexpression or HMGB1 knockdown. Moreover, miR-142-3p overexpression or HMGB1 knockdown increased PI3K, Akt, and mTOR phosphorylation. Inhibition of PI3K or mTOR restored starvation-induced autophagy inhibited by miR-142-3p overexpression or HMGB1 knockdown. Conclusions: These results demonstrated that miR-142-3p regulates starvation-induced autophagy of NSCLC cells by directly downregulating HMGB1 and subsequently activating the PI3K/Akt/mTOR pathway. Further, miR-142-3p overexpression inhibited anticancer drug-induced autophagy and increased chemo-sensitivity of NSCLC in vitro and in vivo. These findings shed light on the therapeutic potential of miR-142-3p in combating acquired NSCLC chemo-resistance.

Retraction of ‘Long non-coding RNA KCNQ1OT1 regulates cell proliferation, apoptosis and chemo-sensitivity through modulating miR-186-5p/NCAM1 axis in acute myeloid leukemia cells’ by Jing Dai et al., RSC Adv., 2019, 9, 36256–36265, DOI: 10.1039/C9RA06378A.

In-vitro chemo-sensitivity experiments are an essential step in the early stages of cancer therapy development, but existing data analysis methods suffer from problems with fitting, do not permit assessment of uncertainty, and can give misleading estimates of cell growth inhibition. We present an approach (bdChemo) based on a mechanistic model of cell division and death that permits rigorous statistical analyses of chemo-sensitivity experiment data by simultaneous estimation of cell division and apoptosis rates as functions of dose, without making strong assumptions about the shape of the dose-response curve. We demonstrate the utility of this method using a large-scale NCI-DREAM challenge dataset. We developed an R package “bdChemo” implementing this method, available at https://github.com/YiyiLiu1/bdChemo.

Guinea pigs (GP), originally from the Andes, have absence of hypoxia-driven carotid body (CB) reflex. Neonatal mammals have an immature CB chemo reflex and respond to hypoxia with metabolic changes arising from direct effects of hypoxia on adrenal medulla (AM). Our working hypothesis is that adult GP would mimic neonatal mammals. Plasma epinephrine (E) has an AM origin, while norepinephrine (NE) is mainly originated in sympathetic endings, implying that specific GP changes in plasma E/NE ratio, and in blood glucose and lactate levels during hypoxia would be observed. Experiments were performed on young adult GP and rats. Hypoxic ventilation (10% O2) increased E and NE plasma levels similarly in both species but PaO2 was lower in GP than in rats. Plasma E/NE ratio in GP was higher (≈1.0) than in rats (≈0.5). The hypoxia-evoked increases in blood glucose and lactate were smaller in GP than in the rat. The AM of both species contain comparable E content, but NE was four times lower in GP than in rats. GP superior cervical ganglion also had lower NE content than rats and an unusual high level of dopamine, a negative modulator of sympathetic transmission. Isolated AM from GP released half of E and one tenth of NE than the rat AM, and hypoxia did not alter the time course of CA outflow. These data indicate the absence of direct effects of hypoxia on AM in the GP, and a lower noradrenergic tone in this species. Pathways for hypoxic sympatho-adrenal system activation in GP are discussed., This work was supported by Grants BFU2015-63706R (MINECO, FEDER-UE) and CIBER CB06/06/0050 from ISCiii (Spain).

Objective To investigate the clinical value and application of ATP based bioluminescence tumor chemo-sensitivity assay (ATP-TCA) in the chemotherapy for ascites caused by recurrent ovarian cancer.

Single nucleotide polymorphism (SNP) rs11671784 is in the loop of pre-miR-27a and the G/A variation can significantly decrease mature miR-27a expression. This study explored the role of miR-27a in chemo-sensitivity of bladder cancer and how rs11671784 G/A variation affects the sensitivity. Blood and tumor samples from 89 bladder cancer cases were analyzed. In-vitro study was performed to explore the mechanism of chemo-sensitivity and the downstream target of miR-27a by using bladder cancer cell lines. This study identified a causative relationship between rs11671784 G/A variation, lowered miR-27a expression, increased RUNX-1 expression and following weakened chemo-sensitivity. rs11671784 G allele has significantly stronger effect over A allele in promoting chemo-sensitivity in bladder cancer. miR-27a mediates chemotherapy at least partially through reducing P-gp expression and increasing apoptosis. In addition, RUNX-1 is a novel direct target of miR-27a, which is involved in its regulation of chemo-sensitivity in bladder cancer.

Cancer stem-like cells (CSCs), a small population of cancer cells with regenerative potential, may lead to the initiation and progression of secondary tumors. Long-term chemotherapeutic drug treatment can also result in the generation of a drug resistant population of cancer stem cells. In this study we have isolated CD44+ and CD117+ enriched ovarian cancer stem-like cells from primary cultured ascites cells removed from ascites fluid of naïve ovarian cancer patients. AXL, a type I receptor tyrosine kinase family member, is found to be over-expressed in ovarian cancer stem-like cells. Cell viability assays showed that ovarian CSCs are chemo-resistant to concentration dependent paclitaxel treatment. AXL was inhibited using a R428 and cell viability assays and apoptotic assays in the presence of paclitaxel were performed, which made the CSCs chemo sensitive. Si-RNA based inhibition of AXL also displayed a similar pattern of improving the sensitivity of the stem-like cells to the chemotherapeutic drug. PI3-kinase/Akt signaling pathway has also been shown to be involved in decreasing the cell viability during the inhibition of AXL. In conclusion, this study establishes the role of AXL, a receptor tyrosine kinase, as one of the key proteins influencing the chemo resistance in ovarian cancer stem-like cells. Citation Format: Jin-Young Kim, Hyewon Chung, So-Jin Shin, Eunyoung Ha, Chi-Heum Cho. AXL inhibition in ovarian cancer stem-like cells increases chemo-sensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1917. doi:10.1158/1538-7445.AM2017-1917

Objective The aim of this study was to explore whether low dose Glycididazolum natrium (CMNa) used during intervention for advanced non-small cell lung cancer (NSCLC) patients can enhance chemo-sensitivity and to evaluate its clinical value.

BACKGROUND: miRNAs might be potentially useful biomarkers for prediction of response to chemotherapeutic agents, radiotherapy and survival. The aim of this retrospective study was to validate miRNA response predictors in a cohort of patients with gastrooesophageal cancer in order to predict overall survival (OS) and disease-specific survival (DSS).MATERIAL AND METHODS: The study population encompassed 53 patients treated with curative intend for loco-regional gastrooesophageal cancer. miRNA expression was quantified from pre-therapeutic and diagnostic, formalin-fixed, paraffin embedded tumour specimens using Affymetrix GeneChip miRNA 1.0 Array. Based on growth inhibition of the NCI60 panel in the presence of cisplatin, epirubicine and capecitabine, a miRNA based response predictor was developed. The Cox proportional hazards model was applied to assess the correlations of the response predictor with OS and DSS.RESULTS: A univariate analysis demonstrated a statistical significant improvement of OS for patients who had undergone surgical resection with prediction scores above the median prediction score (HR: 0.41 (95% CI: 0.17-0.96). Adjusting for surgery and stage, this predictor was identified to be independently associated with both OS (HR: 0.37 (95% CI: 0.16-0.87)) and DSS (HR: 0.32 (0.12-0.87)).CONCLUSION: The miRNA profile predictive for sensitivity to cisplatin, epirubicine and capecitabine was shown to be independently associated with OS and DSS in patients with gastrooesophageal cancer.

596 Background: Classification by molecular subtype can aid in the selection of therapy for patients with breast cancer. However at present, the methodology for molecular subtyping is not standardi...

It has been well documented that tumor suppressor p53 is mutated in about 50% of all human tumors. p53 status might be one of the critical determinants for the chemo-sensitivity of human tumors. In the present study, we have found that p53 family member p73 as well as 14-3-3sigma is down-regulated in response to adriamycin (ADR) in ADR-resistant human breast cancer-derived MBA-MD-436 cells which carry p53 mutation. Like p53, 14-3-3sigma was transactivated by p73 and, in turn, stabilized p73. Luciferase reporter analysis and colony formation assays demonstrated that 14-3-3sigma has an ability to enhance the p73-mediated transcriptional activity as well as its pro-apoptotic function. Furthermore, enforced expression of 14-3-3sigma increased the ADR sensitivity of MBA-MD-436 cells. Taken together, our present results strongly suggest that p73-dependent induction of 14-3-3sigma plays an important role in the regulation of chemo-sensitivity of breast cancers bearing p53 mutation.

The effect of gamma rays, EMS mutagens and their combination on chilli genotypes Kashi anmol (KA-2) and VR-338 (Kashi Gaurav) were investigated in M1 generation to assess the radio and/or chemo sensitivity of different doses. Seeds were irradiated with different concentration of Gamma rays, EMS and combinations. With an increase in doses of Gamma rays, EMS and their combinations, substantial increase in pollen sterility and ovule sterility was reported. Gamma rays were more effective for germination percentage as compared to EMS and their combination in both varieties. Seedling height reduction was predominantly observed in EMS as compared to gamma rays and their combination.

1077 Background: Triple-negative breast cancer (TNBC), which is characterized by negativity for ER, PR, and HER2, is a high risk breast cancer that lacks specific targets for treatment selection. C...

e21116 Background: Most breast cancer patients do not die of their primary tumor but from metastases developing sometimes years after the primary tumor has been removed. Cells from the tumor seem t...

9667 Background: The present study explores the correlation of the erbB oncogenes family and c-myc average gene copy numbers (AGCN) determined by ddPCR, topoisomerase 2 alpha (topo2), PAI, erbB-2, ...

Through injections of NaCN at various locations in awake piglets and rats, we gained insight into the plasticity of arterial chemosensitivity. Less than 8 day old piglets exhibited both carotid and aortic chemosensitivity. The aortic chemosensitivity persisted after 8 days only if CBD had been performed, but CBD after 8 days of age resulted in restoration of aortic chemosensitivity. At the site of aortic chemosensitivity, there was greater serotonin (5-HT) immunoreactivity in CBD than in carotid intact piglets and this increase was dependent upon intact aortic innervation. Intravenous injections of the 5-HT5a receptor antagonist, methiotepin, prior to the NaCN injection eliminated aortic chemosensitivity. Western blots indicated the expression of the 5-HT5a receptors at this aortic site and the protein existed equally in CBD and carotid intact piglets. AOD+CBD resulted in chemosensitivity in the left ventricle which was attenuated by prior injection of the 5-HT5a receptor antagonist. Neonatal and adult rats also developed aortic chemosensitivity after CBD. These data indicate there are multiple sites for plasticity in arterial chemosensitivity, which appears to involve upregulation of serotonin acting at the 5-HT5a receptors.

BECAUSE ventilation is proportional to the alveolar pCO2it is generally assumed that carbon dioxide has a direct excitatory effect on either the neurones in the ‘respiratory centre’1or on a ‘special chemo-receptor system’ independent of the synapses in the respiratory reflex pathways2. An examination of the effect of carbon dioxide on the excitability of peripheral nerve suggests, however, another possible explanation. This has been investigated in ‘normal’ subjects in whom the alveolar carbon dioxide tensions were changed experimentally3.