bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4108: Targeting IL-6 signaling overcomes cetuximab resistance in head and neck squamous cell carcinoma
Authors: O'Keefe Rachel A. , Bhola Neil , Brand Toni M. , Zeng Yan , Johnson Daniel E. , Grandis Jennifer R.
Published: July 2017

Head and neck squamous cell carcinoma (HNSCC), the sixth most common cancer worldwide, has a five-year survival rate of only 50%. The first targeted agent FDA approved for treatment of HNSCC was cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR). Despite EGFR overexpression in up to 90% of HNSCC tumors and ample evidence supporting EGFR as a therapeutic target in HNSCC, the response rate for single-agent cetuximab is below 20%, and resistance to cetuximab-containing therapy remains a major obstacle in the effective treatment of HNSCC. Identification and targeting of mediators of cetuximab resistance is needed to improve patient outcomes.

Secretion of the cytokine interleukin 6 (IL-6) has been proposed as a mechanism of resistance to cetuximab in HNSCC, and inhibition of signal transducer and activator of transcription 3 (STAT3), a downstream mediator of IL-6 signaling, has been shown to overcome cetuximab resistance in preclinical HNSCC models. Thus, we hypothesize that IL-6 signaling mediates resistance to cetuximab and that co-treatment with agents targeting the IL-6 pathway will enhance the therapeutic efficacy of cetuximab in HNSCC.

We have generated cetuximab-resistant variants of the cetuximab-sensitive HNSCC cell lines Cal33 and PE/CA-PJ49. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis indicated that IL6 expression is increased 3.5- to 8-fold in cetuximab-resistant variants compared to the parental cells from which they were derived. In addition, a colony formation assay revealed that, as expected, cetuximab-treated parental cells formed fewer colonies than vehicle-treated cells, while cetuximab treatment had no effect on the ability of cetuximab-resistant PE/CA-PJ49 variants to form colonies. In contrast, treatment with tocilizumab, an IL-6 receptor-neutralizing monoclonal antibody, markedly reduced the colony-forming ability of the cetuximab-resistant variants, but not parental cells. These results suggest that targeted inhibition of IL-6 signaling may effectively inhibit proliferation in cetuximab-refractory HNSCC cells.

Citation Format: Rachel A. O'Keefe, Neil Bhola, Toni M. Brand, Yan Zeng, Daniel E. Johnson, Jennifer R. Grandis. Targeting IL-6 signaling overcomes cetuximab resistance in head and neck squamous cell carcinoma [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 4108. doi:10.1158/1538-7445.AM2017-4108
Abstract 4111: EGFR wild type allele amplification induces acquired resistance to mutation-specific EGFR tyrosine kinase inhibitors in non-small cell lung cancer cells
Authors: Kobayashi Keigo , Nukaga Shigenari , Yasuda Hiroyuki , Masuzawa Keita , Hamamoto Jyunko , Kawada Ichiro , Naoki Katsuhiko , Mimaki Sachiyo , Matsumoto Shingo , Goto Koichi , Tsuchihara Katsuya , Betsuyaku Tomoko , Soejima Kenzo
Published: July 2017

Purpose:

Third-generation EGFR-tyrosine kinase inhibitors (TKIs) are mutation-specific inhibitors that generally have minimal effects on wild type protein. The mechanisms underlying acquired resistance to third-generation EGFR-TKIs remain relatively uncharacterized. The purpose of this study is to clarify the mechanisms of acquired resistance to third-generation EGFR-TKIs in order to improve the prognosis of lung cancer patients harboring EGFR mutations.

Experimental design:

We established third-generation EGFR-TKIs resistant cells using a dose-escalation method. The PC9 (EGFR E746-A750del) and H1975 (EGFR L858R+T790M) human NSCLC cell lines were cultured with rociletinib (CO-1686) or osimertinib (AZD9291) for several months. Their resistance to a third-generation EGFR-TKIs was confirmed by the MTS cell proliferation assay. To clarify the heterogeneity of potential resistance mechanisms, those resistant cell lines were subcloned to isolate resistant clones. DNA isolated from the parental and resistant cell clones was then subjected to whole exome sequencing. Copy number alterations and several genetic alterations potentially relevant to EGFR-TKIs sensitivity were detected.

Results:

We identified Src-AKT pathway contribute to acquired resistance. In addition, we identified that EGFR wild type allele, but not mutation allele, amplification induced acquired resistance. It mirrors the decreased inhibitory pressure for wild type EGFR by mutation-specific EGFR-TKIs.

Conclusion:

We provide evidence of wild type allele-mediated resistance, a novel concept of acquired resistance, occurring in response to mutation-specific inhibitor therapy in cancer treatment.

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Citation Format: Keigo Kobayashi, Shigenari Nukaga, Hiroyuki Yasuda, Keita Masuzawa, Jyunko Hamamoto, Ichiro Kawada, Katsuhiko Naoki, Sachiyo Mimaki, Shingo Matsumoto, Koichi Goto, Katsuya Tsuchihara, Tomoko Betsuyaku, Kenzo Soejima. EGFR wild type allele amplification induces acquired resistance to mutation-specific EGFR tyrosine kinase inhibitors in non-small cell lung cancer cells [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 4111. doi:10.1158/1538-7445.AM2017-4111
Abstract 412: Genetic variation in platinum-sensitive and platinum-resistant high-grade serous epithelial ovarian cancer
Authors: Castellano Tara , Clark Leslie H. , Rashid Naim , Bae-Jump Victoria
Published: July 2017

Background: We examined the association of platinum resistance with genetic mutations in high grade serous ovarian cancer (HSOC) patients undergoing high-throughput genomic tumor sequencing.

Methods: Snap-frozen and fresh frozen paraffin embedded tissue samples were collected from HSOC patients enrolled on UNCseq (NCT01457196). UNCSeq is an institutional protocol which uses next generation sequencing to detect genetic mutations in a wide array of malignancies. Illumina libraries were prepared separately from tumor and a matched normal sample from each patient. Relevant targets were enriched by a custom designed Agilent SureSelect hybrid capture enrichment library using standard protocols. Samples were sequenced on Illumina HiSeq machines in a variety of formats. Mutations with a quality score <100 were filtered from the data set, and only mutations rated to have a moderate to high impact were retained. Medical record review determined platinum sensitivity or platinum resistance. Tumors were defined as platinum sensitive or resistant if patients were noted to have > or < 6 months of disease free interval following completion of induction therapy, respectively.

Results: Overall 39 HSOC cases met inclusion criteria; 32 tumors met criteria for platinum sensitive and 7 platinum resistant. 308 mutations were noted in at least one individual across all patients. The top observed mutations in platinum sensitive HSOC were TP53 (41%, n= 13), GucylA2 (19%, n=6), MLL2 (19%, n=6) and MTOR (16%, n=5). The top observed mutations in platinum resistant tumors were TP53 (71%, n=5), TET1 (43%, n=3), NF1 (43%, n=3) and MLL3 (43%, n=3). There was a trend toward more p53 mutations in resistant tumors (71% versus 41%, p=0.21) There was no difference in the total number of mutations per tumor in platinum sensitive and resistant patients, (3 vs. 4, p=0.516).

Conclusions: We did not detect a difference in the number of genetic mutations in HSOC according to platinum sensitivity. Platinum resistant tumors had a trend toward higher frequency of TP53 mutations than platinum sensitive HSOCs. Furthermore, we identified 3 frequently mutated genes in platinum resistant HSOC: TET1, an epigenetic regulator, NF1, a tumor suppressor gene and MLL3, a histone modifier gene. Ongoing tumor sequencing of HSOCs on UNCseq will help to confirm these results.

Citation Format: Tara Castellano, Leslie H. Clark, Naim Rashid, Victoria Bae-Jump. Genetic variation in platinum-sensitive and platinum-resistant high-grade serous epithelial ovarian cancer [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 412. doi:10.1158/1538-7445.AM2017-412
Abstract 4121: Androgen receptor as a potential target in non-small cell lung cancer
Authors: Brennan Sean , Wang Albert R. , Beyer Hope , Wiese Dylan , Buehler Darya , Saeed Anwaar , Baschnagel Andrew M. , Iyer Gopal
Published: July 2017

The cancer genome atlas (TCGA) has identified androgen receptor (AR) to be mutated, deleted and amplified across human lung squamous cell carcinoma and adenocarcinoma. Expression of AR is critical for early lung development. However, the intriguing expression of AR in non-small cell lung cancer (NSCLC) opens up an alternative treatment paradigm in the event of onset of clinical resistance to lung cancer drugs. To investigate this potential, a) 10 NSCLC cell lines and 3 control prostate cancer cell lines were stimulated with synthetic AR agonist, R1881 at 24, 48 and 72 hours. 0.5-4-fold RNA and protein expression was found across these lung cancer cell lines when compared to unstimulated cells. b) droplet digital PCR revealed varying copies of AR DNA when benchmarked to prostate AR. c) cell proliferation assays of these cell lines with enzalutamide (MVD3100) treatment resulted in 50-65% cell survival at concentrations ranging from 10 - 25 µM. d) Immunohistochemical staining of AR in a NSCLC human tissue microarray (TMA) revealed 10 out of 88 patients (11%) to have AR positive staining in their tumor. This included 6 adenocarcinomas and 2 squamous cell carcinomas. 8 patients had focal while 2 had diffuse staining. Validation of the TMA performed with whole mount slides confirmed diffuse staining in these 11 samples. Taken together, these findings suggest AR is a potential therapeutic target in NSCLC and further work is underway to test these observations in drug resistant lung cancer cell lines and pre-clinical mouse models.

Citation Format: Sean Brennan, Albert R. Wang, Hope Beyer, Dylan Wiese, Darya Buehler, Anwaar Saeed, Andrew M. Baschnagel, Gopal Iyer. Androgen receptor as a potential target in non-small cell lung cancer [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 4121. doi:10.1158/1538-7445.AM2017-4121
Abstract 4132: Roles of the acetyltransferases CBP/p300 in breast cancer
Authors: Muhmud Iqbal , Tian Guimei , Liao Daiqing
Published: July 2017

Intrinsic drug resistance renders certain breast cancer (BC) patients unresponsive to standard-of-care therapies. For example, ~50% of patients with estrogen receptor-positive (ER+) tumors do not respond to endocrine therapies (ETs, e.g., tamoxifen). Acquired drug resistance is another cause for treatment failure and deadly relapse. Therefore, new strategies that tackle both intrinsic and acquired resistance are needed for improving clinical outcome for BC patients. ER-alpha, the defining factor for ER+ tumors, is an estrogen-activated transcription factor (TF) that drives tumor growth and progression. It critically depends on the coactivators CBP/p300 for gene expression underpinning tumor biology of ER+ subtypes that account for ~75% of all BC cases. Recent advances revealed that another hormone receptor, the androgen receptor (AR), is expressed in the majority of ER+ BCs as well as in a subset of ER- BCs. Evidence has shown that AR signaling is implicated in ET resistance. For the HER2-enriched tumors, high levels of AR expression correlate with poor prognosis. Similarly for ER-alpha, CBP/p300 act as key coactivators for AR-mediated gene expression. Additionally, other oncogenic TFs (e.g., beta-catenin/TCF and STAT3) also depend on CBP/p300 for gene activation. Importantly, these pathways are active in all BC subtypes, regardless of the hormone receptor status. CBP/p300 overexpression and heightened acetyltransferase activity are detected in clinical BC samples and correlate with disease progression. Thus, CBP/p300 represent attractive targets for developing novel therapies broadly applicable for treating all major BC subtypes. We have discovered a novel class of highly potent CBP/p300 inhibitors. Our previous studies indicated that this class of compounds is highly effective to suppress tumor growth in vivo using a xenograft mouse model. We will present genomic features of CBP/p300 in different breast cancer subtypes and experimental data underlying potential mechanisms by which CBP/p300 regulate oncogenic phenotypes, as well as effects of pharmacologic inhibition of CBP/p300 on sensitivity of breast cancer cells to standard anticancer therapeutics.

Citation Format: Iqbal Muhmud, Guimei Tian, Daiqing Liao. Roles of the acetyltransferases CBP/p300 in breast cancer [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 4132. doi:10.1158/1538-7445.AM2017-4132
Abstract 415: In vivo shRNA library screening to identify novel targets for head and neck squamous cell carcinoma
Authors: Pickering Curtis R. , Xie Tongxin , Kumar Manish , Parimi Ramya L. , Yang Liang P. , Wang Jiping , Seth Sahil , Bristow Christopher A. , Carugo Alessandro , Robinson Frederick S. , Draetta Giulio F. , Skinner Heath , Frederick Mitchell J. , Myers Jeffrey N.
Published: July 2017

Head and neck squamous cell carcinoma (HNSCC) is a diverse group of tumors from the upper aerodigestive tract that are treated primarily with surgery, chemotherapy, and/or radiation. Recent genomic studies have characterized the genomic alterations in HNSCC but they failed to identify novel oncogenic drivers for therapeutic targeting. In order to identify novel targets we have utilized an in vivo shRNA library screening platform in a panel of genomically characterized HNSCC cell lines. The screens were performed alone or in combination with platinum-based chemotherapy or radiation, and the screening libraries included known druggable targets, DNA repair genes, and HNSCC candidate driver genes. Initial results indicate that this in vivo screening is able to identify targets that may not be found through traditional in vitro screening approaches and related to tumor-stromal interactions and metabolism. These genes emphasize the importance of including the tumor microenvironment in studies to understand driver genes and identify novel therapeutic interventions.

Citation Format: Curtis R. Pickering, Tongxin Xie, Manish Kumar, Ramya L. Parimi, Liang P. Yang, Jiping Wang, Sahil Seth, Christopher A. Bristow, Alessandro Carugo, Frederick S. Robinson, Giulio F. Draetta, Heath Skinner, Mitchell J. Frederick, Jeffrey N. Myers. In vivo shRNA library screening to identify novel targets for head and neck squamous cell carcinoma [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 415. doi:10.1158/1538-7445.AM2017-415
Abstract 4153: CRISPR/Cas9-based oncogene editing enables characterization of rare mutations in cancer cells
Authors: Plenker Dennis , Sos Martin L.
Published: July 2017

In the past decade new insights into key oncogenic pathways and the development of targeted therapies enabled the success of precision medicine. However, only a small part of the cancer genome can be targeted effectively. This is in part due to the fact that the number of cancer cell models for a given oncogenic mutation is limited. We hypothesized that CRISPR/Cas9-mediated genome editing may enhance the ability to functionally study rare genomic lesions or resistance mutations that arise in patients under therapy. As a proof of concept we established, genetically modified PC9 lung cancer cells that harbor an activating EGFR ex19 deletion (EGFRdel E746-A750) into double mutated (EGFRdel E746-A750+T790M) or triple mutated (EGFRdel E746-A750+T790M+C797S) EGFR in order to induce resistance against known EGFR inhibitors. These cell lines fully recapitulated the phenotypic response pattern to first and third generation EGFR inhibitors that have been observed in patients harboring these clinically relevant resistance mutations. In a next step we switched the dependency of PC9 cells from the intrinsic oncogenic EGFR mutation into a rare ex20 SVDins mutation (EGFRD770_N771insSVD) that is typically associated with resistance towards all known EGFR inhibitors. Again, we observed a shift in the response to targeted inhibition of EGFR when compared to parental cells. Since the methodological principles can be applied to an array on known oncogenic mutations our approach may serve as a versatile platform for the functional study of oncogenic mutations that are found in patients. We envision that such reprogrammed cells may be of use for the screening of novel targeted therapeutics and therefore may enable the development of mutation specific drugs that are currently lacking for the majority of patients.

Citation Format: Dennis Plenker, Martin L. Sos. CRISPR/Cas9-based oncogene editing enables characterization of rare mutations in cancer cells [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 4153. doi:10.1158/1538-7445.AM2017-4153
Abstract 4164: TRAIL resistance of glioblastoma cells is associated with DNA damage signalling network
Authors: Sur Idot;lknur , Muslu Kerem , Cingöz Ahmet , Önder Tuğba Bağcı
Published: July 2017

To reduce the risk of ageing associated dysfunctions and maintain the genomic stability, cells need a complex DNA repair mechanisms. Defects in this pathway or accumulation of DNA damage lead to genome instability, tumorigenesis, and ageing. Chemotherapy and radiotherapy are designed to kill cancer cells by inducing DNA damage and triggering cellular ageing. Surgery followed by combined chemotherapy and radiotherapy is currently the standard therapy for glioblastoma multiforme (GBM) which is the most common primary brain tumor. TNF related apoptosis-inducing ligand (TRAIL) is promising anti-cancer agent for GBM therapy, as it induces apoptotic death in only cancerous cells, but not in normal cells. However, the mechanisms underlying TRAIL resistance in GBM have remained elusive. To understand the role of DNA damage response (DDR) mechanism and develop more effective therapeutic approaches, TRAIL resistant and sensitive T98G cells were generated. The effect of DDR proteins (H2AX (Ser319), ATM total, ATR total, CHK1 total, CHK2 total, ATM (Ser1981), ATR (Ser428), CHK1 (Ser345), CHK2 (Ser19) and 53BP1) on TRAIL resistance was detected in TRAIL resistant and sensitive T98G cells. These proteins showed different level of protein expressions in TRAIL resistance and sensitive T98G cells. Most remarkable difference was found in the level of phosphorylated kinase CHK2 (Ser19) with higher expression level in TRAIL resistant T98G cells than TRAIL sensitive T98G cells. Therapies that inhibit CHK2 (Ser19) levels in glioma may enhance the efficacy of TRAIL treatment. In immunofluorescence analysis, increased number of γH2AX foci was noted upon TRAIL treatment. These findings demonstrate that DNA damage signalling pathways contribute to TRAIL resistance and targeted inhibition of DNA repair factors can provide the most effective therapeutic strategies to overcome TRAIL resistance of GBMs. Moreover, the information from this study may hold answers for cancer research in future and serve as a potential suppressor for the treatment of cancer.

Citation Format: İlknur Sur, Kerem Muslu, Ahmet Cingöz, Tuğba Bağcı Önder. TRAIL resistance of glioblastoma cells is associated with DNA damage signalling network [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 4164. doi:10.1158/1538-7445.AM2017-4164
Abstract 4170: Targeting androgen receptor overcomes resistance to tyrosine kinase inhibitors in advanced clear cell renal cell carcinoma
Authors: Adelaiye-Ogala Remi M. , Chintala Sreenivasulu , Orillion Ashley , Elbanna May , Elzey Ben , Damayanti Nur , Miles Kiersten M. , Kao Chinghai , Pettazzoni Piergiorgio , Draetta Giulio F. , Pili Roberto
Published: July 2017

Background: Advanced renal cell carcinoma (RCC) responds initially to anti-angiogenic therapies but eventually develop resistance which may be driven by the expression of key intratumoral pro-survival protein and overall kinome reprogramming. Androgen receptor (AR) expression has been reported in clear cell renal cell carcinoma (ccRCC) but its biological role remains elusive and its association with resistance to tyrosine kinase inhibitors (TKIs) has not been studied. Here we report the role of AR and its association with resistance to TKIs in advanced RCC. Methods: Human RCC cell lines; 786-0, 786-0R (with induced sunitinib resistance), ACHN, URMC2 (with intrinsic sunitinib resistance) were used to assess the combination effect of sunitinib and the AR antagonist enzalutamide in vitro. In vivo studies utilizing 786-0 tumors assessed the combination effect of enzalutamide and sunitinib following acquired resistance to sunitinib. AR expression was detected by qRT-PCR and Western blot analysis, and AR localization by immunofluorescence in treated and non-treated cells. Gene array was used to assess 93 AR associated genes in sensitive and resistant cells. Results: Quantitative RT-PCR data revealed a significant increase in AR expression with sunitinib resistance (>100 folds; p>0.001). In vitro and in vivo studies indicated significant increase in nuclear and cytoplasmic expression of AR with sunitinib treatment in resistant cells which was abrogated with single agent enzalutamide and combination treatment. More interestingly, combination treatment of enzalutamide and sunitinib significantly decreased cell growth and induced tumor regression in vitro and in vivo, respectively. Conclusion: Our data suggest the role of AR both in intrinsic and acquired sunitinib resistance in ccRCC and provide a rationale for combination strategies to restore TKI sensitivity that can be tested in the clinical setting.

Citation Format: Remi M. Adelaiye-Ogala, Sreenivasulu Chintala, Ashley Orillion, May Elbanna, Ben Elzey, Nur Damayanti, Kiersten M. Miles, Chinghai Kao, Piergiorgio Pettazzoni, Giulio F. Draetta, Roberto Pili. Targeting androgen receptor overcomes resistance to tyrosine kinase inhibitors in advanced clear cell renal cell carcinoma [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 4170. doi:10.1158/1538-7445.AM2017-4170
Abstract 4174: The impact of catechol estrogen metabolism on the proliferation rate and Docetaxel (DOC) resistance in hormone-responsive cancers
Authors: Tolba Mai F. , Omar Hany , Noreddin Ayman M.
Published: July 2017

Estrogen-responsive cancers such as breast cancer (BC) and prostate cancer (PC) are on the top of the most commonly diagnosed cancers in USA. Docetaxel (DOC) is considered the first-line of therapy for both metastatic BC and castration-resistant PC. However, its use in therapeutically effective doses is associated with significant toxic reactions and tumor resistance. Estrogens (E2) play an important role in the development and progression of both malignancies. Of special importance is that the catechol E2 metabolite, 4-hydroxyestradiol (4-OHE2) enhances the proliferation of both breast and prostate normal epithelial cells. The goal of this work is to investigate the relationship between catechol-E2 metabolism and cancer cells proliferation and response to DOC. Methods: The cells were exposed to serial concentrations of E2 and 4OHE2 (0.001-10 µM) to assess their effect on cells’ growth rate over 24-92 h. Cell proliferation assays were utilized to assess the density of viable cells at different time points. Cytotoxicity assays were performed to evaluate the median inhibitory concentration (IC50) of DOC alone or in the presence of 4OHE2. Results: Exposure of the estrogen receptor (ER)-positive BC cell line MCF-7 to 0.1 µM of 17-β-hydroxyestradiol (E2) for 3 days significantly boosted the cell proliferation rate compared to control group by about 27% (P<0.05). Exposure of MCF-7 cells to the catechol estrogen metabolite 4-hydroxyestradiol (4OHE2) at 0.1µM for 3 days significally enhanced cell growth by about 31% (P<0.001). Similarly, exposure of the androgen independent, ER-positive- advanced stage PC cells PC-3 to E2 (1 µM, 3 days) significantly enhanced the growth rate by 37% (P<0.05). Moreover, our data showed that simultaneous exposure to 4OHE2 significantly antagonized the cytotoxic activity of DOC with subsequent increase in the IC50 of DOC by 18 folds (P<0.006). Conclusion: these results indicate that altered E2 metabolism with subsequent accumulation of 4-OHE2 can enhance the proliferation rate of E2-responsive cancers in addition to hindering the cytotoxic activity of DOC with subsequent reduction in DOC potency. Further research is in progress to assess the potential merit of modulating the clearance of catechol E2 as a strategy to improve the cancer response to DOC. (This project is supported by Fulbright Scholar grant FY15/16 and L’Oreal-UNESCO for Women in Science-Levant and Egypt award for MFT).

Citation Format: Mai F. Tolba, Hany Omar, Ayman M. Noreddin. The impact of catechol estrogen metabolism on the proliferation rate and Docetaxel (DOC) resistance in hormone-responsive cancers [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 4174. doi:10.1158/1538-7445.AM2017-4174
Abstract 4176: Targeting TAM family members with antibody or small molecule inhibitors enhances therapeutic modalities of HNSCC
Authors: Black Nellie K. , Iida Mari , Rodems Tamara S. , Brand Toni M. , Kimple Randall J. , Wheeler Deric L.
Published: July 2017

Radiation, cisplatin, and cetuximab are clinical therapeutics used in the treatment of head and neck squamous cell carcinoma (HNSCC). Despite clinical success with these modalities, development of both intrinsic and acquired resistance is an emerging problem in the management of HNSCC. Thus, identifying and targeting molecules driving this drug resistance is essential for improving efficacy of treatment approaches.

Recent studies have identified a role for the TAM family of receptor tyrosine kinases (Tyro, Axl, and Mer) in tumor biology, especially the Axl receptor in promoting tumor growth and metastasis. Previously, we identified Axl as a logical molecular target in HNSCC and indicated that it may play a pivotal role in resistance to radiation, cisplatin, and cetuximab. In the current study, we advanced these early findings into pre-clinical models using patient-derived xenografts (PDXs). We have shown that small molecules targeting Axl can enhance therapy in PDXs that express high levels of Axl and have been identified as resistant to radiation, cisplatin, and cetuximab. Current studies are focusing on antibody-based targeting of Axl using PDXs and genetically-modified models of resistance. Furthermore, studies focused on co-targeting of Axl and Mer in vitro and in vivo have shown striking results and denote the importance of establishing logical approaches to target TAMs in the management of HNSCC.

Finally, investigations into the molecular mechanisms of how Axl signaling can lead to resistance have underscored the importance of tyrosine 821 (Y821) of Axl. Overexpression of Axl rendered cetuximab sensitive lines resistant, but cell lines overexpressing Axl-Y821F retained their sensitivity to cetuximab. Advancing this line of study in vivo indicated that tumors expressing Axl were resistant to cetuximab whereas tumors harboring the Y821 mutation were sensitive demonstrating that signals emanating from Y821 may be critical for cetuximab resistant pathways.

Collectively, the studies presented herein identify the TAM family of receptors as key players in radiation, cisplatin, and cetuximab resistance. These results provide rationale for the clinical targeting of TAM receptors to enhance the therapeutic modalities used in treating HNSCC.

Citation Format: Nellie K. Black, Mari Iida, Tamara S. Rodems, Toni M. Brand, Randall J. Kimple, Deric L. Wheeler. Targeting TAM family members with antibody or small molecule inhibitors enhances therapeutic modalities of HNSCC [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 4176. doi:10.1158/1538-7445.AM2017-4176
Abstract 423: Detection of genetic alterations to predict the chemotherapeutic responses in unresectable pancreatic ductal adenocarcinomas
Authors: Park Joo Kyung , Lee Kwang Hyuck , Park Donghyun , Park Woong-Yang , Son Dae-Soon , Lee Jong Kyun , Lee Kyu Taek
Published: July 2017

Background & Aims: Next-generation sequencing (NGS) that enables the analyses of massively parallel sequences of DNA can advance the understanding of the underlying molecular pathophysiologies of cancer. Such recent genomic analyses have revealed a complex mutational landscape for PDACs. The aims of this study were to investigate the genomic profile to predict the chemotherapy response in unresectable PDACs.

Methods: The total of 80 pathologically confirmed PDACs were enrolled and genomic DNA was extracted and quality control metrics of DNA analytes were measured. The specimens that passed a quality control test underwent targeted deep sequencing using a customized cancer panel (CancerSCAN) enriched in the exons of 83 genes.

Results: Clinical prognostic factors associated with survival in PDAC were gender, tumor mass size, stage and chemotherapy response rate. (P=0.078, 0.009, 0.052 and <0.001, respectively). Multivariate Cox proportional-hazards analysis revealed chemotherapy response rate (P < 0.001, hazard ratio (HR) = 1.908, 95% CI, 1.281 to 2.840) is an independent prognostic factor. There were 56 (71%) and 9 (11%) study patients who underwent gemcitabine based chemotherapy and FOLFIRINOX respectively. Response rate of study patients were as follows; CR+PR 14 (20%), SD (27%) and PD 28 (41%). There were only 9 (16%) and 4 (50%) patients who had CR+PR response gemcitabine based chemotherapy and FOLFIRINOX respectively.

Conclusion: Targeted sequencing using EUS-FNA specimens in PDAC showed excellent compatibilities to analyze genomic profiles of PDACs. Furthermore, novel genes associated with survival, metastasis and chemotherapy response in PDAC were identified.

Citation Format: Joo Kyung Park, Kwang Hyuck Lee, Donghyun Park, Woong-Yang Park, Dae-Soon Son, Jong Kyun Lee, Kyu Taek Lee. Detection of genetic alterations to predict the chemotherapeutic responses in unresectable pancreatic ductal adenocarcinomas [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 423. doi:10.1158/1538-7445.AM2017-423
Abstract 4232: Gastrointestinal stromal tumor: Retrospective analysis of 44 cases of center of reference in eastern Algeria
Authors: Boukhalfa Soufyane Ali , Filali Tah
Published: July 2017

Aim: To analyze the clinicopathologic characteristics, prognostic factors, and treatment of gastrointestinal stromal tumors (GISTs).

Methods: We conducted a retrospective analysis of all cases of GISTs treated in the Medical Oncology Unit from 2010 through 2015.

Results: We analyzed 44 patients with a median age of 49.43 years (17-76 years) with sex ratio 1:1. The main symptom was abdominal pain. Thirty patients had limited-stage disease and 14 patients had metastatic disease. We observed 90% of the immunohistochemistry exams were positive for CD117 (c-Kit+). The most frequent location was in the stomach (45%), the high-risk group was predominant (50%) and the average tumor size is 12.84 cm. Surgery was considered R0 (extensive) in 75% of the cases and the main sites of metastases were liver and peritoneum.25 patients received imatinib 400 mg qDay in adjuvant setting,5 patients in neoadjuvant, 13 patients in palliative and 1 patient had best supportive care. A total of 44 patients were followed up for 1 to 78 months.6 patients (13 %) developed recurrence or metastasis during or after adjuvant treatment. Two patients had surgery after neoadjuvant treatment(40%). 4 patients treated in second line with imatinib 800 mg qDay, 5 patients with sunitinib and 2 patients rechallenged in third line with imatinib 800 mg qDay.

Conclusion: Our patients presented mainly in the form of high-risk disease, Surgery is the mainstay treatment when GISTs are localized, Adjuvant therapy is used depending their risk of relapse. In the advanced disease, tyrosine kinase inhibitors have substantially improved the prognosis of GISTs.

Note: This abstract was not presented at the meeting.

Citation Format: Soufyane Ali Boukhalfa, Tah Filali. Gastrointestinal stromal tumor: Retrospective analysis of 44 cases of center of reference in eastern Algeria [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 4232. doi:10.1158/1538-7445.AM2017-4232
Abstract 425: SMRT® Sequencing of full-length androgen receptor isoforms in prostate cancer reveals previously hidden drug resistant variants
Authors: Kohli Manish , Ho Yeung , Hillman David W. , Etten Jamie L. Van , Henzler Christine , Yang Rendong , Li Yingming , Tseng Elizabeth , Hon Ting , Clark Tyson A. , Wang Liguo , Silverstein Kevin , Wang Liewei , Dehm Scott M.
Published: July 2017

Prostate cancer is the most frequently diagnosed male cancer. For prostate cancer that has progressed to an advanced or metastatic stage, androgen deprivation therapy (ADT) is the standard of care. ADT inhibits activity of the androgen receptor (AR), a master regulator transcription factor in normal and cancerous prostate cells. The major limitation of ADT is the development of castration-resistant prostate cancer (CRPC), which is almost invariably due to transcriptional re-activation of the AR. One mechanism of AR transcriptional re-activation is expression of AR-V7, a truncated, constitutively active AR variant (AR-V) arising from alternative AR pre-mRNA splicing. Noteworthy, AR-V7 is being developed as a predictive biomarker of primary resistance to androgen receptor (AR)-targeted therapies in CRPC. Multiple additional AR-V species are expressed in clinical CRPC, but the extent to which these may be co-expressed with AR-V7 or predict resistance is not known. Here we utilized long read sequencing to identify and quantify AR isoforms expressed in CRPC. To unambiguously characterize all AR isoforms, we prepared Iso-Seq™ libraries via 3’ rapid amplification of cDNA ends (RACE) with RNA isolated from prostate cancer cell lines and xenograft tissues using a forward primer anchored in AR exon 1. 3’RACE reactions were subjected to single molecule, real-time (SMRT®) long-read sequencing with a Pacific Biosciences RSII System. Our work identified AR-V9 as a truncated isoform that is frequently co-expressed with AR-V7 in CRPC. Mechanistically, our work re-annotated AR-V7 and AR-V9 mRNAs, showing these two species shared a common 3’ terminal exon containing separate splice acceptor sites. Taking into account this new information, novel siRNAs and antibodies which could distinguish between AR-V7 and AR-V9 were designed, validated and used to measure the relative expression of these two AR isoforms in CRPC cells with a view to determining the potential of AR-V9 as a predictive biomarker of primary resistance to AR-targeted therapies.

Citation Format: Manish Kohli, Yeung Ho, David W. Hillman, Jamie L. Van Etten, Christine Henzler, Rendong Yang, Yingming Li, Elizabeth Tseng, Ting Hon, Tyson A. Clark, Liguo Wang, Kevin Silverstein, Liewei Wang, Scott M. Dehm. SMRT® Sequencing of full-length androgen receptor isoforms in prostate cancer reveals previously hidden drug resistant variants [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 425. doi:10.1158/1538-7445.AM2017-425
Abstract 4255: Associations of coffee consumption and caffeine intake with mammographic breast density
Authors: Yaghjyan Lusine , Colditz Graham , Rosner Bernard , Gasparova Aleksandra , Tamimi Rulla
Published: July 2017

Purpose: Previous studies suggest that coffee consumption and caffeine intake may be associated with reduced breast cancer risk which may result from stimulating effect of coffee on estrogen metabolism enzymes and subsequent changes in bioavailable estrogen. We investigated the association of coffee consumption and caffeine intake with mammographic density by woman’s menopausal status and, in postmenopausal women, by hormone therapy (HT).

Methods: This study included 4,130 cancer-free women within the Nurses’ Health Study and Nurses’ Health Study II cohorts. Percent breast density (PD), absolute dense and non-dense areas were measured from digitized film mammograms using a computer-assisted thresholding technique; all measures were square-root transformed for the analysis to improve normality. Diet was assessed with a food frequency questionnaire; average cumulative coffee/caffeine consumption was calculated using data available from all the questionnaires preceding the mammogram date. Information regarding breast cancer risk factors was obtained from baseline or biennial questionnaires closest to the mammogram date. We used generalized linear regression to quantify associations between exposures and breast density measures, adjusted for potential confounders. Associations were examined separately for regular coffee, decaffeinated coffee, total coffee, and energy-adjusted caffeine intake.

Results: In multivariable analyses, decaffeinated coffee was positively associated with PD in premenopausal women (2+ cups/day: β=0.23, p-trend=0.03). In postmenopausal women, decaffeinated and total coffee were inversely associated with PD (decaffeinated coffee 2+ cups/day: β=-0.24, p-trend=0.04; total coffee 4+ cups/day: β=-0.17). These associations appeared to be driven by the inverse associations of these exposures with absolute dense area. Among current HT users (n=980), regular coffee and caffeine intake were inversely associated with PD (regular coffee 4+ cups/day: β=-0.29, p-trend<0.01; caffeine 4th vs. 1st quartile: β=-0.32, p-trend<0.01). Among past users (n=430), decaffeinated coffee was inversely associated with PD (2+ cups/day β=-0.70, p-trend=0.02).

Conclusions: Our findings suggest that among current HT users, regular coffee and caffeine are inversely associated with mammographic percent breast density.

Citation Format: Lusine Yaghjyan, Graham Colditz, Bernard Rosner, Aleksandra Gasparova, Rulla Tamimi. Associations of coffee consumption and caffeine intake with mammographic breast density [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 4255. doi:10.1158/1538-7445.AM2017-4255
Abstract 4282: Germline TP53 p.R337H mutations and Li-Fraumeni syndrome: A new variant form of the disease
Authors: Freycon Claire , Andrade Kelvin César De , Yacouba Amina , Formiga Maria Nirvana , Bittar Camila , Santiago Karina Miranda , Savage Sharon , Ashton-Prolla Patricia , Hainaut Pierre , Achatz Maria Isabel
Published: July 2017

The founder germline TP53 mutation, p.R337H, was detected in South and Southern Brazil in families with Li-Fraumeni Syndrome (LFS). The aim of this study was to estimate the burden and patterns of cancer in p.R337H carriers and other germline TP53 mutations. We analyzed data on 539 individuals from the LFS/LFL database from A.C. Camargo Cancer Center in São Paulo, Brazil and compared to International Agency for Research on Cancer (IARC) germline TP53 mutations database (R17). A total of 144 p.R337H carriers have developed 147 cancers (16.7% multiple primaries). The most frequent malignancies were soft tissue sarcoma (STS; 25.9%), breast cancer (24.5%) and adrenocortical carcinoma (ACC; 17.7%). Compared to IARC database, p.R337H carriers had a higher risk of ACC and STS, a lower risk of brain tumors and osteosarcomas (P<0.01). Patients with p.R337H were at risk for developing thyroid and kidney cancers. The median age at diagnosis was 43 years in p.R337H carriers, 30 in other mutations carriers and 65 in the general population. The overall penetrance was similar in both groups until age 12 years. Penetrance was lower in p.R337H carriers (27% at 30 years, 55% at 60 years). The lifetime penetrance was significantly higher in females (79%) than in males (48%). p.R337H-associated disease resembles LFS until age 12, and then diverges, with differences in men and women and a predisposition to cancers that are not part of the LFS spectrum. These observations suggest that p.R337H could predispose to a variant form of LFS.

Citation Format: Claire Freycon, Kelvin César De Andrade, Amina Yacouba, Maria Nirvana Formiga, Camila Bittar, Karina Miranda Santiago, Sharon Savage, Patricia Ashton-Prolla, Pierre Hainaut, Maria Isabel Achatz. Germline TP53 p.R337H mutations and Li-Fraumeni syndrome: A new variant form of the disease [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 4282. doi:10.1158/1538-7445.AM2017-4282
Abstract 4284: Gate keeping role for endometrial cancer about Lynch syndrome by surgeon
Authors: Kim Min Kyu , Kwon Min Jung , Yun Min Jeong
Published: July 2017

Background: It is well known that Lynch syndrome increases risk of endometrial and colorectal cancer. There is not much study about detecting Lynch syndrome patient fast among Korean population by gynecologic oncology surgeon. We undertook this study to investigate this.

Methods: A review of endometrial cancer patients who was counseled about Lynch syndrome in Department of Obstetrics and gynecology, Samsung Changwon Hospital by single surgeon was done. Clinical information was extracted from the medical record including age, family and personal history of cancer, immunohistochemistry(IHC), microsatellite instability test(MSI), and gene sequencing results. Risk management and posttest education after result were offered about risk reducing options and cascade testing for affected individual

Results: App patient was 16.There were two germline mutations (both MSH2) (c.23C>T (p.Thr8Met), c.187delG (p.Val63*).Both were negative for MSH2 IHC, But no patient matched criteria of Amsterdam. Four variation of unknown significance (VUS) was found (Three MSH2 and One MLH1).Among those all were abnormal in IHC and there was only one Amsterdam criteria matched patient. There were two unstable MSI patients, one was MSH2 germline mutation and the other was MSH2 VUS. Median age was 57(41~76).Most cases were endometrioid type (11/16, 69 %).Seventy five percent were stage I(12/16).

Conclusion: Two MSH2 germline mutation patients among this population was found. Gynecologic oncology surgeon can be adapted to develop the ability to assess and evaluate genetic risk among endometrial cancer.

Citation Format: Min Kyu Kim, Min Jung Kwon, Min Jeong Yun. Gate keeping role for endometrial cancer about Lynch syndrome by surgeon [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 4284. doi:10.1158/1538-7445.AM2017-4284
Abstract 4285: Impact of subsidies on cancer genetic testing uptake in Singapore
Authors: Li Shao Tzu , Yuen Jeanette , Zhou Ke , NGEOW JOANNE
Published: July 2017

Purpose: Previous reports cite high costs of clinical cancer genetic testing as main barriers to patient’s willingness to test. We report findings of a pilot study that evaluates how different subsidy schemes impact genetic testing uptake and total cost of cancer management.

Methods:We included all patients who attended the Cancer Genetics Service at the National Cancer Centre Singapore ( January 2014-May 2016). Two subsidy schemes, the blanket scheme (100% subsidy to all eligible patients), and the varied scheme (patients received 50%-100% subsidy dependent on financial status) were compared. We estimated total spending on cancer management from government’s perspective using a decision model.

Results: 445 patients were included. Contrasting against the blanket scheme, the varied scheme observed a higher attendance of patients (34 vs 8 patients per month), of which a higher proportion underwent genetic testing (5% vs 38%), while lowering subsidy spending per person (S$1098 vs S$1161). The varied scheme may potentially save cost by reducing unnecessary cancer surveillance when first-degree relatives uptake rate is above 36%.

Findings :Provision of subsidy leads to a considerable increase in genetic testing uptake rate. From the government’s perspective, subsidising genetic testing may potentially reduce total costs on cancer management. Understanding and overcoming barriers for cascade testing in first degree relatives can improve cost-savings.

Citation Format: Shao Tzu Li, Jeanette Yuen, Ke Zhou, JOANNE NGEOW. Impact of subsidies on cancer genetic testing uptake in Singapore [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 4285. doi:10.1158/1538-7445.AM2017-4285