Cancer Therapeutic Response Research Articles

Near infra-red polymeric nanoparticle based optical imaging in Cancer diagnosis

Cancer disease is a foremost health concern and top basis of death in comparison with many diseases including cardiovascular disorders. During initial diagnosis (usually late diagnosis), a majority of cancer patients suffer from metastatic and advanced cancer stages which resulted in limited therapeutic modalities based interventions and effectiveness. Though considerable advancement has been made in combating the disease, continuous and intense efforts are ongoing for early diagnosis and development of therapies. Generally applied treatment options for cancer are surgery, chemotherapy and radiotherapy, which are restricted by failure to early diagnose, insufficient on-targeted drug delivery, systemic toxicity, and lack of real-time monitoring of therapeutic responses in cancer. Noninvasive imaging or minimally invasive imaging methodology is valuable in clinical diagnostic settings. Specifically, noninvasive optical imaging integrated with polymeric nanomaterial have been extensively investigated in the field of cancer diagnostics and therapy. Currently, optical imaging methods go together with polymer-based fluorescent nanoparticles in accomplishing the molecular level detection of tumor boundaries. NIR probe tagged polymeric nanoparticles have potential to provide an advantage in the early cancer detection, therapeutic monitoring and image guided surgery procedures. This article review the recent progress in state-of-the-art NIRF polymeric nanoparticles used for optical imaging particularly on cancer diagnosis.

Long non‑coding RNAs in lung cancer: Regulation patterns, biologic function and diagnosis implications (Review).

Lung cancer is the most common malignancy with the highest mortality worldwide. Emerging research has demonstrated that long non-coding RNAs (lncRNAs), a key genomic product, are commonly dysregulated in lung cancer and have significant functions in lung cancer initiation, progression and therapeutic response. lncRNAs may interact with DNA, RNA or proteins, as tumor suppressor genes or oncogenes, to regulate gene expression and cell signaling pathways. In the present review, first a summary was presented of the causal effects of dysregulated lncRNAs in lung cancer. Next, the function and specific mechanisms of lncRNA-mediated tumorigenesis, metastasis and drug resistance in lung cancer were discussed. Finally, the potential roles of lncRNAs as biomarkers for lung cancer were explored.

Abstract LB-232: A novel approach for liquid biopsy by using nExo

Abstract Exosomes are small extracellular vesicles secreted from all living cells; its contents are highly varied, including proteins, small RNAs and recently discovered, genomic DNA (gDNA). The presence of nuclear content in exosomes suggests that different cell compartments can contribute to exosome cargo; however, little is known about this sub population of nuclear derived exosomes (nExo). Here, we analyzed nExo isolated from ovarian cancer cells and characterized them to explore potential clinical relevance such as cancer detection and therapeutic response. Exosomes were isolated from ovarian cancer cell lines, normal human fallopian epithelial tube cells and bio-fluids from mouse and human samples. To determine the purity of exosomes, nanoparticle tracking system, immunoblotting assay and cryo-transmission electron microscopy were used. To analyze the content of exosomes, protein mass spectrometry and imaging flow cytometry analysis was performed. First, we determined that mass spectrometry analyses for ovarian cancer cell exosomes revealed that 12.5% of proteins are derived from the cell nucleus sub-population. Additionally, using a novel imaging flow cytometry technique which enables us to identify single exosome and to quantify them, we determined that 10% of exosomes carried gDNA. Conversely, normal cells secreted only 0.2% of nExo. Then we hypothesized that the prevalence of gDNA is affected by genotoxic drugs. Treating cells with either the PARP inhibitor olaparib or topoisomerase inhibitor topotecan increased the proportion of nExo secreted from ovarian cancer cells. In addition, PARP proteins exist in ovarian cancer cell exosomes and 80.4 % of the exosome co-localized with gDNA. Using in vivo preclinical models, serum from ovarian cancer bearing mice contained a higher number of nExo than non-tumor controls, and this population was increased in response to treatment of genotoxic drugs. Furthermore, plasma and ascites from ovarian cancer patients contain around 0.3 % of nExo, which include nuclear proteins and gDNA. We demonstrate that nExo are predominantly secreted from cancer cells and could serve as an important biomarker. Although the subpopulation is relatively rare, their presence in bio-fluids isolated from cancer patients holds the potential of serving as novel biomarkers for early detection and therapeutic response to genotoxic agents. Citation Format: Akira Yokoi, Alejandro Villar-Prados, Paul Allen Oliphint, Theresa J. O'Halloran, Jason Roszik, Anil K. Sood. A novel approach for liquid biopsy by using nExo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-232.

Abstract 2159: Label-free impedance analysis as a versatile tool for dynamic screening of cancer molecular therapeutics

Abstract In vitro monitoring cancer cells response to treatment often involves laborious sample processing and collects single data points that are against the dynamic nature of cancer cells. Here we present the adaptation of an impedance-based methodology to dynamically monitor cancer cell behavior and therapeutic response. The technology detects cell death, proliferation or migration by measuring changes in conductance of microelectrodes embedded in 96 and 384-wells cell culture plates. It avoids sample labeling and processing and allows continuous monitoring of cell response. Our data shows validation with cancer cell lines and primary cells monitored for cell invasion/migration through transwells or after a scratch has been performed with a dedicated device, anticancer drug response and receptor signaling activation, with similar results over end point assays. Easy experiment set up and minimal sample processing make the technology ideal for applications in large screening campaigns, while label-free technology allows less artifacts and further analysis on the same samples through orthogonal assays. Citation Format: Fabio Cerignoli, Biao Xi, Brandon Lamarche, Leyna Zhao, Yama Abassi. Label-free impedance analysis as a versatile tool for dynamic screening of cancer molecular therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2159.

Exosomes: Diagnostic Biomarkers and Therapeutic Delivery Vehicles for Cancer.

Exosomes are described as nanoscale extracellular vesicles (EVs) secreted by multiple cell types and extensively distributed in various biological fluids. They contain multifarious bioactive molecules and transfer them to adjoining or distal cells through systemic circulation, participating in intracellular and intercellular communication, and modulating host-tumor cell interactions. Recent research has indicated that exosomes obtained from different biological fluids and their contents (proteins, nucleic acids, glycoconjugates, and lipids) can serve as biomarkers for cancer diagnosis, prognosis, and therapeutic response. Furthermore, the discovery of exosomes as therapeutic delivery vehicles has drawn much attention in antineoplastic drug delivery. They can be utilized for therapeutic delivery of proteins, genetic drugs, and chemotherapeutic drugs. Herein, this review summarizes the biogenesis, structure, and components of exosomes, focusing primarily on their two possible applications as diagnostic biomarkers and therapeutic delivery vehicles for cancers.

Association of Peritumoral Radiomics With Tumor Biology and Pathologic Response to Preoperative Targeted Therapy for HER2 (ERBB2)–Positive Breast Cancer

There has been significant recent interest in understanding the utility of quantitative imaging to delineate breast cancer intrinsic biological factors and therapeutic response. No clinically accepted biomarkers are as yet available for estimation of response to human epidermal growth factor receptor 2 (currently known as ERBB2, but referred to as HER2 in this study)-targeted therapy in breast cancer. To determine whether imaging signatures on clinical breast magnetic resonance imaging (MRI) could noninvasively characterize HER2-positive tumor biological factors and estimate response to HER2-targeted neoadjuvant therapy. In a retrospective diagnostic study encompassing 209 patients with breast cancer, textural imaging features extracted within the tumor and annular peritumoral tissue regions on MRI were examined as a means to identify increasingly granular breast cancer subgroups relevant to therapeutic approach and response. First, among a cohort of 117 patients who received an MRI prior to neoadjuvant chemotherapy (NAC) at a single institution from April 27, 2012, through September 4, 2015, imaging features that distinguished HER2+ tumors from other receptor subtypes were identified. Next, among a cohort of 42 patients with HER2+ breast cancers with available MRI and RNaseq data accumulated from a multicenter, preoperative clinical trial (BrUOG 211B), a signature of the response-associated HER2-enriched (HER2-E) molecular subtype within HER2+ tumors (n = 42) was identified. The association of this signature with pathologic complete response was explored in 2 patient cohorts from different institutions, where all patients received HER2-targeted NAC (n = 28, n = 50). Finally, the association between significant peritumoral features and lymphocyte distribution was explored in patients within the BrUOG 211B trial who had corresponding biopsy hematoxylin-eosin-stained slide images. Data analysis was conducted from January 15, 2017, to February 14, 2019. Evaluation of imaging signatures by the area under the receiver operating characteristic curve (AUC) in identifying HER2+ molecular subtypes and distinguishing pathologic complete response (ypT0/is) to NAC with HER2-targeting. In the 209 patients included (mean [SD] age, 51.1 [11.7] years), features from the peritumoral regions better discriminated HER2-E tumors (maximum AUC, 0.85; 95% CI, 0.79-0.90; 9-12 mm from the tumor) compared with intratumoral features (AUC, 0.76; 95% CI, 0.69-0.84). A classifier combining peritumoral and intratumoral features identified the HER2-E subtype (AUC, 0.89; 95% CI, 0.84-0.93) and was significantly associated with response to HER2-targeted therapy in both validation cohorts (AUC, 0.80; 95% CI, 0.61-0.98 and AUC, 0.69; 95% CI, 0.53-0.84). Features from the 0- to 3-mm peritumoral region were significantly associated with the density of tumor-infiltrating lymphocytes (R2 = 0.57; 95% CI, 0.39-0.75; P = .002). A combination of peritumoral and intratumoral characteristics appears to identify intrinsic molecular subtypes of HER2+ breast cancers from imaging, offering insights into immune response within the peritumoral environment and suggesting potential benefit for treatment guidance.

Cell Reprogramming in Tumorigenesis and Its Therapeutic Implications for Breast Cancer.

Breast cancer is the most common malignancy in women worldwide and can be categorized into several subtypes according to histopathological parameters or genomic signatures. Such heterogeneity of breast cancer can arise from the reactivation of mammary stem cells in situ during tumorigenesis. Moreover, different breast cancer subtypes exhibit varieties of cancer incidence, therapeutic response, and patient prognosis, suggesting that a specific therapeutic protocol is required for each breast cancer subtype. Recent studies using molecular and cellular assays identified a link between specific genetic/epigenetic alterations and distinct cells of origin of breast cancer subtypes. These alterations include oncogenes, tumor suppressor genes, and cell-lineage determinants, which can induce cell reprogramming (dedifferentiation and transdifferentiation) among two lineage-committed mammary epithelial cells, namely basal and luminal cells. The interconversion of cell states through cell reprogramming into the intermediates of mammary stem cells can give rise to heterogeneous breast cancers that complicate effective therapies of breast cancer. A better understanding of mechanisms underlying cell reprogramming in breast cancer can help in not only elucidating tumorigenesis but also developing therapeutics for breast cancer. This review introduces recent findings on cancer gene-mediated cell reprogramming in breast cancer and discusses the therapeutic potential of targeting cell reprogramming.

Modulating the microbiome to improve therapeutic response in cancer.

Although novel therapies, including immunotherapy, have dramatically improved outcomes for many patients with cancer, overall outcomes are heterogeneous and existing biomarkers do not reliably predict response. To date, predictors of response to cancer therapy have largely focused on tumour-intrinsic features; however, there is growing evidence that other host factors (eg, host genomics and the microbiome) can substantially affect therapeutic response. The microbiome, which refers to microbiota within a host and their collective genomes, is becoming increasingly recognised for its influence on host immunity, as well as therapeutic responses to cancer treatment. Importantly, microbiota can be modified via several different strategies, affording new angles in cancer treatment to improve outcomes. In this Review, we examine the evidence on the role of the microbiome in cancer and therapeutic response, factors that influence and shape host microbiota, strategies to modulate the microbiome, and present key unanswered questions to be addressed in ongoing and future research.

Colon Cancer-Associated Transcripts 1 and 2: Roles and functions in human cancers.

The long noncoding RNAs (lncRNAs) Colon Cancer-Associated Transcripts 1 and 2 (CCAT1 and CCAT2) are located in a recurrently amplified region in cancers. Their proximity with the Myc oncogene and their interactions with its promoter provided further evidence for their contribution in the tumorigenesis processes. Several cell line and clinical studies have shown upregulation of these lncRNAs in diverse malignancies. Moreover, some single nucleotide variants within these genes have been associated with cancer risk or therapeutic response in different populations. Besides, these two lncRNAs act as sponges for some tumor suppressor microRNAs (miRNAs), thus promoting cancer evolution. In the current study, we review recent literature about their expression level, interaction with cancer-related pathways, their role in determination of cell fate and their contribution in malignant phenotype characteristics. Taken together, the current literature shows that these lncRNAs are putative targets for design of novel treatment strategies. Moreover, their expression levels in biopsied samples, exosomes, and sera of patients might be applied as diagnostic biomarkers or markers for patient follow-up.

The effects of growth hormone on therapy resistance in cancer.

Pituitary derived and peripherally produced growth hormone (GH) is a crucial mediator of longitudinal growth, organ development, metabolic regulation with tissue specific, sex specific, and age-dependent effects. GH and its cognate receptor (GHR) are expressed in several forms of cancer and have been validated as an anti-cancer target through a large body of in vitro, in vivo and epidemiological analyses. However, the underlying molecular mechanisms of GH action in cancer prognosis and therapeutic response had been sparse until recently. This review assimilates the critical details of GH-GHR mediated therapy resistance across different cancer types, distilling the therapeutic implications based on our current understanding of these effects.

Oxygen-Enhanced and Dynamic Contrast-Enhanced Optoacoustic Tomography Provide Surrogate Biomarkers of Tumor Vascular Function, Hypoxia, and Necrosis.

Measuring the functional status of tumor vasculature, including blood flow fluctuations and changes in oxygenation, is important in cancer staging and therapy monitoring. Current clinically approved imaging modalities suffer long procedure times and limited spatiotemporal resolution. Optoacoustic tomography (OT) is an emerging clinical imaging modality that may overcome these challenges. By acquiring data at multiple wavelengths, OT can interrogate hemoglobin concentration and oxygenation directly and resolve contributions from injected contrast agents. In this study, we tested whether two dynamic OT techniques, oxygen-enhanced (OE) and dynamic contrast-enhanced (DCE)-OT, could provide surrogate biomarkers of tumor vascular function, hypoxia, and necrosis. We found that vascular maturity led to changes in vascular function that affected tumor perfusion, modulating the DCE-OT signal. Perfusion in turn regulated oxygen availability, driving the OE-OT signal. In particular, we demonstrate for the first time a strong per-tumor and spatial correlation between imaging biomarkers derived from these in vivo techniques and tumor hypoxia quantified ex vivo Our findings indicate that OT may offer a significant advantage for localized imaging of tumor response to vascular-targeted therapies when compared with existing clinical DCE methods.Significance: Imaging biomarkers derived from optoacoustic tomography can be used as surrogate measures of tumor perfusion and hypoxia, potentially yielding rapid, multiparametric, and noninvasive cancer staging and therapeutic response monitoring in the clinic.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/20/5980/F1.large.jpg Cancer Res; 78(20); 5980-91. ©2018 AACR.

Loss of CHD1 causes DNA repair defects and enhances prostate cancer therapeutic responsiveness.

The CHD1 gene, encoding the chromo‐domain helicase DNA‐binding protein‐1, is one of the most frequently deleted genes in prostate cancer. Here, we examined the role of CHD1 in DNA double‐strand break (DSB) repair in prostate cancer cells. We show that CHD1 is required for the recruitment of CtIP to chromatin and subsequent end resection during DNA DSB repair. Our data support a role for CHD1 in opening the chromatin around the DSB to facilitate the recruitment of homologous recombination (HR) proteins. Consequently, depletion of CHD1 specifically affects HR‐mediated DNA repair but not non‐homologous end joining. Together, we provide evidence for a previously unknown role of CHD1 in DNA DSB repair via HR and show that CHD1 depletion sensitizes cells to PARP inhibitors, which has potential therapeutic relevance. Our findings suggest that CHD1 deletion, like BRCA1/2 mutation in ovarian cancer, may serve as a marker for prostate cancer patient stratification and the utilization of targeted therapies such as PARP inhibitors, which specifically target tumors with HR defects. ![][1] Chromo‐domain helicase DNA‐binding protein‐1 (CHD1) promotes HR‐mediated DSB repair. The depletion of CHD1 enhances cellular sensitivity to PARP inhibitors, which has potential therapeutic implications for CHD1‐depleted prostate cancers. [1]: /embed/graphic-1.gif

Therapeutic advantage of genetically engineered Salmonella typhimurium carrying short hairpin RNA against inhibin alpha subunit in cancer treatment

BackgroundIn contrast to its well-known endocrine function, the role of inhibin in cancer development and therapeutic response is unclear. Salmonella, particularly less toxic attenuated Salmonella strains, are used to treat cancer in two ways. First, Salmonella accumulate around tumors, penetrate the cell barrier, and replicate inside the tumors. Second, Salmonella can act as a vehicle for delivering anticancer agents or proapoptotic genes to attack tumors. In this study, we aimed to develop a suitable cancer therapeutic strategy by genetically modifying attenuated Salmonella typhimurium to harbor short hairpin RNA (shRNA) expression plasmids targeting alpha subunit of inhibin (sh-INHA). MethodsWe analyzed the expression of human INHA in normal and cancer cells and tissues. We developed genetically engineered attenuated S. typhimurium harboring sh-INHA (S. typhimurium/sh-INHA) and assessed its cancer therapeutic effects by using cell culture models and syngeneic mouse tumor models. ResultsINHA expression levels were markedly higher in colon cancer and melanoma cells and tissues than in their normal counterparts. Suppression of INHA expression mildly reduced cancer cell survival and induced caspase activation and downregulation of anti-apoptotic Bcl-2 and Bcl-xL expressions. Although the genetically engineered S. typhimurium mildly interfered with the invasion of S. typhimurium into host colon cancer and melanoma cells, S. typhimurium/sh-INHA caused remarkable cytotoxicity in cancer compared with unmodified S. typhimurium or S. typhimurium expressing a control scrambled shRNA (S. typhimurium/sh-Cont). Salmonella typhimurium/sh-INHA-treated mice also showed a significantly inhibited growth of colon cancers and melanomas, with a survival advantage. ConclusionOur results suggest that tumor-targeted therapy using S. typhimurium/sh-INHA may provide a novel cancer treatment option.

Basal-like breast cancer engages tumor-supportive macrophages via secreted factors induced by extracellular S100A4.

The tumor microenvironment (TME) may influence both cancer progression and therapeutic response. In breast cancer, particularly in the aggressive triple‐negative/basal‐like subgroup, patient outcome is strongly associated with the tumor's inflammatory profile. Tumor‐associated macrophages (TAMs) are among the most abundant immune cells in the TME, shown to be linked to poor prognosis and therapeutic resistance. In this study, we investigated the effect of the metastasis‐ and inflammation‐associated microenvironmental factor S100A4 on breast cancer cells (BCCs) of different subtypes and explored their further interactions with myeloid cells. We demonstrated that extracellular S100A4 activates BCCs, particularly the basal‐like subtype, to elevate secretion of pro‐inflammatory cytokines. The secreted factors promoted conversion of monocytes to TAM‐like cells that exhibited protumorigenic activities: stimulated epithelial–mesenchymal transition, proliferation, chemoresistance, and motility in cancer cells. In conclusion, we have shown that extracellular S100A4 instigates a tumor‐supportive microenvironment, involving a network of cytokines and TAM‐like cells, which was particularly characteristic for basal‐like BCCs and potentiated their aggressive properties. The S100A4–BCC–TAM interaction cascade could be an important contributor to the aggressive behavior of this subtype and should be further explored for therapeutic targeting.

Abstract 2590: Race-specific differential expression of CCL25 and CCR9 in triple-negative breast cancer

Abstract Breast cancer (BrCa) is the second leading cause of cancer-related deaths among women. Therapeutic intervention of the disease is impeded due to the heterogeneity contributed by inter- and intra-tumoral diversity, as well as difference among cancer-bearing individuals. Triple-negative breast cancer (TNBC) is a hormone-independent and highly aggressive subtype that disproportionally affects African-American (AA) women. However, the molecular basis of racial disparity in therapeutic response and clinical outcome in AA and Caucasian (CA) patients is still obscure. Our group was the first to show the involvement of CCR9 and its natural ligand, CCL25 in cancer progression and therapeutic response, including breast cancer. In this study, we have shown the association of CCR9 and CCL25 with TNBC. Both CCR9 and CCL25 are highly expressed in TNBC cells (MDA-MB-468 and MDA-MB-231) compared to other BrCa subtypes (MCF-7, MDA-MB-361, SKBr-3). Expression of this receptor-ligand pair was significantly elevated in TNBC cells derived from AA compared to those derived from CA patients. RNA-Seq based transcriptome data obtained from The Cancer Genome Atlas (TCGA) confirmed these results. Further, phospho-proteomic profiling of cancer signaling molecules showed race specific hyper-activation of GSK-3α, GSK-3β and NF-κB in AA derived cells. These molecules are known to provide the survival advantage to cancer cells. These findings, therefore, highlight significance of CCR9 and its association with the disparity in observed in TNBC. Hence, CCR9 targeted approach to address the disparity in the therapeutic outcome of TNBC seems to be promising. Citation Format: Jeronay King, Neeraj Kapur, Hina Mir, Dominique N. Gales, James W. Lillard, Shailesh Singh. Race-specific differential expression of CCL25 and CCR9 in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2590.

Abstract 2268: Differential splicing analysis of doxorubicin treatment response in cancer cells

Abstract Background:Splicing of transcripts is an important epigenetic control mechanism that significantly influences expression of protein isoforms in a cell. Alternative splicing is known to contribute to development and progression of cancer, however the impact of cellular splicing profiles on cancer drug response has been largely unexplored. In this study, we integrated two large public data sets and report findings on the basal splicing profiles between doxorubicin treated sensitive and resistant cancer cell lines. We introduced a new method to analyze of splicing data using the quasi-binomial distribution that is incredibly simple, powerful and well suited for comparison of large groups of samples. We also identified exons whose inclusion or exclusion level is likely to be damaging to intended gene products. Finally, we performed RNA-binding protein motif enrichment at these identified exons to characterize proteins that may play a role in their regulation. Methods:Drug response data from the Cancer Therapeutic Response Portal (CTRP) was integrated with RNAseq data from the Cancer Cell Line Encyclopedia (CCLE). AUC values from drug-response time curves in CTRP were used to classify cells as either doxorubicin sensitive, intermediate or resistant. The upper and lower tertiles provided a total of 253 sensitive and 258 resistant cell lines respectively. Splice junction read counts for skipped-exon events were calculated using the matched cell line data from CCLE. Response groups were then used to train a generalized linear model with quasi-binomial family. Results were filtered by group weight significance at an FDR of <=0.01. The remaining events were again filtered for >=10% difference in mean exon inclusion ratio. Results:In total we identified 277 differentially spliced events between doxorubicin sensitive and resistant groups. When performing GO term over-representation our results demonstrated significantly enriched biological processes supporting the role of alternative splicing in EMT and cellular differentiation. This further confirms previous studies linking alternative splicing to these cancer hallmarks, suggesting that splicing may facilitate acquired drug resistance through survival mechanisms similar to those seen in cancer stem cells. Citation Format: Edward Simpson, Yunlong Liu. Differential splicing analysis of doxorubicin treatment response in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2268.

Predicting breast cancer therapeutic response.

In triple-negative breast cancer, therapeutic response to carboplatin and docetaxel is similar. However, carboplatin therapy is superior to docetaxel in patients with germline BRCA1 or BRCA2 mutations, but ‘BRCAness’ does not predict sensitivity to carboplatin.

Epigenetic Modifications as Biomarkers of Tumor Development, Therapy Response, and Recurrence across the Cancer Care Continuum.

Aberrant epigenetic modifications are an early event in carcinogenesis, with the epigenetic landscape continuing to change during tumor progression and metastasis—these observations suggest that specific epigenetic modifications could be used as diagnostic and prognostic biomarkers for many cancer types. DNA methylation, post-translational histone modifications, and non-coding RNAs are all dysregulated in cancer and are detectable to various degrees in liquid biopsies such as sputum, urine, stool, and blood. Here, we will focus on the application of liquid biopsies, as opposed to tissue biopsies, because of their potential as non-invasive diagnostic tools and possible use in monitoring therapy response and progression to metastatic disease. This includes a discussion of septin-9 (SEPT9) DNA hypermethylation for detecting colorectal cancer, which is by far the most developed epigenetic biomarker assay. Despite their potential as prognostic and diagnostic biomarkers, technical issues such as inconsistent methodology between studies, overall low yield of epigenetic material in samples, and the need for improved histone and non-coding RNA purification methods are limiting the use of epigenetic biomarkers. Once these technical limitations are overcome, epigenetic biomarkers could be used to monitor cancer development, disease progression, therapeutic response, and recurrence across the entire cancer care continuum.

Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas

SUMMARYDNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ~20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy.

MP65-16 NOVEL BIOMARKER SIGNATURE FOR PREDICTING PATHOLOGIC RESPONSE OF UROTHELIAL CARCINOMA OF THE BLADDER TO CISPLATIN-BASED NEOADJUVANT CHEMOTHERAPY

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology III1 Apr 2018MP65-16 NOVEL BIOMARKER SIGNATURE FOR PREDICTING PATHOLOGIC RESPONSE OF UROTHELIAL CARCINOMA OF THE BLADDER TO CISPLATIN-BASED NEOADJUVANT CHEMOTHERAPY Patrick Hensley, Matthew Purdom, Natasha Kyprianou, Chi Wang, and Andrew James Patrick HensleyPatrick Hensley More articles by this author , Matthew PurdomMatthew Purdom More articles by this author , Natasha KyprianouNatasha Kyprianou More articles by this author , Chi WangChi Wang More articles by this author , and Andrew JamesAndrew James More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2082AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Cisplatin-based neoadjuvant chemotherapy (NC) has become standard practice in the management of muscle invasive urothelial carcinoma of the bladder, but it confers only a modest survival advantage. Patients with pathologic progression on NC have poor outcomes and may benefit from upfront cystectomy. We previously demonstrated that phenotypic epithelial-mesenchymal transition (EMT) is associated with advanced stage and grade. This study pursued the predictive value of EMT signature effectors of bladder cancer therapeutic response to NC. METHODS A tissue microarray (TMA) was constructed with matched pre-NC transurethral resection (TUR) specimens and post-NC cystectomy specimens from the same patients (N=69) with specimens from patients managed with surgery alone serving as control (N=21). TMA sections were immunostained for the EMT biomarkers E-cadherin (epithelial marker), N-cadherin and Vimentin (mesenchymal markers) and β-catenin (EMT effector) and staining intensity was scored by two blinded reviewers. Data was statistically analyzed using 1-way ANOVA and T-tests. RESULTS Increased expression of the mesenchymal markers Vimentin and N-cadherin on TUR specimen was associated with nodal metastasis and extravesical disease (≥ypT3 or N+) at the time of cystectomy (P=0.019 and 0.002, respectively). Decreased Vimentin and N-cadherin expression independently predicted complete pathologic response to NC (ypT0, P<0.001 and 0.024, respectively). In post-NC cystectomy specimens, only N-cadherin expression was correlated with pathologic stage (P=0.004). In TUR specimens from patients managed with surgery alone, increased expression of β-catenin and N-cadherin predicted extravesical disease at the time of cystectomy (P=0.033 and 0.007, respectively). When comparing pre- and post-NC specimens, treatment with platinum-based NC induced a mixed EMT picture, with stable β-catenin and N-cadherin expression and decreased E-cadherin and Vimentin expression, relative to control patients. Expression patterns in metastatic lymph node tissue was inconsistent. CONCLUSIONS Expression of EMT markers have potential value in predicting pathologic response to cisplatin-based NC. Further validation is necessary to correlate these findings with clinical outcomes and establish these as novel biomarkers of adverse response to NC towards the goal of optimizing patient selection for NC. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e864-e865 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Patrick Hensley More articles by this author Matthew Purdom More articles by this author Natasha Kyprianou More articles by this author Chi Wang More articles by this author Andrew James More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...