bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA16: Targeting cancer stem cells to overcome chemotherapy resistance
Authors: Buckanovich Ronald J. 
Published: August 2014

Abstract
While most ovarian cancer patients will have a complete response with surgery and chemotherapy, the majority will relapse and die of their disease. The high relapse rate in ovarian cancer after complete clinical response is highly consistent with a cancer stem-like cell (CSC) model. The CSC hypothesis suggests that only rare, inherently chemoresistant cancer cells with stem cell like characteristics are capable of proliferating and differentiating to regenerate the various cell types within a tumor, thereby causing relapse of the disease. In theory and in experimental models, the elimination of CSC can overcome chemotherapy resistance. We are developing novel therapies to specifically target ovarian CSC (OvCSC). Aldehyde Dehydrogenase (ALDH) enzymatic activity was one of the first, and remains one of the best supported CSC markers. ALDH enzymes perform numerous critical functions including the biosynthesis of retinoic acid. Our group and others have found that ALDH identifies a population cancer cells with ovarian CSC (OvCSC) activity. Primary human ALDH+ cells initiate and propagate tumors in mice while ALDH-cells do not. ALDH used in combination with the stem cell marker CD133 enriches CSC isolation. ALDH1A+ or ALDH1A1+CD133+ cells in primary tumor samples predict poor prognosis for ovarian cancer patients [9, 11]. ALDH and CD133 are enriched in tumor specimens immediately following chemotherapy [12]. ALDH1A1 is 100 fold upregulated in chemoresistant ovarian cancer cells and ALDH1A knockdown restores chemosensitivity. Finally, normal ovary epithelial stem cells also express ALDH and CD133, and when mutated for p53 and Rb, these cells gain CSC capacity and initiate serous tumors. Taken together these data strongly support a role for ALDH in serous ovarian CSC. Based on the CSC specific function of ALDH and the function of we generated and screened. We have therefore identified and screened dozens of ALDH inhibitors and molecular analogs of known ALDH inhibitors. Using cell lines with well-defined CSC populations, we have identified several compounds which kill cells expressing CSC markers in vitro. CSC die via necrosis. Lead compounds prevent tumor sphere formation in vitro and restrict tumor initiation in vivo. The novel ALDH inhibitors are highly synergistic with chemotherapy and reverse chemotherapy resistance in primary human tumor xenografts. Taken together our data support ALDH as a CSC specific target and identifies novel compounds as potential new therapeutics.
Citation Format: Ronald J. Buckanovich. Targeting cancer stem cells to overcome chemotherapy resistance. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr IA16.
Abstract IA26: Protective immune networks in ovarian cancer
Authors: Nelson Brad 
Published: August 2014

Abstract
Ovarian cancer is a challenging disease for which new treatments are urgently needed. High-grade serous ovarian cancer is the most common and lethal subtype, with a five-year survival rate of only 30-40%. Nevertheless, patients with evidence of an immune response against their cancer – in particular the presence of tumor-infiltrating T cells – show markedly prolonged survival. We recently showed that B cells also contribute to tumor immunity, in that tumors infiltrated by both B cells and T cells are associated with higher survival rates than seen with T cells alone. Tumor-infiltrating T cells and B cells co-localize in organized structures resembling lymphoid tissue. These structures also contain dendritic cells and show the hallmarks of active antigen presentation and lymphocyte activation. We are investigating the hypothesis that these lymphoid structures are sites of immune surveillance, where tumor antigens are presented to T cells and B cells allowing the immune system to keep check on the evolving cancer genome. To explore this concept, we are assessing tumor-infiltrating T cells for recognition of mutations identified by whole exome sequencing. In one patient undergoing standard chemotherapy, we found an example of a CD8+ T cell response to a point mutation in the HSDL1 gene. The T cell response emerged during first remission, peaked at first recurrence, and then disappeared by second recurrence, shortly before the patient succumbed to her disease. Thus, the immune system actively surveys the tumor genome in patients undergoing standard treatment, but these responses can fail in the absence of immunologic intervention. With better understanding of the lymphocytes and structures involved, it should be possible to enhance these natural surveillance mechanisms to confer protective immunity and further increase patient survival.
Citation Format: Brad Nelson. Protective immune networks in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr IA26.
Abstract IA3: In tumor screening for novel targets in papillary serous ovarian cancer
Authors: Baratta Maria Giuseppina , Baratta Maria Giuseppina , Liu Joyce , Liu Joyce , Zwang Yaara , Zwang Yaara , Zwang Yaara , Schinzel Anna , Schinzel Anna , Drapkin Ronny , Drapkin Ronny , Hahn William , Hahn William , Hahn William , Livingston David M. , Livingston David M. 
Published: August 2014

Abstract
In search of new, potential therapeutic target proteins in primary ovarian cancer cells, we have performed in-tumor shRNA screens in an established, human ovarian cancer (ov ca) cell line growing either subcutaneously or intraperitoneally in immunologically incompetent mice. Validation tests were then performed on the confirmed hits in viability/proliferation assays performed, in parallel, in at least two, cultured primary papillary serous ov ca cell strains each of which was generated by direct intraperitoneal injection of primary, patient- derived ov ca cells. The lentiviral shRNA library used contained ~8,000 hairpins, collectively directed against all known human protein kinases and a number of established human oncoproteins. Approximately 40 hits were detected and confirmed in this study, in which the screen involved deep sequencing of DNA isolated from residual tumor material growing in multiple animals. Here the search was for any hairpins that were selectively and specifically depleted from these DNA samples. Currently, we are focusing on two, new hits in this effort with special attention to their effects on primary human ov ca cell tumor formation in nude mice.
Citation Format: Maria Giuseppina Baratta, Maria Giuseppina Baratta, Joyce Liu, Joyce Liu, Yaara Zwang, Yaara Zwang, Yaara Zwang, Anna Schinzel, Anna Schinzel, Ronny Drapkin, Ronny Drapkin, William Hahn, William Hahn, William Hahn, David M. Livingston, David M. Livingston. In tumor screening for novel targets in papillary serous ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr IA3.
Abstract IA4: A dualistic model of ovarian carcinogenesis
Authors: Kurman Robert J. 
Published: August 2014

Abstract
Recent morphologic, immunohistochemical and molecular genetic studies have led to the development of a new paradigm for the pathogenesis and origin of epithelial ovarian cancer (EOC) based on a dualistic model of carcinogenesis that divides EOC into two broad categories designated type I and type II. Type I tumors are comprised of low-grade serous, low-grade endometrioid, clear cell and mucinous carcinomas and Brenner tumors. They are generally indolent, present in stage I (tumor confined to the ovary) and are characterized by specific mutations, including KRAS, BRAF, ERBB2, CTNNB1, PTEN PIK3CA, ARID1A, and PPPR1A, which target specific cell signaling pathways. Type I tumors rarely harbor TP53 and are relatively stable genetically. Type II tumors are comprised of high-grade serous, high-grade endometrioid, malignant mixed mesodermal tumors (carcinosarcomas) and undifferentiated carcinomas. They are aggressive, present in advanced stage, and have a very high frequency of TP53 mutations but rarely harbor the mutations detected in type I tumors. In addition, type II tumors have molecular alterations that perturb expression of BRCA either by mutation of the gene or by promotor methylation. A hallmark of these tumors is that they are genetically highly unstable. Recent studies strongly suggest that fallopian tube epithelium (benign or malignant) that implants on the ovary is the source of low-grade and high-grade serous carcinoma rather than the ovarian surface epithelium as previously believed. Similarly, it is widely accepted that endometriosis is the precursor of endometrioid and clear cell carcinomas and as endometriosis is thought to develop from retrograde menstruation these tumors can also be regarded as involving the ovary secondarily. The origin of mucinous and transitional cell (Brenner) tumors is still not well established, although recent data suggest a possible origin from transitional epithelial nests located in paraovarian locations at the tubo-peritoneal junction. Thus, it now appears that type I and type II ovarian tumors develop independently along different molecular pathways, and that both types develop outside the ovary and involve it secondarily. If this concept is confirmed it leads to the conclusion that the only true primary ovarian neoplasms are gonadal stromal and germ cell tumors analogous to testicular tumors. This new paradigm of ovarian carcinogenesis has important clinical implications. By shifting the early events of ovarian carcinogenesis to the fallopian tube and endometrium instead of the ovary, prevention approaches, for example, salpingectomy with ovarian conservation, may play an important role in reducing the burden of ovarian cancer while preserving hormonal function and fertility.
Citation Format: Robert J. Kurman. A dualistic model of ovarian carcinogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr IA4.
Abstract IA6: Murine models of nonserous ovarian cancer: Effects of mutant Trp53, Pik3ca, and Arida1a in a model of endometrioid carcinoma based on Wnt and PI3K/Akt pathway defects
Authors: Cho Kathleen R. , Wu Rong , Zhai Yali , Sakaguchi Isao 
Published: August 2014

Abstract
A dualistic pathway model of ovarian carcinoma (OvCA) pathogenesis has been proposed in which type I OvCAs are low grade, genetically stable, and relatively more indolent than type II OvCAs, most of which are high-grade serous carcinomas. Endometrioid OvCA (EOC) is a prototypical type I tumor, often harboring mutations that affect the Wnt and phosphatidylinositol 3-kinase/AKT/mTOR signaling pathways. Molecular and histopathologic analyses indicate type I and II OvCAs share overlapping features, and a subset of EOCs may undergo type I→type II progression accompanied by acquisition of somatic TP53 or PIK3CA mutations. We used a murine model of EOC initiated by conditional inactivation of the Apc and Pten tumor suppressor genes to investigate mutant Trp53 or Pik3ca alleles as key drivers of type I→type II OvCA progression. In the mouse EOC model, the presence of somatic Trp53 or Pik3ca mutations resulted in shortened survival and more widespread metastasis. In contrast, bi-allelic inactivation of Arid1a in addition to Apc and Pten actually prolonged survival and tumors with Arid1a inactivation showed more epithelial differentiation than their counterparts with intact Arid1a alleles. Our findings indicate that the adverse prognosis associated with TP53 and PIK3CA mutations in human cancers can be functionally replicated in mouse models of type I→type II OvCA progression. Moreover, the models should represent a robust platform for assessment of the contributions of Trp53, Pik3ca, and Arid1a mutations to the response of EOCs to conventional and targeted drugs.
Citation Format: Kathleen R. Cho, Rong Wu, Yali Zhai, Isao Sakaguchi. Murine models of nonserous ovarian cancer: Effects of mutant Trp53, Pik3ca, and Arida1a in a model of endometrioid carcinoma based on Wnt and PI3K/Akt pathway defects. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr IA6.
Abstract A250: ABT-414: An anti-EGFR antibody-drug conjugate as a potential therapeutic for the treatment of patients with squamous cell tumors.
Authors: Phillips Andrew C. , Boghaert Erwin R. , Vaidya Kedar S. , Ansell Peter J. , Shalinsky David R. , Zhang Yumin , Voorbach Martin J. , Mudd Sarah , Holen Kyle D. , Humerickhouse Rod A. , Reilly Edward B. 
Published: August 2014

Abstract
ABT-414 is an antibody-drug conjugate (ADC) comprised of an anti-EGFR antibody (ABT-806) conjugated to the potent cytotoxic monomethylauristatin F. ABT-414 binds a unique epitope of EGFR which is largely inaccessible when EGFR is expressed at physiological levels but is accessible in tumors that express EGFRde2-7 [also referred to as EGFR variant III (EGFRvIII)] and in tumors with wild-type amplified EGFR or excessive wild-type EGFR activation. These properties of ABT-414 should limit the effects of the toxin on normal tissues. ABT-414 is highly effective in both mutant and wild-type EGFR-positive human tumor xenografts in mice producing complete regressions and cures observed in the most sensitive models. Squamous cell tumors display a relatively high expression of EGFR. Immunohistochemical analysis reveals &gt;70% of squamous lung and esophageal cancers and &gt;90% of oral cavity tumors show moderate to strong staining for EGFR. Given the high unmet need in these patients and the in vivo data supporting improved ABT-414 efficacy in tumors with high EGFR expression, a Phase I/IIa study evaluating the safety, pharmacokinetics and efficacy of ABT-414 in subjects with EGFR-positive, refractory solid tumors has been initiated with a phase IIa expansion at the MTD in squamous NSCLC. Additionally, this study will evaluate the use of SPECT imaging with an indium-111-labeled parental antibody (ABT-806i) as a predictive tool for patient response. Tumor uptake by ABT-806i SPECT imaging correlates with antitumor response in xenograft models, and ABT-806i has been shown to effectively target tumor sites in select cancer patients. A fluorescent in situ hybridization (FISH) probe to detect EGFR amplification and EGFR IHC are also being evaluated with the goal of identifying patients who are most likely to respond to ABT-414 treatment.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A250.
Citation Format: Andrew C. Phillips, Erwin R. Boghaert, Kedar S. Vaidya, Peter J. Ansell, David R. Shalinsky, Yumin Zhang, Martin J. Voorbach, Sarah Mudd, Kyle D. Holen, Rod A. Humerickhouse, Edward B. Reilly. ABT-414: An anti-EGFR antibody-drug conjugate as a potential therapeutic for the treatment of patients with squamous cell tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A250.
Abstract B182: Utilization of quantitative multiplex immunofluorescence to assess biomarkers in ovarian cancer; ability to create an objective phenotype with respect to outcome.
Authors: Cardenas-Goicoechea Joel , Long Nguyen , Kalir Tamara , Donovan Michael J. 
Published: August 2014

Abstract
Introduction:Ovarian cancer is the fifth most common cause of cancer deaths among women with the majority of cases diagnosed at an advanced stage where therapeutic options are limited to surgical resection and adjuvant platinum-based chemotherapy regimens. Given the paucity of reliable tissue biomarkers to predict response to therapy, we used a validated quantitative multiplex immunofluorescent (QMIF)platform on formalin-fixed, paraffin-embedded (FFPE) ovarian tissues to quantify biomarker expression patterns and assessed association with outcome.
Methods: 89 patients were evaluated using tissue microarrays consisting of three 0.6mm tumor cores per diagnostic specimen; fallopian tubes and four different ovarian cell lines were included as pos/neg controls. CK7, VEGF, PERK1/2 and TP53 were evaluated with QMIF, with individual and combined antibody features constructed utilizing intensity and area values. Kaplan-Meier with log-rank test along with multivariate Cox proportional hazards model were employed to determine biomarker assocation with respect to overall (OS) and progression free survival (PFS).
Results: Mean age 59yrs, 80% serous, 88% Grade 3 and 85% &gt;/= Stage IIIC. Median follow-up 32m; 5-year OS 51% and platinum resistance 54%. In multivariate analysis CK7+TP53+ was an independent prognostic marker for both PFS and OS (p-value &lt;0.001 and 0.04), i.e greater amounts associated with decreased survival. By contrast, increased levels of PERK1/2 were associated with a decreased tumor recurrence and increased platinum sensitivity (p=0.020 and 0.006) while increasing amounts of VEGF were associated with greater tumor recurrence (p=0.004) as well as platinum sensitvity (p=0.03).Conclusion: Quantitative assessment of TP53, PERK1/2 and VEGF provides valuable (biological) information with respect to chemoresponse and tumor recurrence. The application of QMIF to biomarker investigation will provide another level of complexity to tumor phenotypic characterization which is currently not available using standard subjective, chromogenic IHC assays.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B182.
Citation Format: Joel Cardenas-Goicoechea, Nguyen Long, Tamara Kalir, Michael J. Donovan. Utilization of quantitative multiplex immunofluorescence to assess biomarkers in ovarian cancer; ability to create an objective phenotype with respect to outcome. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B182.
Abstract B215: Correlation of PSMA ADC exposure with reduction in tumor growth rate determined using serial PSA measurements from a Phase I clinical trial.
Authors: Rotshteyn Yakov , Mercier F , Bruno R , Stambler Nancy , Israel Robert J. , Wong Vivien 
Published: August 2014

Abstract
Background: PSMA ADC is a fully humanized antibody to PSMA conjugated to the potent microtubule disrupting agent monomethyl auristatin E (MMAE). The safety and PK of PSMA ADC as well as changes in PSA levels were evaluated in a Phase I dose escalation study in patients with taxane-refractory metastatic castration-resistant prostate cancer (mCRPC) (PSMA ADC 1301). Stein et al. (2010) has previously demonstrated correlation between growth rate derived from serial PSA measurements with survival in patients with mCRPC and suggested that growth rate could serve as a novel endpoint indicative of response to therapy and overall survival.
Methods: The PK parameters for PSMA ADC, Total antibody (Ab) and free MMAE obtained from PSMA ADC Study 1301 (N=52) were calculated using non-compartmental analysis. The final data set contains 253 longitudinal PSA observations from 52 subjects dosed with 0.4-2.8 mg/kg PSMA ADC. The Stein model was re-expressed as a 7-parameter population model to describe the longitudinal PSA data which includes: Baseline PSA level (Y0), PSA decrease rate (D), PSA increase rate (G), inter-patient variability for Y0, G and D respectively, and residual variance. Model parameters were estimated using Phoenix/NLME®. Exposure-efficacy relationships and correlation between G and covariates were determined.
Results: PSMA ADC, Total Ab, and MMAE exposure increased linearly with increasing PSMA ADC dose. Longitudinal PSA data were correctly fitted to the re-expressed Stein model. G continuously decreased with increasing PSMA ADC exposure, suggesting an exposure dependent drug effect. There was no apparent saturation of this effect at the maximum observed exposure, and no influence of age, baseline albumin and ALT/AST levels on G was evident.
Conclusions: In a Phase I study where PSMA ADC (0.4-2.8 mg/kg) was administered to patients with mCRPC, we observed a correlation of PSMA ADC exposure with the reduction of G, suggesting that PSMA ADC may provide dose-dependent therapeutic benefit to subjects with mCRPC.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B215.
Citation Format: Yakov Rotshteyn, F Mercier, R Bruno, Nancy Stambler, Robert J. Israel, Vivien Wong. Correlation of PSMA ADC exposure with reduction in tumor growth rate determined using serial PSA measurements from a Phase I clinical trial. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B215.
Abstract B269: Effects of blocking aberrantly expressed CSF-1R in Hodgkin lymphoma.
Authors: Campion Liam , Deangelis Nikki , Ferrante Catherine , Verona Raluca , Seetharam Shobha , Manthey Carl , Snyder Linda 
Published: August 2014

Abstract
The human genome contains a large number of repetitive elements that have been suspected to play a role in human diseases. Recent literature has shown that aberrant activation of one of these repetitive elements, a long terminal repeat (LTR), leads to lineage inappropriate expression of the CSF-1 receptor (CSF-1R) transcript in Hodgkin's lymphoma (HL) clinical samples and cell lines. CSF1-R, also known as Feline McDonough Sarcoma (FMS), is the receptor for CSF-1 and IL-34, and under normal circumstances it plays an important role in monocyte survival, proliferation, and differentiation as well as osteoclast generation. Aberrant expression of CSF-1R has been shown previously to support proliferation and survival in HL cells. To confirm the role of CSF-1R in HL, we determined that 17 of 17 HL clinical samples and 7 of 7 HL cell lines were positive for the aberrant CSF-1R transcript by TaqMan and traditional PCR, while non-HL cell lines were negative for the aberrant CSF-1R transcript. The HL lines were further characterized for surface expression of CSF-1R by flow cytometry and CSF-1 secretion by ELISA. L-1236 cells expressed the highest levels of CSF-1R and CSF-1. Treatment of the HL cell lines with CSF-1R-Fc, resulted in reduced viability in four of the five lines, consistent with the hypothesis that HL cell lines are sensitive to CSF-1 as a growth factor. Additionally, it was found that treating the L-1236 HL cell line with the CSF-1R small molecule inhibitor JNJ-40646527 had a significant effect on viability of the HL cell line L-1236, with an IC50 of 264 nM at 72 hrs. JNJ-40646527 did not have a significant effect on the viability of several other HL cell lines. These results indicate that aberrant LTR driven CSF-1R expression may play a role in the pathogenesis of Hodgkin's lymphoma (HL) and could be a potential target for Hodgkin's lymphoma therapy.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B269.
Citation Format: Liam Campion, Nikki Deangelis, Catherine Ferrante, Raluca Verona, Shobha Seetharam, Carl Manthey, Linda Snyder. Effects of blocking aberrantly expressed CSF-1R in Hodgkin lymphoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B269.