bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2539: CTLA-4 blockade for hormone refractory prostate cancer: Dose-dependent induction of CD8+ T cell activation and clinical responses
Authors: Fong Lawrence , Kwek Serena , Kavanagh Brian , O'Brien Shaun , McNeel Douglas , Weinberg Vivian , Rini Brian , Small Eric J.
Published: May 2019

CTLA-4 is a costimulatory molecule expressed on activated T cells that delivers an inhibitory signal to these T cells. CTLA4 blockade with antibody treatment has been shown to augment T cell responses and anti-tumor immunity in animal models and is being developed as an immunotherapy for cancer patients. We performed a phase I trial in patients with metastatic, hormone refractory prostate cancer (HRPC) where sequential cohorts of 3-6 patients were treated with escalating doses (0.5, 1.5 or 3 mg/kg) of ipilimumab, a fully human anti-CTLA-4 antibody (Medarex/BMS), given IV on day 1 of each 28-day cycle x 4 cycles. Patients also received GM-CSF (sargramostim, Berlex) 250 mg/m2/d SC on days 1-14 of the 28-day cycles. Patients were monitored for toxicity as well as for T cell activation. PSA and radiographic tests were performed at baseline and through therapy to evaluate for clinical response. 24 patients have been treated in the initial phase of this study. Of 6 patients treated on the highest dose level (3.0 mg/kg x 4), 3 (50%) had confirmed PSA declines of >50%, and one of these patients had a partial response in hepatic metastases. Immune-related adverse events associated with ipilimumab treatment were also seen more frequently at higher doses of treatment. Expansion of CD25+CD69+ CD8 T cells was also seem primarily at the highest dose level. The treatment also induced an antibody and CD8 T cell immune response to NY-ESO-1. These results demonstrate that CTLA-4 blockade induces not only the expansion of activated effector CD8 T cells in vivo in cancer patients, but also can induce from the endogenous T cell repertoire of these patients T cells that are specific for tumor-associated antigens. CD8 T cell activation, toxicity, and clinical responses also appear to be dose-dependent. Supported by NIH P50 CA89520.
Abstract 4188: Dietary energy balance impacts spontaneous pancreatic lesions in the K5.COX-2 transgenic model of pancreatic cancer
Authors: Lashinger Laura M , Malone Lauren , Daniels Elizabeth , Smith Nicole C. , Pavone Amy , Colby Jennifer L. , Fischer Susan M. , Hursting Stephen D.
Published: May 2019

Pancreatic cancer is the fourth leading cause of cancer death in both men and women in the United States. Obesity, which has increased dramatically over the past 40 years, has emerged as an important risk factor for pancreatic cancer, although the mechanisms underlying the obesity-pancreatic cancer association have not been identified. Calorie restriction (CR), a dietary strategy for inducing negative energy balance and preventing or reversing obesity, has significant anti-cancer effects in several species, for a variety of tumor types, and for both spontaneous and chemically-induced tumors. However, the effects of dietary energy balance modulation on pancreatic tumor formation have not been well studied. We hypothesized that spontaneous tumor development in the K5.COX-2 transgenic mouse model of pancreatitis-driven pancreatic cancer would be reduced in lean mice, relative to overweight or diet-induced obese (DIO) mice. In order to test this hypothesis, we placed 6-8 week old K5.COX-2 transgenic mice on one of three diets for 14 weeks (n=12/group): lean (30% CR), overweight (AIN-76A diet fed ad libitum), or a high calorie/high fat DIO regimen. K5.COX-2 transgenic mice develop spontaneous pancreatic lesions as early as 4 weeks with 100% becoming moribund within 6-8 months. Based on histologic analysis of the percentage of pancreas that is comprised of enlarged and dilated ductal lesions, the CR animals were significantly protected from spontaneous pancreatic lesion formation (7.5%±1.44) as compared to the overweight (45%±10.5) and DIO (57.5%±9.46) groups. Furthermore, CR mice had smaller lesions at time of harvest with none exhibiting signs of moribundity. Conversely, the DIO group generally had the largest lesions, although there was no statistical difference between the overweight and DIO groups. In addition, several mice in the overweight and DIO groups had to be sacrificed early due to extensive abdominal distention, morbidity from enlarged cystic lesions, and other signs of distress. Further investigation is needed to discern how CR exerts its effects. Preliminary analyses suggest that IGF-1 may be playing a significant role. Moreover, pro-inflammatory cytokines were shown to be significantly reduced in sera of CR-animals as compared to the other two groups. In conclusion, using a model of pancreatitis-induced pancreatic tumorigenesis, our findings indicate that dietary energy balance modulation can alter the development of pancreatic cancer. This could have direct implications for the prevention and control of pancreatic tumors due to chronic inflammation and/or obesity.
Abstract 4741: Application of nanotechnology for enhanced early detection of prostate cancer in African-American men
Authors: Phelan Catherine M , Ostapenko Sergei , Chornokur Anna , Tanner Richard , zhang jin , Pow-Sang Julio , Steel John Jack , Sellers Thomas
Published: May 2019

Background: African American men in the US have the highest incidence and mortality from prostate cancer in the world. Five-year survival rates are almost 100% of African American men diagnosed with early stage prostate cancer but only 29% for men diagnosed in the late stages of the disease. Early detection is thus the key to improved mortality and morbidity. We are investigating nanotechnologies to enhance the detection of prostate cancer biomarkers at extremely low levels in blood serum. Our goal is to engineer a multi-biomarker panel that will provide sufficiently high sensitivity and specificity such that it can be applied as a screening test and decrease prostate cancer morbidity and mortality among African-American men.

Objectives: 1.To engineer quantum dot - antibody conjugates targeting established prostate cancer biomarkers (antigens): prostate specific antigen (PSA), Kallikrein 2 (KLK2), Kallikrein 14 (KLK14), Osteoprotegerin (OPG), Antip53Ab, Caveolin-1 (Cav-1) and Interleukin-6 (IL-6) 2. To define the photoluminescence signatures of bound versus unbound QDs, reflecting antigen-antibody complex formation. 3. To derive optimal cutpoints for the sensitivity and specificity of the novel QD-conjugated biomarkers individually, and in combination, for the early detection of prostate cancer in African-American men.

Results: We have established an African American prostate cancer case-control collection. We have successfully conjugated antibodies to the above biomarkers to quantum dots and these are undergoing characterization. We have observed that the bio-conjugated QD shows a spectral shift of the maximum position on average by 4 nm in comparison to non-conjugated QDs. The shift is towards a shorter wavelengths “blue” shift for conjugated quantum dots. Its existence was confirmed with repetition of the conjugation scheme with identical parameters and the “blue” shift was observed in all repeated experiments. The PL spectral shift observed on bio-conjugated QDs with antigens may be attributed to the existence of an external local electric field that is imposed by the surrounding biomolecules (Stark effect). The shift varied depending on the different antibodies attached and on QDs of different wavelengths.

Conclusions: We have observed a spectral shift of the bio-conjugated quantum dots compared to unconjugated quantum dots. The benefit of this observation may lie in the fact that the shift is different for each antibody, thus will show a peak at different wavelengths. This effect may provide a powerful tool for multiplexing proteins for early cancer detection. This study has enormous potential impact on improved detection of this disease in the early and more curable stage which in turn would lead to decreased morbidity and mortality.
Abstract 512: Gene expression profiling reveals tumor immunobiological differences in prostate cancer between African-American and European-American men
Authors: Wallace Tiffany A , Prueitt Robyn L , Yi Ming , Stephens Robert M , Ambs Stefan
Published: May 2019

The incidence and mortality rates of prostate cancer are significantly higher in African-American men when compared to European-American men. We tested the hypothesis that differences in tumor biology contribute to this survival health disparity. Using microarray technology, we obtained gene expression profiles of primary prostate tumors resected from 33 African-American and 36 European-American patients. These tumors were matched on clinical parameters. We also evaluated 18 non-tumor prostate tissues from 7 African-American and 11 European-American patients. The resulting datasets were analyzed for expression differences on the gene and pathway level comparing African-American with European-American patients. Our analysis revealed 162 transcripts to be differentially expressed between African-American and European-American prostate cancer patients at a false discovery rate of 5% or less. Using a disease association analysis, we identified a common relationship of these transcripts with autoimmunity and inflammation. These findings were corroborated on the pathway level with numerous differentially expressed genes clustering in immune response, defense response, antigen presentation, B-cell/T-cell function, cytokine signaling, and inflammatory response pathways. Most commonly, the genes involved in these pathways were more highly expressed in tumors of African-American patients when compared with those of European-American patients. Amongst the immune-specific genes over-expressed by African-American patients was indoleamine 2,3-dioxygenease, HLA-E, and HLA-G. All three of these genes are well-known contributors of immunologic tolerance in tumors. Furthermore, a distinctive interferon signature was identified in the African-American prostate tumors, suggesting the possibility of viral involvement in disease etiology in this African-American population. In conclusion, the gene expression profiles of prostate tumors indicate prominent differences in tumor immunobiology between African-American and European-American men. The profiles portray the existence of a distinct tumor microenvironment in these two patient groups.
Abstract 5158: Serological autoantibody profiling in bladder cancer using protein arrays
Authors: Orenes-Piñero Esteban , Herrera Emilia , Rico Daniel , Barderas Rodrigo , Gonzalez-Pisano David , Casal Ignacio , Algaba Ferran , Palou Joan , Urrutia Manuel , Navajo Jose , Sanchez Lydia , Sanchez-Carbayo Marta
Published: May 2019

Cancer cells might release at least part of their contents into the blood stream directly or through extracellular fluids upon cell damage or death. Cancer proteins not present in non-neoplastic cell subpopulations might then elicit a host immune response. The serum autoantibody repertoire from cancer patients might therefore, be exploited for the identification of tumor-associated antigens (TAAs). The recognition that human tumors stimulate the production of autoantibodies against such autologous cellular proteins (TAAs) has opened the door to the possibility that autoantibodies could be translated into serological tools for early diagnosis and/or disease management. In this report, we attempt at exploring the serum proteome of patients with bladder cancer using protein arrays. The serum autoantibody profiles of 18 patients with bladder cancer and 6 control specimens including cases affected with other neoplasias, benign urological diseases and healthy individuals was investigated using protein arrays containing more than 12,000 proteins. Data analyses included T-test as well as clustering strategies using the Prospector and CIMMiner softwares. Supervised clustered heatmaps served to highlight identified biological differences among autoantibody profiles arrays of bladder cancer cases and controls. Moreover, protein expression patterns of the identified immunogenic TAAs were assessed by immunohistochemistry on tissue microarrays (n=92). Supervised clustering analysis segregated bladder cancer patients from controls. A panel of 171 autoantibodies was identified to be differentially expressed in bladder cancer patients as compared to control individuals in a significant manner. Bladder cancer TAAs included proteins involved in cell proliferation, signal transduction, apoptosis, DNA-binding and transcription factors, among others. Immunohistochemical analyses on tissue arrays served to validate the increased protein expression of identified TAAs in bladder tumors. Moreover they revealed the relevance of expression patterns of proteins such as clusterin for bladder cancer diagnostics, staging and outcome prognosis. Protein expression patterns of clusterin were significantly associated with clinico-pathological variables such as tumor size (P=0.034), T1 substaging (P=0.013) or progression into muscle invasive disease (P=0.020). Thus, the novel application of high-throughput protein arrays for serum autoantibody profiling is providing critical information not only to identify TAAs candidate biomarkers for bladder cancer diagnostics and potential immunological therapeutic targets, such as clusterin, but also to further characterize bladder cancer progression.
Abstract 5537: Surgical resection and survival in octagenarians and younger age cohorts of patients diagnosed with non-small cell lung cancer.
Authors: Dillman Robert O , Zusman Douglas R , Joyo Colin I
Published: May 2019

Background and Purpose: As life expectancy has increased, and more former smokers are surviving into old age, an increasing proportion of newly diagnosed patients with non-small cell lung cancer (NSCLC) are over the age of 80 years. This has led to questions regarding the appropriateness of subjecting elderly patients with newly diagnosed NSCLC, to surgical resection, even if they have only localized disease. Patients and Methods: The Hoag Cancer Center data base was used to identify patients with non-small lung cancer diagnosed during 2000-2006, who underwent a surgical resection at Hoag Hospital. Actuarial survival curves were generated for each age cohort. Results: Of 1293 total patients, 17.2% were 80 years of age or older, 36.1% age 70-79, 29.2% age 60-69, 12.9% age 50-59, and 4.6% < 50 years of age. Surgical resections of primary lung cancer included 400 lobectomies, 59 wedge resections, and 23 pneumonectomies. There was a strong correlation (.954) between older age and a higher proportion of male patients. There was also a difference in the proportional distribution of histologies by age group (p=.0005) primarily because of a .973 inverse correlation between older age and adenocarcinoma histology, which was the predominant histology in all age groups. There also were differences in the stage distribution of cases by age (p<.0001), primarily because of a .961 correlation between older age and localized disease, and conversely, a .989 inverse correlation with distant metastatic disease. The proportion of the 482 patients undergoing surgery did not differ significantly among all cohorts (p=0.62), but a somewhat smaller proportion of patients age 80 or older underwent surgical resection of their primary lung cancer (31.7%) compared to patients less than 80 years of age (31.7% vs 38.5%, p=.046). Only 48/75 (64.0%) of patients age 80 or older with localized NSCLC underwent surgical resection compared to 254/306 (83.0%) for patients younger than age 80 (p=.0003). There was a similar trend for patients who had regionally advanced disease: 18/52 (34.6%) of patients age 80 or older underwent surgical resection versus 124/251 (49.4%) for patients less than age 80 (p=.052). Actuarial survival curves for patients revealed observed 5-year survival rates of 62%, 53%, 63%, 63%, and 79% from oldest to youngest cohort. Conclusion: A smaller proportion of patients 80 years of age or older underwent surgery compared to those less than 80 years of age, but survival for octogenarians with newly diagnosed NSCLC, who were selected to undergo surgical resection, was comparable to younger age groups. Older patients should not be denied potentially curative surgery simply because of age.
Abstract 555: Gene expression differences in primary breast tumors from African American and Caucasian women.
Authors: Field Lori A , Love Brad , Deyarmin Brenda , Kane Jennifer , Hooke Jeffrey A , Ellsworth Rachel E , Shriver Craig D
Published: May 2019

Background: Incidence of breast cancer varies across ethnic groups. Overall incidence is highest among Caucasian women (CW); however, incidence in women younger than 40 as well as mortality is highest among African American women (AAW). Although socioeconomic disparities are often blamed for these differences, AAW are more likely than CW to present with large, aggressive tumors with poor prognostic features such as estrogen receptor negativity, triple negative phenotype, and lymph node involvement, suggesting that molecular factors may also contribute to the younger age of onset and worse outcomes in AAW. In the present study, we have compared primary breast tumors from AAW and CW by gene expression profiling to identify differentially expressed genes that may explain why diagnosis at a young age, aggressive tumor biology and lower survival are more prevalent in AAW than CW with breast cancer.

Materials and Methods: Breast tumor specimens were obtained from 26 pairs of age and stage-matched AAW and CW enrolled in the Clinical Breast Care Project (CBCP). Tumor cells were isolated by laser microdissection (Leica) and RNA isolated using the RNAqueous Micro kit (Ambion). RNA was amplified and labeled with biotin-11-UTP using two rounds of amplification with the MessageAmp II aRNA Amplification kit (Ambion). Fragmented aRNA was hybridized to the HG U133A 2.0 array (Affymetrix). A Mann-Whitney U test was used to identify differentially expressed genes (p ≤ 0.001).

Results: Sixty-five genes were differentially expressed between AAW and CW. Twenty-eight genes were more highly expressed in AAW, including SOS1, TSPO, and PSPH, while 37genes had lower expression in AAW, including ZNF228, SCAMP4, and PSD3.

Discussion: These results support a model in which molecular factors influence breast cancer onset, progression and prognosis in AAW. Genes with higher expression in tumors from AAW function in steroid, fatty acid, and serine biosynthesis, signal transduction, cell proliferation and adhesion, and cytoskeleton organization and biogenesis. Functions of genes with lower expression in AAW tumors include regulation of transcription, vesicular transport, iron metabolism, signal transduction, and extracellular matrix organization and biogenesis. These results suggest that breast tumors from AAW and CW differ at the gene expression level and that these differences may be responsible for the more aggressive clinical features of breast tumors in AAW compared to CW.
Abstract 5568: Elevated interleukin-12 is a plasma marker of poor prognosis in stage III melanoma patients
Authors: Chun Yun S , Wang Yuling , Vo Amy H , Liu Huey , Wang Daniel Y , Gershenwald Jeffrey E , Cormier Janice N , Ross Merrick I , McClain Dana M , Schacherer Christopher W , Reveille John D , Lee Jeffrey E
Published: May 2019

Background: The heterodimeric cytokine interleukin-12 (IL-12) can both induce and suppress cellular immunity; the IL-12 p40 subunit is also a component of IL-23, which can promote tumor growth. IL-12 plasma levels have been reported to rise with age. Since survival in melanoma patients also depends on age, we investigated the relationship between IL-12, age and survival in a large cohort of melanoma patients.

Methods: Melanoma patients underwent blood draw for determination of combined IL-12-p40 levels by ELISA. Clinical data was obtained from a prospective database. AJCC stage of disease, age and overall survival (OS) were determined from the date of blood draw.

Results: Plasma IL-12 levels were determined in 658 patients (445 stages I-II, 150 stage III, 63 stage IV). IL-12 levels rose with age, with mean levels of 75, 84, 96 and 112 pg/ml in ages <40, 40-59, 60-79 and ≥80 yr, respectively (p=0.012). After median follow-up of 13 mo, age was confirmed as a predictor of shorter OS on univariate analysis (p=0.009). However, in a multivariate model, while both advanced stage (p<0.0001) and elevated IL-12 (p=0.006) were independent predictors of shorter OS, age (p=0.339) was not. Stage-specific analysis demonstrated that the association between IL-12 and OS was limited to patients with regional metastasis (stage III, table). The risk of death among stage III patients with elevated IL-12 (> 150 pg/ml) was >4-fold greater than that of patients with normal IL-12. Furthermore, the association of elevated IL-12 with OS in stage III patients was independent of the extent of regional disease.

Conclusions: An elevated plasma level of IL-12 is an independent predictor of poor prognosis in melanoma patients with regional metastasis. The association between IL-12 and advanced age could help explain the link between age and poorer prognosis in melanoma. Elevated IL-12 may be a marker of an immunosuppressive, tumor-promoting response in melanoma patients.

Prognostic factorUnivariate PMultivariate PHazard ratio (95% CI)Gender (M v. F)0.461--Age (yr)0.0300.349-Extent of disease (stage III A v. B v. C)0.0310.031Elevated IL-12 (> 150 pg/ml)0.0010.0044.763 (1.660-13.669)
Abstract LB-139: Efficacy, safety, and changes in blood markers following sunitinib monotherapy in patients with advanced hepatocellular carcinoma: Experience from a multidisciplinary Phase II study
Authors: Pavlickova Petra , Vogt Peter K.
Published: May 2019

Patients with advanced hepatocellular carcinoma (HCC) have a very poor prognosis. HCC is a highly vascular tumor with increased levels of angiogenic factors, including VEGF and VEGFR2. Sunitinib is an oral multitargeted receptor tyrosine kinase inhibitor with activity against VEGFR2, PDGFRβ, and c-KIT. We performed a multidisciplinary Phase II study to evaluate the efficacy, toxicity, and changes in angiogenic parameters following sunitinib administration in patients with advanced HCC. Eligibility criteria included unresectable or metastatic measurable HCC. Patients were treated with sunitinib at 37.5 mg po qd on a standard 4 weeks on, 2 weeks off regimen (6 weeks/cycle). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed to assess changes in tumor permeability. Plasma markers were assayed by multiplex protein array. In a subset of patients, viable circulating endothelial cells (CECs) and circulating progenitor cells (CPCs) were evaluated by flow cytometry in fresh whole blood samples at days 1, 15, 29, 57, 85, and 133. The primary endpoint of the study was progression-free survival (PFS). The targeted 34 patients have been enrolled: median age=63 (range 30-81); M/F=29/5; ECOG 0/1=15/19; CLIP 1/2/3=13/12/9. The treatment was generally well tolerated. Grade 3/4 toxicities included SGOT/SGPT (18/9%), neutropenia (12%), lymphopenia (15%), thrombocytopenia (12%), fatigue (9%), hand-foot syndrome (6%), rash (6%), hyperbilirubinemia (6%), and ataxia/disequilibrium (3%). One patient had a partial response and 10 patients had stable disease of at least 12 weeks. The median PFS was 4.0 months (95% CI: 2.8-7.0) and the median overall survival was 10 months (95% CI: 7.5-not estimable). Following 2 weeks of sunitinib administration, the mean tumor permeability (Ktrans) decreased by an average of 40% from the baseline. Sunitinib decreased sVEGFR2 levels and increased PlGF and VEGF levels in most patients. Interim analyses suggested that sunitinib treatment increase the number of CECs at day 15. The number of CPCs was significantly decreased by sunitinib at days 15, 29, and 57 compared to baseline (P<0.01). Sunitinib administered in the current dose schedule can be safely given with close monitoring in the majority of HCC patients. Preliminary evidence of antitumor activity was observed. Changes in functional parameters on DCE-MRI were seen following sunitinib administration. Complete data on VEGF, PlGF, bFGF, and sVEGFR2 in plasma, CECs, and CPCs– and their correlation with changes in DCE-MRI and clinical response– will be presented.
Abstract LB-141: The Adenoma Prevention with Celecoxib (APC) trial: Five-year efficacy and safety results
Authors: Bertagnolli Monica M. , Zauber Ann G. , Hawk Ernest T
Published: May 2019

The APC Trial was a placebo-controlled randomized study of celecoxib for prevention of sporadic adenomas in high risk patients. This study showed that, after 3 years of treatment, patients taking 200 mg of celecoxib bid had 33% fewer adenomas and 57% fewer advanced lesions, and patients taking 400 mg of celecoxib bid had 45% fewer adenomas and 66% fewer advanced lesions. This study also found that celecoxib use was associated with a small but significant increase in cardiovascular risk. After completing the 3 year treatment study, APC trial enrollees were offered participation in a 2 year off treatment observational study during which additional safety and efficacy data were collected. Colonoscopies at 5 years after initiating study treatment were performed on 639 patients, and showed a cumulative advanced adenoma incidence of 0.125 in patients taking 200 mg bid celecoxib, and 0.158 in patients taking 400 mg celecoxib bid, compared to 0.212 for patients on placebo (41% and 25% reductions, respectively, P<0.0001). Investigator reported, non-adjudicated selected cardiovascular events occurred 35 times in 676 patients randomized to placebo, 45 times in 683 patients randomized to celecoxib 200 mg bid, and 46 times in 669 patients randomized to 400 mg celecoxib bid. This selected category of events included all reports of myocardial infarction or ischemia, death from any cause, cerebrovascular disease, cardiovascular therapeutic procedures, or venous thrombosis or thromboembolism. One third of APC Trial participants used cardioprotective aspirin, and year 5 colonoscopy data showed increased adenoma incidence and severity in this subset, suggesting the presence of more aggressive disease in aspirin users. These data, together with additional new placebo-controlled analyses of celecoxib cardiovascular safety, suggest that chemoprevention with celecoxib may be safe and effective for some high risk colorectal adenoma patients.
Abstract LB-203: Phase I/II study of the androgen receptor antagonist MDV3100 in castration-resistant prostate cancer
Authors: Scher Howard I. , Beer Thomasz , Higano Celestia S , Danila Daniel C , Shelkey Julia , Hirmand Mohammed , Hung David , Morris Michael J , Larson Steve M , Sawyers Charles L
Published: May 2019

Introduction: Overexpression of the androgen receptor (AR) is believed to contribute to the progression of CRPC. MDV3100 is a small molecule AR antagonist with a novel mechanism of action that blocks nuclear translocation of AR, DNA binding, and has no agonist activity when AR is overexpressed. MDV3100 has been shown to be effective in preclinical models of CRPC. In July 2007, a multi-center first-in-man Phase 1-2 trial was initiated to determine safety, pharmacokinetics (PK), and antitumor activity including effects on prostate-specific antigen (PSA), bone and soft tissue metastases, and in selected pts fluorodeoxyglucose (FDG) and fluorodihydrotestosterone (FDHT) uptake by positron emission tomography (PET).

Methods: Pts were administered MDV3100 orally, once daily, starting at 30 mg with sequential escalations in cohorts of 3 pts. Enrollment was expanded at 60 mg and above to include up to 12 chemotherapy-naïve and 12 post-chemotherapy pts, once the safety of a dose was established. PK parameters for the dose-escalation cohorts were estimated using a 2-compartment model.

Results: 85 pts have been enrolled to date on doses up to 240 mg. 21 pts at 60 mg, and 22 pts at 150 mg have been followed for 12+ and 8+ weeks respectively. MDV3100 has been well-tolerated without dose-limiting toxicity. PK were dose-linear with a half-life of approximately one week. At doses of 30, 60, 150, and 240 mg, geometric mean steady state Cmax values were 2.8, 6.1, 17.3, and 23.7 µg/mL and AUC24hr were 61, 120, 361, and 480 µg*hr/mL, respectively. Effective AR blockade by MDV3100 has been shown by PSA declines and by PET findings. Evaluation at the 12 week timepoint for 21 pts at 60 mg showed 9 pts (43%) had >50% decline in PSA from baseline. To date, 8 pts have had FDG and FDHT PET at baseline of whom 4 have had 1 or more follow-up scans. All 8 had abnormal FDHT accumulation at baseline while 4 of 4 with follow-up scans had no FDHT accumulation.

Conclusions: MDV3100 is a novel AR antagonist in clinical investigation. The observed PSA declines are consistent with the inhibition of AR signaling. The inhibition of FDHT accumulation demonstrates receptor blockade in vivo. MDV3100 has been well-tolerated to date and appears to be a promising candidate for the treatment of CRPC. Pt follow-up and dose escalation are continuing. The analysis of the association between PSA declines and clinical outcomes is ongoing and will be reported at a future date.
Abstract LB-204: Results of a Phase 3 trial evaluating safety and efficacy of specific immunotherapy, recombinant idiotype (Id) conjugated to KLH (Id-KLH) with GM-CSF, compared to non-specific immunotherapy, KLH with GM-CSF, in patients with follicular non-Hodgkin's lymph
Authors: Levy Ronald , Robertson M J , Ganjoo K , Leonard J , Vose J , Denney Dan
Published: May 2019

Introduction: MyVax® personalized immunotherapy consists of the tumor-specific Id protein, produced using molecular methods, conjugated to Keyhole limpet hemocyanin (KLH) and administered in a series of sc immunizations with GM-CSF.

Methods: This is a multi-center, randomized, blinded, controlled trial examining the safety and efficacy of MyVax compared to a control immunotherapy in patients with previously untreated follicular non-Hodgkin's lymphoma (fNHL). Patients received 8 cycles of CVP followed by a 6-month rest period. Patients who maintained at least a partial response for 6 months post CVP were randomized to receive MyVax or control immunotherapy in a 2:1 ratio. All patients received GM-CSF at each immunization and for the next 3 days. Patients received a series of 7 immunizations over 24 weeks. Sera for Id- and KLH-specific humoral immune response (IR) assays were collected prior to, during, and for 1 year following immunization.

Results: 287 patients were randomized and 278 patients received at least one immunization. Anti-Id IRs were observed in 41.0% of evaluable patients. No statistical difference in PFS and time to subsequent anti-lymphoma therapy (SALT) was seen in the patients who received MyVax compared to those who received the control immunotherapy. Both arms of the study have an apparent plateau of PFS >30% at 5 years. A highly statistically significant improvement in PFS (P=0.0017) was seen in patients mounting an anti-Id immune response (IR+) vs. IR- patients with >2-fold increase (39.7 vs 18.1 months) in PFS. The IR+ patients show a statistically significant improvement in PFS over the control immunotherapy patients while there is not a statistically significant difference in PFS between the IR patients and the control immunotherapy patients. The degree of clinical benefit correlates with the titer of the anti-Id IRs, but not with the titer of the anti-KLH IRs. High risk FLIPI patients did as well as the other patients in both PFS and SALT. Clinical response improvements were observed on both arms post immunization.

Conclusions: There was no difference in PFS between the patients receiving specific immunotherapy versus those receiving control immunotherapy. As previously reported in Phase II trials, fNHL patients mounting anti-Id IRs have a significantly improved clinical outcome.
Abstract LB-240: Clustering of phospho-proteins targeted by enzastaurin identifies significant biomarker association with patient outcome and novel associations between biomarker groupings in a glioblastoma multiforme cohort
Authors: Dolled-Fillhart Marisa , Pinard Robert , Waldron Don , Ang Agnes , Goodrich Leo , Myrand Scott , Thornton Don , Graff Jeremy , Mullaney Brian
Published: May 2019

Introduction: Enzastaurin (LY317615.HCl) is a novel acyclic bisindolylmaleimide currently in Phase II clinical trials in combination with temozolomide and radiation for the front-line treatment of glioblastoma multiforme. Enzastaurin was identified as an ATP-competitive inhibitor of PKC-β subsequently as an inhibitor of other AGC-family kinases, including other PKC isoforms, p90RSK, GSK3β, and p70S6K. In a wide array of human cancer cell lines, including glioblastoma cell lines, enzastaurin treatment blocks signaling through the PI3 kinase/AKT/mTOR pathway. Accordingly, enzastaurin suppresses the phosphorylation of GSK3Bser9, AKTser473, CREBser133, and the S6 ribosomal protein at ser235/236 and ser240/244. We therefore sought to evaluate the levels of these key phosphorylation events in a series of primary human glioblastoma multiforme tissues in order to determine whether any or all of these phosphorylation events might be related to patient survival.

Methods: A retrospective glioblastoma multiforme cohort of 115 patients was evaluated by quantitative immunofluoresence using AQUA® analysis for PhosphoCREB ser133, PhosphoS6 ser240/244, PhosphoGSK3B ser9, and total GSK3B. AQUA® technology quantitatively measured protein expression in patient samples, allowing for relative concentrations of the phosphorylated markers to be calculated and grouping of patients by clustering of AQUA® scores.

Results: Spearman-Rho analysis identified strong direct correlations between PhosphoCREB ser133 and PhosphoS6 ser240/244 and between PhosphoCREB ser133 and PhosphoGSK3Bser9 expression in this cohort of patients. Univariate Kaplan Meier survival analysis of these patients based on clustered AQUA® scores revealed that these markers were indeed inversely related to disease-specific survival (phosphoGSK3B ser9 P<0.05). Multiparametric Correlative Discovery™ analysis also indicated a strong association of the cluster of patients with low levels of phosphoprotein expression and better survival. Conclusions: These data reveal that the signaling pathways targeted by enzastaurin were activated specifically in patients with the poorest survival and also suggest that these phosphomarkers, alone or in concert, may be useful for patient stratification.
Abstract LB-247: A multidisciplinary phase II study of AZD2171 (cediranib), an oral pan-VEGF receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma
Authors: Batchelor Tracy T , Sorensen Gregory , di Tomaso Emmanuelle , Duda Dan G , Zhang Wei-Ting , Ancukiewicz Marek , Lahdenranta Johanna , Louis David , Plotkin Scott , Ivy Percy , Loeffler Jay S , Wen Patrick , Jain Rakesh K
Published: May 2019

Targeted agents are promising new therapeutics that have entered clinical trials for glioblastoma. AZD2171 (cediranib) is a potent, oral pan-VEGF receptor tyrosine kinase inhibitor with a half-life of 20 hours compatible with once-daily dosing. A primary target of AZD2171, VEGFR2, is expressed on glioblastoma endothelium. We have demonstrated normalization of tumor vessels in recurrent glioblastoma patients administered AZD2171 on a daily basis. Normalization has rapid onset, is reversible, and is associated with alleviation of brain edema (Batchelor TT, et al. Cancer Cell 2007;11:83-95). In this Phase II study of 31 recurrent glioblastoma subjects we now report clinical outcomes, including the proportion of patients alive and progression-free at 6 months (APF6) as the primary endpoint. Secondary endpoints include radiographic response proportion; progression-free survival; and overall survival and toxicity. At this time we are presenting radiographic response data, APF6, PFS, and OS on 31 patients. Thirty patients have experienced disease progression and one patient remains in follow-up without progression. The primary and secondary endpoints are tabulated below:

Radiographic Responses Partial Response (more than 50% decrease in volume) in 16/30 (56%)

APF6 [95% CI] 25.8% [14.7%, 46.9%]

PFS [95% CI] 117 days [88, 145]

OS [95% CI] 221 days [172, 285]

Only one of the first 16 patients was removed from the study due to toxicity (fatigue). Dose limiting toxicities were observed in 9/16 patients with hypertension; fatigue and diarrhea were encountered most often. There have been no intracerebral hemorrhages. AZD2171 alleviated brain edema, a major cause of morbidity in glioblastoma patients, and had a steroid-sparing effect in many of the patients enrolled. Blood biomarkers were serially assessed and it was observed that plasma VEGF, PlGF, and SDF1α were increased after treatment. Plasma PlGF and VEGF decreased upon cediranib discontinuation. Plasma bFGF and SDF1α and viable circulating endothelial cells increased when tumors escaped treatment with AZD2171. AZD2171 is a promising therapy for glioblastoma and an attractive therapeutic partner for chemotherapy or radiation.
Abstract LB-330: A novel role of tumor suppressor BRCA1 in regulating integrity of heterochromatin structure.
Authors: Zhu Quan , Pao Gerald , Tonnu Nina , Verma Inder M
Published: May 2019

Introduction: BRCA1, as well as BRCA2, were identified as the hereditary breast and ovarian cancer susceptibility genes that can account for almost all of inherited cases of breast cancers. BRCA1 is a multifunctional nuclear protein with a RING domain at the N-terminus. Heterochromatin is chromatin containing inactive genes. Pericentromeric heterochromatin is composed of highly repetitive tandem DNA repeats whose transcription is constitutively silenced. In mice, the repeats are classified as major and minor satellite repeats. Heterochromatin protein 1 (HP1) plays a critical role in maintaining heterochromatin structure.

Methods: To study the biological function of the tumor suppressor BRCA1, we deleted BRCA1 in nestin positive neuronal stem cells in the brain and showed that the animals displayed severe neuro-developmental deficits. In the course of this work we discovered a novel molecular defect in BRCA1 deficient cells, i.e., a failure to maintain integrity of the heterochromatic structure.

Results: In the absence of BRCA1, the number of heterochromatic centers is severely reduced in mouse neuronal cells. HP1 proteins are destabilized, and more importantly, the transcription of satellite DNA is derepressed in mouse neural progenitor cells, mouse fibroblasts, and human cancer cells, including a BRCA1 deficient breast cancer cell line. The defect in silencing invariably appears after the loss of the BRCA1 allele in our paradigm prior to exhibiting any neoplastic phenotype. What is the mechanism of BRCA1 in regulating the heterochromatin integrity? ChIP analysis showed that BRCA1 physically associates with both major satellite DNA and minor satellite DNA, whereas the association is diminished in the BRCA1 knockout animals. More intriguingly, the absence of BRCA1 binding to satellite DNA correlates with a drastic reduction of ubiquitinated histone H2A at the constitutive heterochromatin region. Because BRCA1 contains an E3 ubiquitin ligase activity which is enhanced by BARD1 and the complex ubiquitinate histone H2A in vitro, we examined the heterochromatin silencing in cells with different BRCA1 mutants. These experiments showed that the E3 ligase activity of BRCA1 is required for repression of satellite DNA transcription.

Conclusions: Our working model is that mutations of BRCA1 may destabilize the protein complex and lead to defects in the heterochromatin integrity, thereby affecting the stability of the genome which is a hallmark of cancer. Given that mutants in the RING domains are the same as in women who have pathological diseases, we hypothesize that deregulation of satellite DNA transcription can be explored as an early detection marker for breast cancer progression in BRCA1 patients.
Abstract LB-332: A novel TIMP-2-mediated cytoplasmic mechanism for the regulation of receptor tyrosine kinase, VEGFR-2
Authors: Sivendran Renuka , Li Hongmei , Seo Dong-Wan , Diaz Tere , Wei Beiyang , Stetler-Stevenson William G.
Published: May 2019

The vascular endothelial growth factors (VEGFs) and their receptors (receptor tyrosine kinases) are critical for angiogenesis. The binding of VEGF-A induces dimerization and autophosphorylation of its receptor, VEGFR-2. This initiates a signaling cascade that results in increased cell proliferation, migration, and permeability. The introduction of tissue inhibitor of metalloproteinase-2 (TIMP-2) protein or a dominant negative mutant that has no MMP inhibitory activity (Ala+TIMP-2) intercepts this signaling cascade and affects these cellular functions. To elucidate the mechanisms of this disruption in VEGFR-2 signaling, we explored direct (competition binding, substrate affinity, total binding capacity) and indirect (receptor degradation, receptor dimerization by cross-linking, and FRET) mechanisms that could facilitate the inhibition of growth factor signaling by TIMP-2. Our studies showed that TIMP-2 did not directly compete for binding to VEGFR-2 as previously reported for TIMP-3 (Qi JH. Nature Medicine 2003;9:407-15). Further, TIMP-2 did not increase the internalization and degradation of VEGFR-2, nor did it decrease the affinity of the VEGF-A ligand. In contrast, TIMP-2 decreased the total cellular binding capacity for VEGF-A. These data suggest a novel mechanism by which TIMP-2 may regulate the binding conformation or state of VEGFR-2 dimerization, thereby influencing the cell sensitivity to VEGF-A stimulation. To study the conformation or state of VEGFR-2 dimerization, we conducted cross-linking analysis of VEGFR-2, and the results showed that TIMP-2 pretreatment prior to VEGF-A treatment significantly decreased VEGFR-2 dimer formation. In order to study this quantitatively, we designed a fluorescence resonance energy transfer (FRET) system that would detect the intracellular dimers of VEGFR-2. We fused Cerulean or Venus to the C-terminus of human VEGFR-2, transfected porcine aortic endothelial (PAE) cells, and selected stable cells expressing the constructs. Sensitized emission FRET analysis of the transfected PAE cells showed that Ala+TIMP-2 pretreatment prior to VEGF-A treatment decreased the VEGFR-2 dimerization to basal levels. This demonstrated that TIMP-2 regulates the binding capacity of VEGFR-2 by modulating the monomer-dimer equilibrium of VEGFR-2. This is the first demonstration of a cytoplasmic signaling mechanism influencing the monomer-dimer equilibrium of a receptor tyrosine kinase. This may potentially be a common mechanism for cellular regulation of growth factor sensitivity for this class of receptor tyrosine kinases.
Abstract LB-334: Signals from the microenvironment induce a malignant program accompanied by de novo epigenetic remodeling
Authors: Dumont Nancy , Crawford Yongping G. , Reynolds Paul A. , Wilson Matthew B. , Sigaroudinia Mahvash , Gauthier Mona L. , Fordyce Colleen A. , Tlsty Thea D.
Published: May 2019

Introduction: The active acquisition of epigenetic changes is a poorly understood but important process in development, differentiation, and disease. Our work has recently demonstrated that repression of the p16/pRb pathway in human epithelial cells, a condition common to stem cells and many tumor cells, induces dynamic epigenetic remodeling resulting in the targeted methylation of selected CpG islands. We hypothesized that cells in this epigenetically-plastic state can be programmed by the microenvironment to acquire epigenetic changes that promote tumorigenesis.

Methods: Normal human mammary epithelial cells (HMEC) and HMEC with repressed p16 were first transduced with constitutively active Ha-rasV12. In order to mimic the secretory aspects of the extracellular environment, the cells were subsequently cultured in a serum-rich environment.

Results: When p16-repressed cells were challenged with oncogenic stress, they failed to undergo the classic proliferative arrest as documented in normal cells. When further stressed by being cultured in a serum-rich environment, they spontaneously immortalized and exhibited phenotypic changes indicative of epithelial to mesenchymal transition (EMT). The EMT was accompanied by de novo methylation of the E-cadherin promoter and increased motility.

Conclusions: These data demonstrate that signals from the microenvironment can induce phenotypic and gene expression changes that result in de novo epigenetic alterations important in tumor progression.
Abstract LB-78: A randomized trial on folic acid supplementation and risk of recurrent colorectal adenoma
Authors: Wu Kana , Platz Elizabeth A , Willett Walter C , Selhub Jacob , Fuchs Charles S , Giovannucci Edward
Published: May 2019

Results from two recently published randomized trials (Logan et al., 2008 and Cole et al., 2007) found little evidence for a protective effect of folic acid supplementation on the recurrence of colorectal adenomas. In one trial (Cole et al., 2007) folic acid supplementation even appeared to be non-significantly associated with higher risk of advanced adenoma. This following paper reports on results from another randomized controlled trial of folic acid (1000 micrograms/day) versus placebo among participants of two large prospective cohorts, the Health Professionals Follow-up Study (HPFS) and the Nurses’ Health Study (NHS), who had a previous diagnosis of colorectal adenoma. The primary endpoint of interest was any new diagnosis of adenoma during the study period (May, 1996 to March, 2003). 346 subjects were randomized to folic acid and 346 subjects to placebo for a period of three to up to 6 1/2 years. The incidence of at least one recurrent adenoma was not associated with folic acid supplementation (RR=0.86, 95% CI=0.64-1.16, p=0.32). There was some suggestion of an inverse association between folic acid supplementation and recurrent distal adenoma (multivariate adjusted relative risk (RR) =0.67, 95% confidence interval (CI)=0.39-1.15, p=0.14), and early stage adenoma (small and tubular) (RR=0.74, 95% CI=0.48-1.15, p=0.19), but none of the associations reached statistical significance. Advanced adenoma (large or adenomas with villous component) was not associated with folic acid supplementation, but the number of advanced cases was low (16 cases folate group, 18 cases placebo group; RR=0.96 95% CI=0.50-1.84, p=0.90). However, when associations were examined by folate blood concentrations drawn prior to time of randomization (<=7.5 ng/mL vs. >7.5 ng/mL) significant inverse associations were found for total recurrent adenoma (43 cases placebo, 32 cases folate, RR=0.64 (95% CI=0.43-0.96, p=0.03), distal adenoma (20 cases placebo, 9 cases folate, RR=0.36 (95% CI=0.14-0.61, p=0.001), early adenoma (22 cases placebo, 10 cases folate, RR=0.36 (95% CI=0.17-0.76, p=0.007), advanced adenoma (14 cases placebo, 9 cases folate, RR=0.48 (95% CI= 0.22-1.06, p=0.07) among those with low folate levels. No associations were found for participants with higher folate levels at baseline (at least one adenoma: 30 cases placebo, 30 cases folate, RR=1.30 (95% C=0.83-2.03, p=0.25). Occurrence of deaths, cancer and cardiovascular disease did not differ by treatment status. Our results do not support a protective effect of folic acid supplementation on the recurrence of colorectal adenomas; however, there may be some benefit on adenoma recurrence among those with a lower folate levels at baseline. The role of additional folic acid supplementation as a potential preventive measure for colorectal adenomas/cancer needs to be reevaluated especially with regard to dose and timing.