Citations

Abstract Breast cancer is the most common invasive cancer in women worldwide and treatment related toxicity has high inter-patient variability. Our goal was to identify additional genetic predictors of toxicity by completing a pathway based analysis taking advantage of the genotyping results obtained through a GWAS of the same patients. For our analysis, we have utilized GWA data from the SUCCESS-A trial in which 3,754 breast cancer patients were treated with adjuvant chemotherapy. We have included SNPs associated with 112 genes involved in drug disposition and 375 genes in selected cancer pathways. We identified 35 SNPs associated with neutropenia (P-value <1×10−4). These patients initially received three cycles consisting of 5-fluorouracil (5-FU), cyclophosphamide, and epirubicin. Currently we are characterizing the function of three SNPs located within an intron of the hyaluronan mediated motility receptor (HMMR) gene that are associated with the neutropenia phenotype (P-value <1×10−4). These SNPs are highly associated with the expression of a gene encoding a B-cell survival factor, TNFSF13B, (P-value <1×10−5). Our in vitro studies using lymphoblastoid cell lines (LCLs) selected based on the genotypes of HMMR gene showed that heterozygous and homozygous variant cells (n = 6) have an increased sensitivity to 5-fluorouracil, but not cyclophosphamide or epirubicin when compared with homozygous wild-type cells (n = 6). LCLs exposed to the previously mentioned chemotherapeutic agents resulted in an upregulation of TNFSF13B gene expression and downregulation of HMMR gene expression. We have utilized a pathway based approach to analyzing GWA data to identify several SNPs in the HMMR gene highly associated with the expression of one of the top signals in the cytopenia GWAS. Our goal is to further characterize the role of HMMR gene variants in chemotherapy response by assessing whether combinations of these agents in vitro (including 5-FU) also have a genotype dependent response to cytotoxicity. Citation Format: Behzad Bidadi, Krishna R. Kalari, Matthias Rubner, Alexander Hein, Matthias W. Beckmann, Peter A. Fasching, Brigitte Rack, Wolfgang Janni, Richard Weinshilboum, Liewei Wang. Utilizing a pathway based analysis of genome wide association data to identify biomarkers of toxicity in breast cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5488. doi:10.1158/1538-7445.AM2015-5488

Abstract 5-Fluorouracil (5-FU) is a cornerstone drug for the treatment of several aggressive tumors; however, adverse 5-FU toxicity contributes to approximately 1,300 deaths annually in the U.S. While three genetic variations in dihydropyrimidine dehydrogenase (DPD; DPYD gene) are well-established predictors of toxicity (i.e., *2A, I560S, D949V), the contributions of additional reported missense DPYD variants (>130) have not been adequately evaluated in clinical studies. Our lab has previously developed methods to study DPYD variants for potential clinical relevance to 5-FU toxicity using in vitro and cellular approaches (see Offer et al. Cancer Research 2013 & 2014). In the current study, we measured the in vitro enzyme activity of 47 uncharacterized missense variants that have been previously reported in dbSNP and NHLBI ESP databases. Additionally, we assessed the impact of these variants on 5-FU sensitivity in multiple transgenic human cellular models using real-time cellular analysis. Approximately one-third of the studied variants showed significantly reduced enzyme activity compared to wild type. Of the DPD-deficient variants identified in this study, 8 were profoundly deficient (<12.5% of “wildtype” activity), with enzyme activities similar to *2A. Two deficient variants showed modest reductions in enzyme activity (12.5-25% activity), similar to I560S. The remaining 5 deleterious variants exhibited mild deficiency (>25% activity, but significantly lower than “wildtype”), similar to D949V. Cellular sensitivity to 5-FU for cells expressing these variants paralleled the in vitro enzyme activity results, with deleterious variants showing reduced tolerance to 5-FU relative to cells transgenic for wildtype DPD. These trends were observed in multiple cell lines derived from various tissues and tumor types. Overall, our results add to the growing database of deleterious DPYD variations. Many of these variants have been observed primarily in non-Caucasian racial groups, consistent with our previous reports. These data suggest that the deleterious variants classified in this study may be important predictors of 5-FU toxicity, particularly in individuals of non-Caucasian ancestry. Additionally, these data suggest that genetic testing for rare variants may improve the success of predictive tests for 5-FU toxicity. Finally, this study suggests that in vitro and cellular models may be important pharmacogenomic methods to rapidly characterize variants of potential relevance in additional drug-gene pathways. Citation Format: Shikshya Shrestha, Steve Offer, Robert B. Diasio. Functional analysis of rare dihydropyrimidine dehydrogenase variants relevant to 5-fluorouracil toxicity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5487. doi:10.1158/1538-7445.AM2015-5487

Abstract Background Intra-tumor heterogeneity is the driving force behind disease progression and metastasis, drug resistance, and relapse in cancer patients. Defining personalized treatment regimens and increasing the arsenal of targeted therapies available will provide the best chance of prolonging survival and finding curative treatments. Recent work by our group and others has shed light on aberrant de novo lipogenesis as a feature of many cancers including kidney, breast, and lung cancer. Of the molecules involved in fatty acid metabolism, stearoyl-CoA desaturase 1 (SCD1) is frequently over-expressed. Targeted inhibition of SCD1 demonstrates a loss of tumor cell viability in a variety of cancer models. While there currently are specific small molecule inhibitors for SCD1 none are under investigation as anti-cancer therapeutics. In order to evaluate the efficacy of SCD1 inhibitors against ccRCC in both a preclinical and eventually a clinical setting we sought to generate unique compounds and test their biological efficacy. Methods Utilizing an innovative in silico approach, we designed new inhibitors for SCD1 via a scaffold hopping approach while searching for different “core” scaffolds. Critical interaction moieties from the chemical R-groups were held fixed, while generated cores were rapidly scanned for best-fit criteria (shape, docking, pharmacophore fit (QSAR)) into our Z-matrix. Following de novo compound generation and synthesis, we implemented iterative analog generation for the top hits. Using this method and diversity of chemical space, we pursued three divergent species of compounds into the nanomolar regime. Biological testing of the novel compounds included high-throughput proliferative-based screening, oleic acid rescue, and evaluation of the endoplasmic stress response. Enzymatic inhibition of SCD1 was evaluated by LC-MS. Preclinical pharmacokinetics was established using a range of doses administered intravenously and orally. Anti-tumor response was evaluated in an ectopic model of renal carcinoma, both as a single agent and in combination with SOC. Results A cohort of potential unique small molecule inhibitors against SCD1 were designed and synthesized. Of these, a select group of compounds demonstrated potent and selective enzyme inhibition and reduced tumor growth in in vitro and in vivo models of ccRCC. These novel inhibitors reliably reproduced activation of ER stress markers, authenticating this biological response as a harbinger for successful abrogation of SCD1 activity. Conclusions We have established an effective, expedited, and economical format for in silico modeling of novel agents based on a scaffold-hopping methodology. Our findings provide compelling evidence supporting the therapeutic benefit of SCD1 inhibitors for clinical use as broad-spectrum anti-tumor agents alone or in combination with SOC. Citation Format: Christina A. Von Roemeling, Thomas R. Caulfield, Derek C. Radisky, Ilah Bok, Laura A. Marlow, James Miller, Mojda Sidiqi, Anthony B. Pinkerton, Winston W. Tan, Amy L. Lane, Han W. Tun, John A. Copland. Accelerated drug discovery platform yields synthesis of novel stearoyl-CoA desaturase 1 inhibitors that demonstrate anti-tumor efficacy in several models of aggressive cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4459. doi:10.1158/1538-7445.AM2015-4459

Abstract The oncogenic EGFR/HER2/K-RAS “pathway” activation is pivotal in driving uncontrolled cell proliferation, aggressive tumor growth and systemic metastasis. Guided by studies in Drosophila, SIAH (seven-in-absentia homologue), the most downstream gatekeeper required for proper RAS signaling and tumor cell survival, was identified as a suitable target for anti-neoplastic therapy. We have shown that anti-SIAH-based therapy leads to the complete blockade of tumorigenesis in highly aggressive pancreatic, lung and breast cancer cells expressing a proteolysis deficient mutant protein, SIAHPD, at the onset of tumor initiation. In this study, we aim to determine if this anti-SIAH strategy is effective against well-established and late-stage pancreatic and triple negative breast (TNBC) tumors in a xenograft mouse model in vivo. We established stable cancer cell lines with doxycycline (DOX)-inducible SIAH2PD expression. One million MiaPaCa-SIAH2PD or MDA-MB-231-SIAH2PD cells were injected subcutaneously bilaterally in the dorsal scapular areas or bilaterally into the mammary fat pads, respectively, in 4-week-old female athymic nude mice. Tumor growth was monitored 3 times per week. Once tumors reached certain volume, SIAH2PD expression was induced via oral DOX treatment. Tumor growth in these mice was compared to control. Immunohistochemical (IHC) and immunofluorescence (IF) staining for endogenous SIAH and FLAG-tagged exogenous SIAH2PD were performed on formalin-fixed, paraffin-embedded sections of tumor tissue. Expression of SIAH2PD blocks oncogenic K-RAS signaling and K-RAS-mediated tumor growth in established pancreatic (MiaPaCa) and triple negative breast (MDA-MB-231) tumors in athymic nude mice. The immunohistochemical (IHC) and immunofluorescent (IF) staining reveals that in control tumors there is high expression of endogenous SIAH and none of SIAH2PD, while in tumors responding to treatment there is pronounced SIAH2PD and diminished endogenous SIAH expression. Oncogenic HER2/EGFR/K-RAS activation promote neoplastic transformation and tumorigenesis. In this study, we have identified a new vulnerability in the oncogenic K-RAS signaling pathway and we have demonstrated a novel and effective way to block K-RAS-driven tumor growth in well-established pancreatic adenocarcinoma and TNBC tumors in a xenograft model. In the follow-up studies, we hope to develop a small molecule inhibitor against SIAH, test their efficacy against patient-derived stage IV and II tumors in our “xenopatient” models. In the future, we aim to translate these exciting findings to the cancer clinics to benefit our cancer patients with metastatic diseases in VA. Citation Format: Minglei Bian, Vasilena Zheleva, Xiaofei Gao, Justin Odanga, Monica Njogu, Zena Urban, Bruce Knudsen, Richard A. Hoefer, Roger R. Perry, Amy H. Tang. Inhibition of late-stage tumor growth of human pancreatic and triple-negative breast cancer by blocking the most downstream “gatekeeper” signaling module, SIAH E3 ligase, in the oncogenic ERBB/ K-RAS signaling pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4366. doi:10.1158/1538-7445.AM2015-4366

Abstract Purpose: Methylated DNA markers can discriminate upper from lower GI neoplasms (Gastroenterology 2013;144(5):S84). It is unknown if organ-specific molecular prediction of GI tumor site can be achieved. Experimental design: An unbiased search for neoplasm markers at each major GI organ site was conducted by reduced representation bisulfite sequencing. Top marker candidates were then blindly validated by methylation specific PCR on independent tissue DNA samples from normal mucosa [17 esophagus (E), 13 stomach (S), 33 pancreas (P), 35 bile duct/liver (BD), 21 colorectal (CR)] and neoplasia [42 E, 43 S, 36 P, 48 BD, 97 CR]. Recursive partitioning (rPart) trees modeled all stepwise combinations of single markers to classify controls vs neoplasms and then neoplasms by site (CR, gastroesophageal or pancreaticobiliary). A 2nd model was designed from tissue data for blinded clinical piloting on 42 independent plasma DNA samples (14 normal and 28 cancers (14 P, 14 CR). Results: From the top 100 markers, 95 were validated and used for rPart modeling. A 3- marker panel (chr12.133484978-5047, BMP3, chr11.123301058-255) was selected for the universal detection of GI neoplasms, as it classified neoplasms and control tissues with 95% accuracy. Two markers (chr7.25896389-501, QKI) then assigned lower vs upper GI neoplasms with 94% accuracy. Finally, 3 markers (PDGFD, ELOVL2, PCBP3) called pancreaticobiliary vs gastroesophageal neoplasms with 94% accuracy. All 8 markers applied in a single model (Table) accurately predicted control vs tumor by site [88% (p <0.0001)]. In plasma, a 2-marker panel (BMP3, QKI) was 78% accurate in assigning patients to cancer or control groups (p<0.0009) and 83% accurate in assigning cancer origin to CR or P sites (p<0.0001). Predicted by ModelTissue SourceControlsColorectal neoplasiaPancreatico-biliary cancerGastro-esophageal neoplasiaControls1169102Colorectal neoplasia18617Pancreatico-biliary cancer10654Gastro-esophageal neoplasia12872 Conclusion: Panels of methylated DNA markers were identified for both universal detection of GI neoplasia and accurate prediction of tumor site. Pilot testing of these markers in plasma supports potential clinical feasibility. Citation Format: John B. Kisiel, William R. Taylor, Tracy C. Yab, Hassan M. Ghoz, Patrick H. Foote, Mary E. Devens, Douglas W. Mahoney, Thomas C. Smyrk, Lisa A. Boardman, Gloria M. Petersen, Navtej S. Buttar, Lewis R. Roberts, Graham P. Lidgard, David A. Ahlquist. Accurate site prediction of gastrointestinal cancer by novel methylated DNA markers: Discovery & validation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4252. doi:10.1158/1538-7445.AM2015-4252

Abstract Background: Epithelial ovarian cancer (EOC) is composed of five major histologic types: 1) high-grade serous carcinoma (HGSC), accounting for most cases (∼70%); and the rarer 2) clear cell, 3) endometrioid, 4) mucinous, and 5) low- grade serous carcinoma (LGSC). As EOC risk factors are histology specific, as are the site of precursor lesions, accurate subtyping is critical to understanding EOC prognostic factors and etiology. Our aim was to compare two currently employed histology assignment strategies using gene expression, DNA methylation, and clinical outcome data Methods: Histology assignment based on: a) pathologist, and b) an integrated pathologist and IHC prediction algorithm (pathIHC) (using ARID1A, CDKN2A, DKK1, HNF1B, MDM2, PGR, TP53, TFF3, VIM, and WT1 staining patterns), was compared for tumors of all histologies at the Mayo Clinic, Rochester. The 500 most variable probes from Illumina Methylation450 BeadChips (N = 259) and Agilent 4×44K expression arrays (N = 245) were used to perform unsupervised hierarchical clustering. Fisher's Exact test was used to test the association of clusters with histology. Cox proportional hazards regression analysis was used to test the association of clusters and histology with time to progression (TTP) and time to death (TTD). Results: Eighty-two percent of tumors were concordant between histology assignment strategies. Clustering based on methylation data produced two distinct clusters. PathIHC produced more homogenous clusters (p-value = 2.8×10-16) than pathology alone (p = 1.3×10-9). Cluster M1, characterized by high levels of methylation across almost all probes, was enriched for the rarer EOC subtypes; cluster M2, characterized by moderate levels of methylation across 50%-75% of probes, was predominantly HGSC. These patterns were observed irrespective of histology assignment strategy; however, when using histology by pathologist, cluster M2 had more endometrioid and LGSC tumors interspersed with HGSC tumors. Clustering based on expression data also produced two clusters. PathIHC produced slightly more homogenous clusters (p = 9.0×10-11, pathology alone, p = 2.3×10-10). Cluster E1 was enriched for the rarer EOC subtypes; cluster E2 was primarily serous lineage tumours (HGSC and LGSC), particularly when using histology by pathIHC. Considering only clinical outcomes, histologies by pathology were more significantly different in terms of TTP (p = 1.1×10-6) and TTD (p = 1.7×10-3) than histologies by pathIHC (TTP, p = 5.4×10-6; TTD, p = 5.7×10-3). Conclusions: Histology by pathIHC produced more homogeneous clusters in both the methylation and expression data; thus, molecular data supports this strategy. Differences in clinical outcomes (TTP and TTD) between histology groups were more pronounced when using assignment by pathologist; thus, clinical data supports this strategy. Citation Format: M A. Earp, S J. Winham, S M. Armasu, B L. Fridley, M C. Larson, Z C. Fogarty, K R. Kalli, C Wang, G L. Keeney, J M. Cunningham, S Ramus, M Kobel, E L. Goode. Comparison of pathology versus IHC-based ovarian carcinoma histology assignment using gene expression, DNA methylation, and clinical outcome data. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4246. doi:10.1158/1538-7445.AM2015-4246

Abstract Acinar cell carcinoma of the pancreas (ACC) is an uncommon malignancy, accounting for less than 1% of all pancreatic neoplasms. Because of its rarity, only a few retrospective studies are available to help guide management. We previously reported the case of a patient with metastatic ACC who achieved prolonged survival with doxorubicin as a result of personalized treatment designed in part on the basis of molecular and in-vitro data collected on analysis of the tumor and primary cells in culture developed from the liver metastasis. We now report the characterization of a patient derived xenograft (PDX) mouse model originating from this patient's ACC liver metastasis tissue. Antitumor activity of multiple drugs (5-FU, irinotecan, oxaliplatin, gemcitabine, bevacizumab, erlotinib, doxorubicin and imatinib) used as single agent therapy is demonstrated. Of the targeted and cytotoxic therapies used, oxaliplatin produced a dramatic and prolonged response to therapy even after withdrawal of treatment. Bevacizumab produced a significant response, as well. Serum lipase and tissue amylase levels correlated with the antitumor response to therapy. Thus, we have developed and characterized an ACC PDX model that may be used in drug discovery for the treatment of this rare cancer for which no standard of care exists. Note: This abstract was not presented at the meeting. Citation Format: Laura A. Marlow, Adam C. Mathias, Louis K. Dawson, William F. Durham, Kenneth A. Meshaw, Robert J. Mullin, Aidan J. Synnott, Ricardo Paz-Fumagalli, Murli Krishna, Daniel Von Hoff, Daniel L. Small, Gerardo Colon-Otero, John A. Copland. Therapeutic responses in a novel patient-derived xenograft mouse model for rare acinar cell pancreatic carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1475. doi:10.1158/1538-7445.AM2015-1475

Abstract Ovarian cancer is the most lethal gynecologic malignancy and the fifth leading cause of cancer deaths among women. The current standard of care post surgical cytoreduction is combination platinum/taxane chemotherapy. The initial response varies widely; subsets of carcinomas demonstrate resistance or sensitivity from the onset. The underlying cause of this response heterogeneity remains incompletely understood. Patient-derived xenografts (PDX) serve as useful in vivo models to study molecular response markers and test the efficacy of targeted therapies. Our group has demonstrated a high engraftment rate (>70%) of ovarian cancer PDXs (Avatars) by injecting treatment naïve patient tumor directly into the peritoneal cavity of an in immunocompromised mouse host in an effort to better mimic the anatomic context by which ovarian cancer naturally develops. We now have 328 engrafted Avatar models representing the wide range of ovarian cancer subtypes, including serous (65%), mixed epithelial (10%), endometrioid (7%), clear cell (4%), mucinous (3%), carcinosarcoma (1%) and other (10%). Using these models, we are performing a massively parallel sequencing strategy referred to as BROCA-HR to detect all mutation classes (e.g. gene rearrangements, copy number variations, etc.) and gene aberrations within the Fanconi Anemia-BRCA homologous recombination (HR), non-homologous end joining (NHEJ), PTEN, and DNA Mismatch repair pathways. To date, 148 Avatar models have undergone BROCA sequencing. Observed deleterious mutations included 12 BRCA1 (8%), 6 BRCA2 (4%), and 4 PIK3CA (3%); additional loss of function mutations were also evident in the following genes: ATM, RAD51C, FANCM, FANCD2, FANCA, CHEK2, PALB2, MHS6, CDK12 and GEN1. These models are representative of mutations seen in the TCGA mutation set. Models harboring said mutations are currently being tested with platinum agents and/or PARP inhibitors. Taken together, the Avatars represent a high throughput model system for pre-clinical testing in vivo that effectively recapitulates ovarian cancer (e.g. mutations in BRCA1, BRCA2 and other DNA damage response proteins). We have been able to establish avatars at a high rate, including those with mutations in BRCA1, BRCA2 and other DNA damage response genes. These models will be a unique resource for future studies of biomarkers and novel therapeutic approaches. This work is funded by the Ovarian Cancer Research Fund (750563), Mayo Ovarian SPORE (CA136393), National Cancer Institute (RO1 CA184502). Note: This abstract was not presented at the meeting. Citation Format: Kunal A. Lodhia, Marc A. Becker, Xiaonan Hou, Kimberly R. Kalli, Maria I. Harrell, Elizabeth M. Swisher, John S. Weroha, Paul Haluska. Characterization of 148 ovarian cancer tumografts (Avatars) using BROCA-HR deep sequencing. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1474. doi:10.1158/1538-7445.AM2015-1474

Abstract BACKGROUND/PURPOSE The Mayo Clinic has developed a large panel of patient-derived xenografts (PDX) from patients with glioblastoma multiforme (GBM). Here we report initial molecular profiling of the Mayo PDX panel and a comparison of patient and PDX molecular profile and response to therapy. METHODS & MATERIALS Clinical data was retrieved by retrospective chart review. Animal data from all PDX investigations conducted between 2004-2014 were retrieved from experimental logs and subsequently consolidated into a database for analysis. RESULTS From 1999 to 2014, 182 patient tumor samples of varying histological grades were attempted for xenograft with 73 resulting viable PDX lines. Viable xenografts were only produced from WHO grade IV tumor specimens, yielding an overall success rate of 49% for these tumors. GBM patients that produced viable xenografts compared to those that did not exhibited a trend for decreased overall survival (P = 0.18). There was no significant association between successful xenografting and whether tissue was from newly diagnosed (45/93%) or recurrent (20/40; 50%) tumors. Patient age > 45 at diagnosis was correlated with increased PDX viability in GBMs (p = 0.05). Of the viable PDX models analyzed, EGFR mutation was identified in 17 lines, TERT mutation was found in 13 lines, IDH mutation in 1 line, and MGMT hypermethylation in 25 lines. RNAseq was performed on orthotopic tumor samples from 53 PDX models. After excluding contaminating murine sequence reads, expression analysis demonstrated 32 models with a mesenchymal phenotype. Array comparative genomic hybridization was performed on 9 patient samples and derivative early, mid and late passage PDX tumors. Using unbiased hierarchical clustering, there was a high concordance between patient and xenograft models. Within the PDX panel, fractionated radiation (RT) alone and RT combined with temozolomide (TMZ) was tested in orthotopic tumors in 38 lines. The overall median survival benefit (ratio of median survival for treated vs. placebo) in PDX lines treated with RT only was 1.6 (range: 0.9-2.5) and with RT/TMZ was 2.5 (range: 1.1 - 8.9). There was a positive association between observed patient survival and the corresponding survival benefit in the PDX for subjects treated with RT/TMZ (r = 0.2; n = 17). Response to adjuvant TMZ was evaluated in 42 tumor lines, and response to bevacizumab was tested in 33 tumor lines, and correlations with clinical treatment response are being evaluated. CONCLUSIONS: The Mayo GBM PDX panel is widely used in the neuro-oncology community. The initial molecular analysis suggests a good correlation between patient and PDX at the level of genotypic characteristics and therapeutic sensitivity. Citation Format: Dioval A. Remonde, Brett L. Carlson, Mark A. Schroeder, Brock Armstrong, Sen Peng, Lisa Evers, Paul A. Decker, Jeanette Eckel Passow, Michael E. Berens, Nhan L. Tran, Robert B. Jenkins, Jann N. Sarkaria. Characterization of patient-derived xenograft (PDX) models to evaluate clinical and therapeutic responses of glioblastoma multiforme. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1468. doi:10.1158/1538-7445.AM2015-1468

Abstract Patient derived xenografts (PDX) mouse models for many types of cancer have demonstrated therapeutic responses similar to those seen in patients. Thus, resected patient tumor tissue directly implanted into immune compromised mice followed by therapy and tumor growth analysis is thought to be the closest preclinical model to predict patient therapeutic responses. To date, few models are available for the different histotypes of thyroid cancer derived from follicular thyrocytes; these include papillary, follicular, Hurthle cell, squamous and anaplastic thyroid carcinoma. We have developed eight PDX models in athymic nude mice representing all of these subtypes. The models have been extensively characterized for mutational status (i.e. BRAF, telomerase, RAS, PTEN, TP53, RB, etc) as well as validation by short tandem repeat (STR) analysis to match that of the originating patient tumor tissue. Squamous and anaplastic thyroid cancers are rare tumor types with no FDA approved therapies. Each model demonstrated their own unique responses to radiation, cytotoxic or molecular targeted therapies such as doxorubicin, sorafenib (tyrosine kinase inhibitor), cisplatin, paclitaxel, sunitinib (tyrosine kinase inhibitor), erlotinib (EGFR inhibitor), trametinib (MEK inhibitor) and vemurafenib (BRAF inhibitor). We expect that these models may provide useful in vivo models for thyroid cancer research as well as models for therapeutic guidance based upon histotype, mutational status and response to therapies. Citation Format: Laura A. Marlow, Adam C. Mathias, Louis K. Dawson, William F. Durham, Kenneth A. Meshaw, Robert J. Mullin, Daniel L. Small, Aidan J. Synnott, Dragana Milosevic, Brian C. Netzel, Stefan K. Grebe, Kevin Wu, Robert C. Smallridge, John A. Copland. Characterization of novel thyroid PDX models and their response to combination therapies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1458. doi:10.1158/1538-7445.AM2015-1458