bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A31: Revisited use of tamoxifen for improving melanoma therapy
Authors: Morad Samy A.F , Bridges Lance C. , Cabot Myles C. 
Published: May 2015

Abstract
The rapid increase in the incidence of malignant melanoma, a highly aggressive, drug-resistant cancer, has not been accompanied by significant therapeutic breakthroughs for decades, despite the introduction of biochemotherapies. The Dartmouth regimen, of which tamoxifen is a standard component, has also had little impact on outcome. Therefore, examination of alternative melanoma vulnerabilities is essential. Sphingolipid (SL) metabolism is an area of cancer science that has recently risen to prominence. This is because ceramide, the aliphatic backbone of SL's, can act as a powerful tumor censor. However, cancer cells rapidly inactivate ceramide via two major metabolic routes: glycosylation to form glucosylceramide and hydrolysis, which generates sphingosine 1-phosphate, a mitogenic SL. These actions severely blunt ceramide anticancer properties, thwarting potential utility in treatment. Our previous work has shown that tamoxifen is a potent inhibitor of ceramide metabolism at glycosylation and hydrolysis. Herein, we exploit these unique actions and pair tamoxifen with a cell-permeable ceramide, C6-ceramide, and demonstrate that this novel drug duo, unlike the single agents, was highly effective in inhibiting melanoma cell (A375 and cell lines established from patients) proliferation, inducing caspase-dependent apoptosis, promoting cell cycle arrest, diminishing cellular adhesion and migration, reducing cell surface expression of integrins, and downregulating expression of the main source of drug resistance in melanoma, survivin, all essential elements of a drug regimen useful for limiting melanoma growth. Because integrin expression often correlates with conversion of melanoma growth from radial to vertical, we propose that tamoxifen can serve as an effective adjuvant to C6-ceramide for countering metastatic potential. Whereas the role of tamoxifen in the Dartmouth regimen has always remained elusive, its role as a ceramide sensitizer is clear and presents novel inroads for improving melanoma therapy.
Citation Format: Samy A.F Morad, Lance C. Bridges, Myles C. Cabot. Revisited use of tamoxifen for improving melanoma therapy. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A31.
Abstract A39: A platform to assess multiple therapy options simultaneously in a patient's own tumor
Authors: Klinghoffer Richard , Moreno-Gonzalez Alicia , Carleton Michael , Grenley Marc , Hatton Beryl , Frazier Jason , Kerwin William , Tretyak Ilona , Hedin Nathan , Dey Joyoti , Casalini Joseph , Ditzler Sally , Olson James , Caffo Nathan 
Published: May 2015

Abstract
Assessment of anti-cancer drug efficacy is an imprecise and challenging undertaking. Early candidate selection is typically based on results from systemically treated animal models and later by performance in human trials where patients are exposed to often toxic levels of drug, prior to obtaining readouts of tumor response. In both of these testing models, only one drug can be tested at a time. Using these methods, over 90% of candidate new oncology drugs fail to provide benefit for patients in human clinical trials.
To improve the predictive value of preclinical candidate selection in animal models and enable a new type of pre-Phase 1 toxicity-sparing comparative drug efficacy study in humans, amenable for use in the solid tumor clinic, we have developed a technology platform called CIVO™. This platform allows for simultaneous assessment of multiple drugs or drug combinations directly in a single solid tumor to assess efficacy, resistance and drug synergies.
In this study, precise, controlled delivery of classic chemotherapy drugs vincristine and doxorubicin induced spatially defined (ranging 0.3 – 2.0 mm in diameter), readily detectable, and mechanism-specific cellular changes around sites of tumor microinjection across three xenograft models of lymphoma. The extent of apoptosis induced via CIVO™ microdosing of each drug (&lt;1/100th the effective dose used to treat human patients) correlated with drug effect on tumor growth mediated by conventional systemic drug dosing. Consistent with utility for detecting pre-existing tumor resistance to certain drugs, CIVO™ microdosing predicted diminished responses to both vincristine and doxorubicin in tumors derived from cells that had previously acquired resistance to doxorubicin. This lack of efficacy was confirmed by systemic treatment of the resistant tumors. The CIVO™ platform is concurrently being evaluated for correlation to systemic treatment in immune-intact canine patients with autochthonous tumors.
The data presented here generated in drug-responsive and non-responsive solid tumors in the preclinical setting sets the stage for future application of this technology to demonstrate tumor responsiveness to novel drug candidates in the context of human patients.
Citation Format: Richard Klinghoffer, Alicia Moreno-Gonzalez, Michael Carleton, Marc Grenley, Beryl Hatton, Jason Frazier, William Kerwin, Ilona Tretyak, Nathan Hedin, Joyoti Dey, Joseph Casalini, Sally Ditzler, James Olson, Nathan Caffo. A platform to assess multiple therapy options simultaneously in a patient's own tumor. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A39.
Abstract A57: Effects of pre-exposure to siRNA on silencing response: Do cells become resistant to siRNA silencing?
Authors: Aliabadi Hamidreza Montazeri , Mahdipoor Parvin , Kucharsky Cezary , Chan Nicole , Uludag Hasan 
Published: May 2015

Abstract
Development of resistance against cytotoxic effect of different generations of anticancer drugs is considered inevitable and remains a major concern for cancer therapy. An alternative therapeutic approach based on protein silencing via RNA interference (RNAi) have shown considerable promise; however, our information about the factors affecting siRNA efficiency and the limitations to their efficacy are limited. This study focused on determining the possibility of development of resistance against siRNA treatment as a result of repeated exposure to siRNA that could affect cellular internalization of the particles, silencing efficiency at mRNA level, and ultimately, the observed cellular response. Two approaches to siRNA exposure were undertaken: one involving a single high concentration exposure to eradicate siRNA-responsive cells, and one involving multiple exposures with a gradually increasing siRNA concentration to study the potential intracellular adaptations. Our results demonstrated a temporary decrease in silencing efficiency at mRNA level without significant alteration in siRNA cellular uptake. We conclude that cells would respond to repeated siRNA exposure in a similar fashion after a temporary initial alteration; however, we could not rule out the possibility of a change in phenotypical response (e.g., number of viable cells) as a result of adjustments in (or selection of cells reliant on) alternative pathways.
Citation Format: Hamidreza Montazeri Aliabadi, Parvin Mahdipoor, Cezary Kucharsky, Nicole Chan, Hasan Uludag. Effects of pre-exposure to siRNA on silencing response: Do cells become resistant to siRNA silencing? [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A57.
Abstract B05: Recurrence and hormone therapy resistance of cervical cancer in a transgenic mouse model
Authors: Mehta Fabiola , Chung Sang-Hyuk 
Published: May 2015

Abstract
Persistent HPV infection and other cofactors are required for the progression of cervical cancer. Oral contraceptive use or multiple parities increases risk for cervical cancer in HPV-positive women. These risk factors have hormonal balance skewed toward estrogen (i.e., an increase in estrogen levels is much greater than an increase in progesterone levels). It is consistent that transgenic mice expressing HPV16 E6 and E7 (K14E6/K14E7) develop cervical cancer only when treated with physiological levels of estrogen. Using this validated mouse model, we demonstrated that estrogen receptor alpha (ERα) antagonists (e.g., raloxifene) or a progesterone receptor (PR) agonist [e.g. medroxyprogesterone acetate (MPA)] is efficient in treating cervical cancer. Cervical cancer recurs after raloxifene therapy, and recurring disease remains sensitive to raloxifene. The present study investigates whether cervical cancer recurs after stopping MPA treatment. Consistent with our prior results, K14E6/K14E7 mice (7 of 7) developed cervical cancer after 6-month estrogen treatment (initial cancer), which regressed in 14 of 14 mice upon 2-month MPA treatment (i.e., complete response). When the mice were re-treated for 2 months with estrogen after MPA therapy, cervical cancer was observed in 6 of 6 mice (100%). As a control, a group of mice were left untreated for first 6 months, and then treated with MPA for 2 months followed by 2-month estrogen treatment. We defined cervical disease in this group as newly arising disease. Cancer incidence in this group (25%; 4 of 16 mice) was significantly lower. These results indicate that cervical cancer recurs if MPA treatment is discontinued. Interestingly, recurrence was also observed in 8 of 8 mice without readministration of estrogen, indicating that recurring cancers are independent of exogenous estrogen (we do not know whether they depend on endogenous estrogen). Strikingly, when mice bearing recurring cancers were re-treated with MPA, cancer incidence (100%, 5 of 5 mice) and cancer multiplicity remained similar to a control group, and moderate reduction in cancer size was observed. These results indicate that recurring cervical cancers acquired resistance to PR agonist therapy. This resistance was not due to loss of PR because PR status in recurring cancers was similar to that in initial cancers. Further study is warranted to determine a mechanism of therapy resistance in this mouse model, which is anticipated to facilitate development of a more efficient therapy for the disease.
Citation Format: Fabiola Mehta, Sang-Hyuk Chung. Recurrence and hormone therapy resistance of cervical cancer in a transgenic mouse model. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B05.
Abstract B14: Cisplatin induced activation of the epidermal growth factor receptor as a mechanism for epigenetic silencing in ovarian cancer cell platinum resistance
Authors: Granados Michaela Lee , Hudson Laurie G. , Samudio-Ruiz Sabrina Leigh 
Published: May 2015

Abstract
The 5-year survival rate for women diagnosed with ovarian cancer remains dismally unchanged at 44%. Resistance to platinum compounds in ovarian cancer imparts a major obstacle to increasing patient survival. The epidermal growth factor receptor (EGFR) plays a role in the regulation of growth and differentiation in normal cells, and proliferation in malignant cells. It is known that disregulation of the EGFR pathway, including prolonged receptor activation, is associated with platinum resistance in cellular models and our lab revealed a novel mechanism by which constitutive EGFR activation regulates DNA methyltransferase (DNMT) activity and DNA methylation. Platinum resistance is associated with epigenetic downregulation (via DNA methylation) of genes involved in platinum drug response, particularly genes important for drug uptake. Given the established link between platinum resistance and alterations to DNA methylation, our studies investigated the effects of acute cisplatin treatment on EGFR activation and DNMT activity. We hypothesized that acquired chemoresistance resulting from cisplatin treatment is initially triggered by cisplatin-induced EGFR activation and subsequent alterations to DNMT activity. We show activation of EGFR upon treatment of OVCA433 cells with cisplatin. Functional EGFR activation following cisplatin treatment was also observed by evaluating activation of downstream targets, Jak2 and Akt. Hence, cisplatin facilitates activation of EGFR and its downstream signaling pathways. Moreover, there was also a significant increase in DNMT activity in cisplatin treated cells when compared to untreated passage controls. These observations unmask a potential mechanism by which initial exposure to cisplatin can activate EGFR signaling and cause epigenetic alterations that may contribute to the development of platinum resistance. By understanding the underlying mechanism for development of platinum resistance and discovering targets of methylation, we may be able to enhance sensitivity to platinum based chemotherapeutics.
Citation Format: Michaela Lee Granados, Laurie G. Hudson, Sabrina Leigh Samudio-Ruiz. Cisplatin induced activation of the epidermal growth factor receptor as a mechanism for epigenetic silencing in ovarian cancer cell platinum resistance. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B14.
Abstract B25: A comparison of resistance mechanisms to 1st, 2nd, and 3rd generation EGFR TKIs in NSCLC
Authors: Paul Sarah M. , Ye Xioafen , Modrusan Zora , Seshagiri Somasekar , Yauch Robert , Shames David S. 
Published: May 2015

Abstract
Reversible EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib offer significant clinical benefit to patients with EGFR mutation positive NSCLC compared to chemotherapy alone. In nearly all cases resistance emerges after approximately a year on therapy, often due to the EGFR T790M (50-60% of cases). Irreversible pan-HER TKIs, including dacomitnib and afatinib were developed in part to address the emergence of T790M mutations. Both molecules showed promise, but the T790M mutation is still a dominant resistance mechanism and the number and severity of adverse events in the clinic underscore the unmet need for better targeted treatments for NSCLC patients. Third generation TKIs—AZ9291 and CO-1686—were designed against activating EGFR mutations in order to spare the wild type pathway and developed for efficacy in the T790M setting. However, resistance to the new class of EGFR TKIs is inevitable, prompting us to investigate the impact of erlotinib resistance mechanisms on AZ9291 and ask what new mechanisms are involved. NSCLC cell lines harboring activating EGFR mutations with (H1975) or without T790M (HCC4006 and HCC827) were exposed to erlotinib, dacomitnib, or AZ9291 at IC 75 or greater for three months to generate resistance. The PTEN null line H1650 was found to be resistant to all three TKIs without long-term drug exposure, implicating constitutive PIK3 pathway signaling as one mechanism of resistance. In addition, AZ9291 resistance in H1975 resulted in an epithelial to mesenchymal transition (EMT) at the phenotypic level and a corresponding increase in vimentin staining, with at least a 1000-fold increase in IC 50. Preliminary results indicate both acquired and de novo mechanisms account for AZ9291 resistance in H1975. AZ9291 resistance in HCC827 resulted in resistance to erlotinib and dacomitnib, implicating either additional mutations in EGFR or in downstream genes. Expression of E-cadherin was markedly increased in the AZ9291 resistant HCC827 line. An analysis of EGFR mutation status, PTEN status, Met expression, and EMT gene expression and methylation signatures will be presented, and the possible implications for patients will be discussed.
Citation Format: Sarah M. Paul, Xioafen Ye, Zora Modrusan, Somasekar Seshagiri, Robert Yauch, David S. Shames. A comparison of resistance mechanisms to 1st, 2nd, and 3rd generation EGFR TKIs in NSCLC. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B25.
Abstract B42: Adaptive drug resistance is associated with phenotypic reprogramming and hypersensitivity to HDAC inhibitors
Authors: Samulitis Betty k. , Pond Erika , Pond Kelvin , Cress Anne E. , Dorr Robert T. , Landowski Terry H. 
Published: May 2015

Abstract
Pancreatic cancer is the fourth leading cause of cancer death in the United States. One of the major reasons for the poor prognosis of pancreatic cancer is its high resistance to gemcitabine and other currently available chemotherapeutic agents. In the present study, we have developed gemcitabine-resistant cell lines to investigate the mechanisms by which adaptive resistance occurs during pancreatic tumor progression. Gemcitabine-resistant (GR) cell lines were established from the MiaPaCa2 cell line. Increasing drug selection pressure resulted in the establishment of populations that proliferate in the continuous presence of 300 nm (GR300), 800 nM (GR800), or 2µM (GR2000) gemcitabine. Using a SCID mouse xenograft mouse model, we demonstrate that the gemcitabine resistant phenotype is maintained in vivo. Growth inhibition profiles demonstrate cross resistance to Ara-c (cytarabine), and 2-chlorodeoxyadenosine (2CDA/cladribine), but no resistance to DNA damaging agents or microtubule inhibitors. Most strikingly, the gemcitabine resistant subclones demonstrated a dose dependent hypersensitivity to the Class I histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA/Vorinostat) (IC50: MP 1.6uM; GR300 1.0uM; GR800 0.2uM; GR2000 0.08uM). This collateral hypersensitivity extended to additional Class I HDAC inhibitors including MS-275 (Entinostat) and Trichostatin A, but not to the Class IIa selective agent MC1568. There was no significant difference in basal levels of histone acetylation, but the gemcitabine resistant clones demonstrated a greater increase in histone acetylation in response to HDAC treatment. Cell morphology of the gemcitabine resistant cells demonstrate an EMT-like phenotype, however evaluation of classic EMT markersidentified no significant changes in expression compared to the parental cell line. Invasive potential was measured using matrigel invasion assays, and found to be increased in a dose dependent manner. These data demonstrate that selection for drug resistance co-selects for an invasive phenotype with EMT-like characteristics. In addition, the resistance phenotype that emerges under drug pressure is associated with a phenotypic reprogramming that can be exploited to devise new therapeutic options for patients with advanced pancreatic adenocarcinoma.
Citation Format: Betty k. Samulitis, Erika Pond, Kelvin Pond, Anne E. Cress, Robert T. Dorr, Terry H. Landowski. Adaptive drug resistance is associated with phenotypic reprogramming and hypersensitivity to HDAC inhibitors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B42.
Abstract B54: Characterizing pathway vulnerabilities and tumor heterogeneity through signaling-associated complexes
Authors: Smith Matthew A. , Clark Leah , Hall Richard , Fisher Kate , Yoshida Takeshi , Vuaroqueaux Vincent , Fiebig Heinz-Herbert , Chen Ann , Haura Eric B. 
Published: May 2015

Abstract
Signaling pathways controlling cellular proliferation are major targets of cancer therapeutics, however, accurate assessment of activation status of targetable signaling cascades remains a challenge. We have developed proximity ligation assay (PLA)-based methodologies to detect signaling-associated complexes for a variety of receptor tyrosine kinases, intracellular adaptors and phosphorylation events in formalin-fixed, paraffin-embedded tissues. By assessing the degree of functional association of oncogenic kinases (such as EGFR and ALK) with intracellular adaptor molecules, it is possible to characterize the activation status of targetable kinase activity and monitor variations across tissue types, within tissues and in response to perturbations. Here, we present data for a panel of PLAs using cell lines, patient specimens and patient-derived xenografts models. We show that EGFR-GRB2 PLA reflects erlotinib pharmacodynamics and has predictive capacity for response to both erlotinib and cetuximab. We demonstrate that PLA can identify alterations in multiple bypass signaling cascades associated with therapeutic escape using both in vitro models of acquired resistance and patient specimens. We observe striking intratumoral variation in abundance of signaling-associated complexes, likely reflecting influences from the tumor microenvironment and phenotypic heterogeneity. We are currently expanding our PLA panel to include emerging therapeutic targets (MET and FGFR1) and evaluating performance of these assays to characterize signaling complexes in circulating tumor cells obtained from advanced stage non-small cell lung cancer patients. Collectively, our data suggests that PLA-based methodologies can be harnessed to explore the cancer interactome and can be important tools to enable precision medicine.
Citation Format: Matthew A. Smith, Leah Clark, Richard Hall, Kate Fisher, Takeshi Yoshida, Vincent Vuaroqueaux, Heinz-Herbert Fiebig, Ann Chen, Eric B. Haura. Characterizing pathway vulnerabilities and tumor heterogeneity through signaling-associated complexes. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B54.