bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B74: Essential role of Skp2 in castration-resistant prostate cancer
Authors: Chen Zhenbang
Published: June 2012

Prostate cancer (PCa) is the most frequently diagnosed cancer in African American men. African American men died of PCa in a 2.39-fold higher rate as compared with Caucasian counterparts. For patients with the metastasis PCa, androgen-deprivation chemotherapy is commonly applied and results in an initial regression of PCa. However, the relapses of this malignance were reported in many cases, and eventually PCa patients still died of recurrent growth of Castration Resistant Prostate Cancer (CRPC). Molecular mechanisms contributing to CRPC remain poorly understood. The purpose of this research is to define anticancer effects of Skp2 inactivation on the recurrence of CRPC using mouse models. In this experiment, Pten/p53 conditional double and Pten/p53/Skp2 conditional triple knockout mice were generated, and prostate tumorigenesis was evaluated and compared under the condition of castration and non-castration in mice. Here we report for the first time that Skp2 inactivation significantly inhibits the recurrence of CRPC in mice using Pten/p53 conditional mouse models. Loss of Skp2 significantly suppresses both the initiation and progression of prostate tumorigenesis in Pten/p53 mutant mice at 3 months of age and 6 months of age, respectively. Prostate tumors of Pten/p53/Skp2 triple mutant mice are significantly smaller as compared to that of age-matched Pten/p53 double mutant mice. Pathological analysis revealed that triple mutant mice develop less aggressive phenotype of prostate cancer than double mutant mice. Pten/p53 mice responded to surgery castration by decreasing the size of prostate tumors initially, but the recurrent growth of prostate cancer resulted in the death of all mice at 6 months of age. Most importantly, loss of Skp2 remarkably inhibits the recurrent growth of CRPC in Pten/p53 mutant mice. Three months post castration, prostate tumor weights of Pten/p53/Skp2 mutant mice were significantly decreased as compared to that of age-matched Pten/p53 mutant mice. Suppression on the recurrent growth of CRPC by Skp2 inactivation is contributed by induction of G2 cell cycle arrest and cellular senescence. Our findings suggest that drugs targeting on Skp2 function may be a novel and effective chemotherapy option to control CRPC in patients.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B74.
Abstract B86: HIV and HPV risk and prevention factors among Tongan and Chamorro young adults in Southern California: A qualitative assessment
Authors: DiStefano Anthony , Aromin Jay , Dimaculangan Jeany , Vunileva ‘Isileli , Tanjasiri Sora P. , Peters Ruth , Tui‘one Vanessa , Takahashi Lois , Sablan-Santos Lola , Quitugu Lourdes , Quenga Joey , Hui Brian , Barrera-Ng Angelica
Published: June 2012

Background: Racial/ethnic minority and medically underserved populations are at significant risk of the intersection of HIV/AIDS, HPV, and cancer. Little is known about the intersection of these public health issues in Pacific Islander communities.

Purpose: Establishing the ground work for understanding the intersection of these diseases, we assessed HIV and HPV risk and prevention factors among Chamorro and Tongan young adults in Southern California.

Methods: Under guidelines of CBPR, a qualitative study was implemented utilizing community based focus groups with male and female young adults, and parents (n=69); and key informant interviews with medical, mental health, and social service providers, and community leaders from social, youth, and faith-based groups (n=26).

Results: Utilizing grounded theory, common factors impacting HIV-HPV risk and prevention among young adults were identified: 1) religio-cultural taboos limit communication about sexual health between generations and from community leaders; 2) limited knowledge of HIV and particularly HPV engender misperceptions about disease transmission and prevention; 3) sexual abstinence, especially for young women, is promoted by parents and religious leaders; however, 4) the norm of expected abstinence leads to low levels of condom acceptance; and 5) collectivist notions of filial shame associated with HIV-HPV testing and utilization of other sexual health services, constrains prevention.

Discussion: Quantitative exploration of the relationship between factors identified and behavior, as well as research to identify HIV/HPV links to cancer in these communities is needed. Future consideration must include multigenerational, gender appropriate and cultural norms –especially related to religion and the interplay between individualism and collectivism.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B86.
Abstract B87: The effect of imaging on clinical management of breast pain
Authors: Howard Mary Beth , Battaglia Tracy A. , Freund Karen M.
Published: June 2012

Breast pain is a common complaint to both primary care and breast specialists. Current literature recommends imaging for women with breast pain to provide reassurance of benign etiology. The current study sought to determine if imaging is a valuable tool in providing reassurance for women with breast pain, through measuring the association between initial imaging in the evaluation of women with breast pain and subsequent clinical services utilization

From 2006–2009, 916 women were referred to an urban, Safety Net, diagnostic breast health practice for breast pain. We compared the subsequent clinical utilization of women who had imaging ordered at their initial visit to women who did not have imaging ordered. Clinical utilization was defined as the number of follow-up visits, diagnostic imaging studies, and biopsies completed within the 12 months following the initial provider visit. The study population was stratified based on the presence or absence of clinical breast exam findings.

Sixty-percent of women referred for breast pain were age 40 or younger, 87% were from racial/ethnic minority groups, 45% were non-English speaking, and 73% had public or no health insurance. Twenty five percent of women had imaging ordered at initial provider visit for breast pain. Minority and non-English speaking women were less likely to receive initial imaging. Of those who received initial imaging, 75% had radiographic findings which required no additional follow-up, yet 98% returned for additional evaluation. In adjusted analyses, women with imaging ordered at initial provider visit had increased clinical services utilization (OR 25.4, 95% CI: 16.7, 38.6). When the study population was stratified by clinical breast exam results, the risk-adjusted association between initial imaging and subsequent clinical services utilization remained. Women with normal clinical breast exams who received initial imaging exhibited increased odds for subsequent clinical services utilization (OR 23.8, 95% CI: 12.9, 44.0) than women who did not initial imaging. Six cancers were diagnosed in the study population; yet imaging in the absence of clinical breast exam abnormalities did not result in any cancer identification.

Initial imaging for women with breast pain increased the odds of subsequent clinical utilization and did not increase diagnostic certainty in ruling out malignancy.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B87.
Abstract ED04-04: Perspectives on the production of race and cancer disparities
Authors: McMullin Juliet
Published: June 2012

Scholars of social medicine have long called for a recognition of politics, history and economics in our understanding of disease occurrence among individuals and groups. And yet, larger social discussions of disease are often infused with categories such as race/ethnicity and culture that are used to explain cancer rates in lieu of the social conditions that play a greater role in unequal cancer burdens. Drawing on multidisciplinary collaborative cancer prevention and screening efforts with community groups, this paper will discuss how cultural anthropology's attention to social context and cultural meaning systems in the cancer continuum can reveal processes that lead to production of race and subsequently obscure the role of social inequalities in the production of cancer disparities.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):ED04-04.
Abstract PL02-01: Global disparities and prevention strategies in liver cancer
Authors: Groopman John
Published: June 2012

Hepatocellular carcinoma (HCC) is a major cause of cancer morbidity and mortality in many parts of the world, including Asia and sub-Saharan Africa, where there are upwards of 1,000,000 new cases each year and over 370,000 deaths annually in the People's Republic of China (P.R.C.) alone. The major etiological factors associated with development of HCC in these regions are infection with hepatitis B (HBV) and/or hepatitis C (HCV) virus and lifetime exposure to high levels of aflatoxin B1 (AFB1) in the diet. Detailed knowledge of the etiology of HCC has spurred many mechanistic studies to understand the pathogenesis of this often fatal disease and this knowledge is critical for translation to preventive interventions in high risk populations. HBV is a significant risk factor for HCC in the economically developing world where there are over 500 million viral carriers. The contribution of HBV to the pathogenesis of liver cancer is multifactorial and is further complicated by the identification of mutant variants in HBV that alter the carcinogenic process. The HBV genome encodes its essential genes with overlapping open-reading frames; therefore, a mutation in the HBV genome can alter the expression of multiple proteins. In many cases of HCC in Asia and Africa, a double mutation in the HBV genome, an adenine to thymine transversion at nucleotide 1762 and a guanine to adenine transition at nucleotide 1764 (1762T/1764A), has been found in tumors.

The molecular basis for the formation of these nucleotide changes and their temporal appearance during the course of HBV infection is unclear. Thus, whether these mutational changes can be acquired and transmitted from person to person is unknown. Nonetheless, this segment of the HBV genome contains an overlapping sequence for the base core promoter and the HBV X gene; therefore, the double mutation in codon 130 and 131 of the HBV X protein reported in human HCC corresponds to the 1762 and 1764 nucleotide changes. Thus, the linkage of this alteration with disease outcomes makes it a candidate biomarker for the early detection of HCC risk in individuals. Financial support for this work was provided by the National Institute of Environmental Health Sciences through Grants P01 ES006052 and P30 ES003819.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):PL02-01.
Abstract PL06-03: Effect of patient navigation on time from definitive diagnosis to initiation of treatment (T2) for breast, prostate, colorectal, and cervical cancers
Authors: Patierno Steven , Raich Peter C.
Published: June 2012

Background: Barriers to timely initiation of treatment in newly diagnosed cancer patients may add to cancer health disparities of low income, uninsured and minority populations.

Objectives: To conduct a clinical trial to evaluate the impact of patient navigation on the time from cancer diagnosis to initiation of the first treatment in a medically underserved patient population.

Methods: Nine sites participated in the National Cancer Institute Patient Navigation Research Program (PNRP) study. 2,107 cancer patients enrolled in the study, 1,033 in the navigated and 1,074 in the control groups. Analysis was on the individual patient level, due to site population heterogeneity.

Results: Demographics included 39% Black, 32% White, and 27% Hispanic; 85% female, 15% male. Insurance status included 17% uninsured, 45% public, and 38% private. The navigated and control groups were well balanced for major covariates. Mean and median times from diagnosis to first treatment were not impacted by patient navigation. Treatment patterns did differ in that more mastectomies were performed in the control vs. navigated breast cancer patients (32 vs. 21%), while more cone biopsies (23 vs. 15%) and fewer LEEP procedures (49 vs. 65%) were performed in the control vs. navigated cervix cancer patients.

Implications: Patient navigation did not impact the time from cancer diagnosis to start of first treatment in a medically underserved population, while it may have impacted certain patterns of care.

Next Steps: We plan further analyses by site and cancer type, assess covariate effects, perform a sensitivity analysis, and assess patient-navigator interactions.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):PL06-03.
Abstract PL07-01: Linkage disequilibrium-based analysis of DNA repair and GST genes in malignant gliomas: A unique tool in defining the association between genetic diversity and survival
Authors: Ali-Osman Francis , Owzar Kouros , Lipp Eric , Adams Bart , Illyasova Dora , McClendon Roger , Reardon David , Friedman Alan , Friedman Henry , Bigner Darrel
Published: June 2012

Inherited genetics are increasingly being identified as a significant factor that contributes to both treatment outcome and treatment-associated toxicities in cancer patients undergoing therapy. The specific SNPs and genes involved are, however, still poorly understood. In this study, we exploited the unique advantages of a linkage disequilibrium-based approach to examine the relationship between genetic diversity in regions of DNA repair and GST genes with survival in adults with anaplastic astrocytoma and glioblastoma multiforme treated on temozolomide and carmustine-based protocols. We genotyped a subset of 1,267 tagging SNPs within or near haplotype blocks of 27 genes in 301 patients. The SNPs were selected to be in high LD with and, thus, to be predictive of the diversity of the target region containing the gene and 20 kb flanking 3′ and 5′ of it. Genotyping was conducted on a high-throughput customized Affymetrix platform. Associations between genotypes and survival was performed using the Fisher's exact test, after testing for Hardy-Weinberg conformity and gender mismatches. The results identified several tSNPs in and around the loci of 11 genes (EXO1, DDB2, LIG1, MGMT, MSH2, MSH4, PAN3, RAD52, TDG, XRCC1, and XRCC5) to be highly associated with survival. Several other SNPs showing a statistical tendency to be associative. Although, a number of SNPs/genes was associated with survival in both anaplastic astrocytoma and GBM, a subset of genes and SNPs were associative in GBMs but not in AAs and vice versa. We then examined 28 SNPs in all eight members of the GST family (A1, M1, M3, P1, O1, S1, T and Z) allowing the identification of seven specific SNPs that were highly associated with treatment outcome/survival. The identification of highly polymorphic regions associated with the loci of DNA repair and GST genes as determinants of alkylating agent-based therapy in malignant gliomas is consistent with the established role of enhanced DNA repair and drug metabolism in tumor resistance to these agents. Ongoing studies are directed at these associative SNPs to gain insight into the biology underlying their association with treatment outcome.

Supported by grants RO1 CA 153050, RO1 CA127872, RO1 CA 112519 and P30-CA114236 from the NIH, USA.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):PL07-01.
Abstract PL07-02: Whole genome approaches to identify pharmacogenomic markers of anticancer agents
Authors: Stark Amy , Delaney Shannon , Im Hae Kyung , Wheeler Heather , Gamazon Eric , Dolan M. Eileen
Published: June 2012

Preclinical and clinical genome-wide association studies (GWAS) in oncology provide an unprecedented opportunity for a comprehensive and unbiased assessment of the heritable factors associated with drug response. For chemotherapeutic drugs, there are many challenges with performing a clinical GWAS, including staggering costs because a homogenous population of patients treated with the same dosage regimen and minimal confounding variables is required. To get around these issues, we have developed preclinical cell-based models as a pharmacogenomic discovery tool but also a means to replicate or validate findings from clinical GWAS. Our model utilizes HapMap lymphoblastoid cell lines (LCLs) derived from individuals within different world populations (Caucasian, African, Asian, African American) that are evaluated for drug sensitivity to chemotherapeutic agents (platinating agents, antimetabolites, cyclophosphamide, paclitaxel). Evaluation of inter-ethnic differences revealed that LCLs from Africans tend to be more sensitive to antimetabolites and less sensitive to platinating agents than Caucasian derived LCLs. These LCLs are rich in genetic data as many are part of the International HapMap and the more recent 1000 Genome project. We utilized this data to identify disproportionately more expression quantitative trait loci (eQTLs, indicating that a SNP genotype is associated with the transcript abundance level of a gene) associated with pharmacologic traits than expected by chance based on minor allele frequency. We are attempting to unravel the functional consequence of top pharmacologic GWAS SNPs with local and distant regulatory roles in cellular resistance to chemotherapeutic agents. For example, we discovered a SNP (master regulator) that is local to PRPF39 and distant to more than 100 genes that is associated with cisplatin-induced cytotoxicity in LCLs derived from African populations. Our cell-based model provides potential targets for therapeutic intervention and provides us with a greater understanding of the genetic contribution to interethnic variation in chemotherapeutic sensitivity.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):PL07-02.
Abstract PL08-01: Differential splicing of oncogenes and tumor suppressor genes between African and Caucasian Americans: Contributing factor in prostate cancer health disparities?
Authors: Lee Norman H. , Wang Bi-Dar , Patierno Steven R.
Published: June 2012

There are striking population disparities in prostate cancer (PCa) risk and survival outcome borne out of current health statistics data. This is particularly evident between African Americans (AA) and their Caucasian American (CA) counterparts. Epidemiologic studies have shown that higher mortality and recurrence rates of PCa is still seen in AA men even after adjustment for socioeconomic status, environmental factors and health care access. To test whether differential mRNA splicing may play a role in PCa health disparities, RNA from PCa and patient-matched normal prostate needle biopsies from AAs and CAs was processed and hybridized onto the Affymetrix human Exon 1.0 ST arrays. A 4-way statistical design (10% FDR, >1.5 fold-change) was employed in the following comparisons: AA normal vs. CA normal, AA cancer vs. CA cancer, AA cancer vs. AA normal, and CA cancer vs. CA normal. Our analysis identified >800 genes undergoing differential mRNA splicing between AA and CA cancer specimens. Notably, many of these genes reside within canonical oncogenic signaling pathways. To further delineate the functional consequences of these splice variants, exon-specific and/or exon junction-specific small interfering RNAs (siRNAs) were employed to suppress splice variants for 4 oncogenes (PIK3CD, FGFR3, MET and RASGRP2) in PCa cell lines derived from the AA and CA patient populations. The targeted knockdown of population-specific splice variants appears to have differential effects on cell proliferation and invasive. For example, the splice variant for phosphoinositide-3 kinase delta (PI3KCD) found in AA PCa specimens encodes a more aggressive version of the gene (i.e., leading to greater proliferation and invasion of cancer cells) compared to the variant counterpart found in CA PCa specimens. Taken together, our data suggest that differential mRNA splicing may be critical in PCa health disparities between the AA and CA populations. These findings should advance our knowledge on the molecular mechanisms underlying PCa health disparities, and may facilitate the development of novel strategies for PCa detection, diagnosis, prognosis, and therapy in the AA population. This work was supported by NCI grant 5U01-CA-116937, ACS-IRG-08-091-01 and the Affymetrix Collaborations in Cancer Research Program.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):PL08-01.
Abstract PL08-02: Fine mapping of genetic associations in African American colorectal cancer
Authors: Ellis Nathan A. , Kupfer Sonia S.
Published: June 2012

Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified risk variants in 14 genomic regions through the study of Europeans with CRC. In genotype analysis of a European American CRC case-control group, effects sizes and directions of association for 24 SNPs tested, which localize to 10 of the 14 previously identified regions, were consistent with GWAS results; in contrast, in an African American CRC case-control group, the associations ran in the opposite direction for 9 of 22 SNPs tested, indicating significant genetic heterogeneity in CRC associations in African Americans compared to European Americans. We conclude that genetic markers that identify CRC risk in persons of European ancestry do not identify CRC risk in African Americans. Two hypotheses may explain the genetic heterogeneity between European and African Americans: (i) The risk alleles in both populations are the same, however, the genetic architecture differs such that other SNPs that are linked to these same risk alleles will make better markers for African American CRC risk. (ii) The underlying risk alleles are different between the two populations. A corollary of this hypothesis is that the allele frequencies of the risk alleles must be low (<5%), because most the frequent genetic polymorphisms are shared between European and African populations. Distinguishing these hypotheses is important because genetic risk associated with rare alleles could have larger effect sizes (ORs>2, for example), which could make genetic risk modeling more determinative. Furthermore, identification of multiple rare alleles, each with a moderate risk effect, could explain the missing heritability problem. To address these hypotheses, we have drilled down on each of the genetic regions identified in the European GWAS using systematic genotyping and deep re-sequencing in African American CRC cases and population-matched controls. Analysis of tagSNPs in two genes so far analyzed, GREM1 and BMP4, have demonstrated multiple, independent SNP associations, which are not correlated with SNPs previously identified in persons of European descent. Because novel SNP associations are detected in each of these genes, we suggest that rare alleles underlie these genetic risk associations. We are presently using the deep re-sequencing analysis to identify candidate risk variants, which we will then test in functional studies. Ultimately, the analysis will permit better quantification of CRC risk, and it may lead to risk assessment models that can be used clinically for screening and surveillance.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):PL08-02.
Abstract A111: A phase I, dose escalation study of TB-403, a monoclonal antibody directed against PlGF, in patients with solid tumors
Authors: Lassen Ulrik , Nielsen Dorte , Sørensen Morten , Rønnengart Eva , Eldrup Katrine , Bentzon Karin , Winstedt Lena , Niskanen Titti , Pakola Steve , Stassen Jean-Marie , Glazer Steven
Published: June 2012

Rationale and Objectives: TB-403 is a humanised recombinant immunoglobulin G isotype 1 monoclonal antibody expressed in Chinese hamster ovary cells and directed to the receptor-binding site of placental growth factor (PlGF). The antibody is highly specific and does not cross-react with vascular endothelial growth factor A (VEGFA). PlGF levels are low in normal tissues, but up-regulated in several pathological conditions, including several types of cancer. TB-403 has been shown to significantly inhibit tumor growth in xenograft tumor models. The primary objective of the phase 1 study was to determine the maximum tolerated dose (if < 30 mg/kg) and to evaluate safety and tolerability of TB-403 in patients with advanced solid tumors. Secondary objectives included evaluation of pharmacokinetics (PK), objective tumor response and drug effect on PlGF and other molecular markers.

Methods: In this multi-center study, cohorts of 3 patients were treated with 8 weekly doses of 1.25, 5, or 10 mg/kg or 3 doses of 20 and 30 mg/kg once every three weeks (q3w). Six additional patients were treated with 30 mg/kg q3W. Patients showing objective tumor response or stable disease (SD) after 8 weeks were offered extended therapy. Main eligible criteria were: solid tumor with no other treatment options, ECOG performance status 0–1, normal organ function, and no prior anticancer therapy within 30 days (bevacizumab within 60 days).

Results: A total of 23 patients were accrued. No DLT, changes in ECG, laboratory findings or urine analysis were seen, except for one patient with an unrelated biliary stenoses. Of related or possibly related grade III or IV adverse events only one episode of pulmonary embolism, one case of dyspnoea and a case of dry skin were observed. Related or possibly related grade I and II adverse events included skin rash (1 patient), fatigue (5 patients), fever (1 patient), diarrhoea (1 patient), and hypertension (1 patient). No objective responses according to RECIST criteria were observed but five patients had SD ≥ 8 weeks, including 2 patients (pancreatic adenocarcinoma and esophageal squamous carcinoma) treated with weekly 5 mg/kg TB-403 with SD > 10 months.

Conclusion: TB-403 was well tolerated. MTD was not established due to lack of dose-limiting toxicity up to a dose of 10 mg/kg weekly and 30 mg/kg q3w. Prolonged SD (> 10 months) was seen in two patients treated with 5 mg/kg weekly TB-403. Pharmacokinetic and molecular pharmacodynamic data will be presented.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A111.
Abstract A123: MGMT and MMR testing: NSCLC susceptibility to temozolomide
Authors: Emery Ivette F. , Battelli Chiara , Cai Li , Hayes Daniel
Published: June 2012

Background: The functional status of DNA repair systems impacts the sensitivity of tumors to chemotherapeutics. The anti-neoplastic activity of alkylating agents, such as temozolomide, is affected by the direct repair enzyme, O6-Methylguanine-DNA methyltransferase (MGMT), and by the mismatch repair system (MMR). Lack of MGMT makes a tumor susceptible to temozolomide, while a non-functional MMR renders the tumor resistant to this agent. We assayed these repair systems in a group of patients affected by Non-small cell lung cancer (NSCLC) in order to investigate the potential benefit of temozolomide to these patients, a group with one of the highest mortality rate and for which alkylating agents are not currently used.

Method: The status of MGMT and MMR were determined by MGMT promoter hypermethylation and by Microsatellite Instability (MSI) testing on 96 paraffin-embedded NSCLC samples. MGMT hypermethylation results in gene silencing and low levels of the protein. This test was conducted at OncoMethylome by methylation-specific PCR of the gene's promoter sequences. MSI testing was conducted at LabCorp by multiplex PCR of six microsatellite regions. Samples with a normal MMR system show genomic stability in the microsatellite regions, while samples with an impaired MMR system show instability in one or more of these regions.

Results: Ninety three (93) samples yielded interpretable results. Most of them (80) had no detected defects in the two repair mechanisms assessed. Nine (9) samples (10%) had hypermethylation of the MGMT promoter and four (4) samples (4%) had microsatellite instability. The defects were not overlapping. These results indicate that NSCLC has a low rate of MGMT silencing by promoter hypermethylation and also a very low rate of mutations in the MMR proteins Conclusions: MGMT silencing by promoter hypermethylation sensitizes cells to apoptosis by temozolomide, but only in the presence of a functional MMR system. If MMR is disabled, apoptosis is not triggered. Our results indicate that although NSCLC is not particularly susceptible to alkylating agents, there are no indications that it has active mechanisms of resistance to them. Our understanding of the molecular characteristics of NSCLC suggests that alkylating agents such as temozolomide, in combination with inhibitors that artificially lower the expression of MGMT, may be viable option to treat NSCLC.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A123.
Abstract A131: Tissue distribution and tumor uptake of novel folate receptor targeted epothilone, BMS-745493 in CD2F1 mice after systemic administration
Authors: Gan Jinping , Wang Lifei , Shen Hong , Jian Wenying , Menard Krista , Hong Yang , Yuan Tian , Zhang Duxi , Bonacorsi Samuel , Lee Francis
Published: June 2012

BMS-753493 is an epothilone folate conjugate targeting folate receptor over-expressing tumor cells. The tissue distribution of radioactivity in tumor bearing mice was studied using quantitative whole body autoradiography (QWBA) after a single intravenous administration of [3H]BMS-753493 or its active epothilone moiety, [3H]BMS-748285, to female CD2F1 mice bearing bilateral tumors: murine lung tumor M109, and its folate receptor expressing variant 98M109.

[3H]BMS-753493 derived radioactivity was extensively distributed to tissues. Organs that had the highest radioactivity were gastrointestinal tract and contents, liver, kidney, heart, bone marrow and tumors. In contrast, very little radioactivity was observed in the brain and spinal cord. Folate receptor over-expressing tumor 98M109 had higher radioactivity levels than M109 tumors at all time points, and 98M109 tumor had higher radioactivity than all normal tissues at 24 and 48 h post dose. Similar to [3H]BMS-753493 distribution, [3H]BMS-748285 derived radioactivity was extensively distributed to tissues after IV administration of [3H]BMS-748285. However, no difference in radioactivity was observed between the 98M109 tumor and all normal tissues at 24 and 48 h post dose, although slightly higher radioactivity was observed in 98M109 tumor as compared to M109 tumor. The preferential distribution of BMS-753493-related material to folate receptor expressing tumor 98M109 was further demonstrated in a study with unlabeled materials followed by LC/MS/MS measurement. After administration of BMS-753493, levels of BMS-748285 were much higher in 98M109 tumors than in M109 tumors, while no difference was observed between those two tumors after administration of BMS-748285. Similarly, much lower levels of BMS-748285 were observed in the heart and kidney tissues after administration of BMS-753493 as compared to those observed after dosing of BMS-748285. The relatively lower levels of active epothilone in normal tissues after BMS-753493 dosing suggest a potential wider therapeutic window for BMS-753493.

In summary, this study has clearly demonstrated that the epothilone folate conjugate, BMS-753493, enabled the preferentially distribution of the active epothilone to the folate receptor over-expressing 98M109 tumor. This preferential distribution supports targeted delivery of cytotoxics through the folate receptor and correlates well with in vivo antitumor activity observed in mouse xenograft models over-expressing folate receptors.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A131.
Abstract A15: A phase I and pharmacokinetic study of the vascular disrupting agent AVE8062 in combination with docetaxel, administered once every 3 weeks to patients with advanced solid tumors
Authors: Tresca Patricia , Tosi Diego , Van Doorn Leni , Fontaine Helene , Van der Gaast Ate , Veyrat-Follet Christine , Oprea Corina , Dieras Veronique , Eskens Ferry Alm
Published: June 2012

Background: AVE8062 is a Vascular Disrupting Agent, derivative of Combretastatin A4, which targets endothelium and causes shutdown of blood perfusion. Preclinical synergy between AVE8062 followed by docetaxel prompted clinical exploration of this combination.

Methods: Objectives were to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and PK profile of intravenous AVE8062 on day 1 followed by D 75 mg/m2 on day 2 administered once every 3 weeks. Anti-tumor activity was assessed every 2 cycles.

Results: Twenty-nine adult pts with advanced solid tumors (M/F 11/18), median age 51 (range 28–71), were enrolled and treated at AVE8062 dose levels of 11.5 mg/m2 (N=3), 15.5 mg/m2 (N=5), 20 mg/m2 (N=3), 25 mg/m2 (N=6), 30 mg/m2 (N=3), 35 mg/m2 (N=3) and 42 mg/m2 (N=6). Median number of cycles per patient was 3 (range 1–14).

The most common tumor types were breast (n=10) and oesophagus (n=7).

At 25 mg/m2 AVE8062, neutropenic infection at cycle 1 defined DLT in one patient (pt), whereas at 42 mg/m2 AVE8062 grade 3 headache and asthenia in two pts defined DLTs. Additional grade 3 or 4 study drug related adverse events (AE) included sepsis, febrile neutropenia and respiratory failure in one pt at 20 mg/m2 AVE8062, and nail toxicity in 1 pt at 25 mg/m2. The most common grade 3 or 4 haematological toxicity was neutropenia (11/29 pts). No other grade 3 or 4 adverse events were experienced by more than 2 pts. Grade ¾ related AEs were: grade 3 anemia, grade 4 sepsis, grade 3 respiratory failure, grade 4 febrile neutropenia, grade 3 neutropenic infection, grade 3 nail toxicity, grade 3 oesophageal fistula, grade 3 headache and grade 3 fatigue.

The PK profile of AVE8062, its main metabolite RPR258063 and D were similar to those found in monotherapy studies.

The MTD for the combination AVE8062/D was set at 35/75 mg/m2. Ten additional patients will be enrolled at this dose level then new dose levels of AVE8062 with D 100 mg/m2 will be studied.

Among 23 evaluable pts, 3 had partial responses (breast cancer) and 13 had stable disease (mainly oesophageal cancer, head and neck, pancreatic adenocarcinoma, liver and unknown origin carcinoma).

Conclusion: AVE8062 in combination with D was well tolerated. The recommended dose for this combination is 35 mg/m2 AVE8062 day 1 and 75 mg/m2 D day 2, every 3 weeks.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A15.
Abstract A156: Mechanisms of resistance to Aurora kinase B inhibitors in leukemia: Development and characterization of in vitro models
Authors: Failes Timothy W. , Mitic Gorjana , Abdel-Halim Heba , Liu Marjorie , Bray Mark R. , Hibbs David E. , Kavallaris Maria
Published: June 2012

Aurora kinase inhibitors are generating great interest as new mitosis targeting drugs in cancer chemotherapy. Whilst these new agents are progressing through clinical trials against both solid and haematological malignancies, knowledge of the molecular factors that influence sensitivity and resistance remains limited. Development of optimal treatment modalities and the design of next generation Aurora inhibitors requires an understanding of processes and pathways of drug sensitivity mechanisms. In this study we report the development and characterisation of an in vitro derived leukaemia model of resistance to the Aurora B inhibitor ZM447439. CCRF-CEM cells were selected for resistance in 4uM ZM447439 and designated CEM/AKB4 cells. Cytotoxicity assays showed that CEM/AKB4 cells were 13.2 fold resistant to ZM44739 compared to parental CEM cells. Resistance was not associated with the multi-drug resistance phenotype and CEM/AKB4 cells showed no cross-resistance to a number of tubulin-targeting mitotic poisons or DNA-damaging agents. The CEM/AKB4 cells remained sensitive to the Aurora kinase A inhibitor, ENMD-2076. Cell cycle analysis revealed that exposure of CEM cells to ZM447439 (0.4–4 uM) caused extensive cell cycle disruption and cell death. In contrast, the cell cycle profiles of CEM/AKB4 cells at the same concentrations of drug were barely altered. Full length sequencing of the Aurora B gene revealed a single point mutation in the kinase domain corresponding to a G160E amino acid substitution. Molecular modelling of drug binding in Aurora B containing this mutation suggested that resistance is mediated by the glutamate substitution preventing formation of an active binding motif for Aurora B inhibitors. Moreover molecular docking of an Aurora B inhibitor with a novel binding motif was unchanged in the mutant enzyme suggesting this drug may abrogate resistance. Aurora kinase B inhibitor resistant cells are a valuable tool for identifying resistance mechanisms and the design of new kinase inhibitors active against Aurora kinase B mutations.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A156.
Abstract A159: The Redox/ Fyn/c-Cbl pathway and its interaction with Cool-1: A novel pathway that regulates chemosensitivity in glioblastoma
Authors: Stevens Brett , Folts Christopher , Cui Wanchung , Noble Mark
Published: June 2012

GBMs are the most common primary brain tumor, accounting for 52 percent of all diagnosed brain tumors. It is also the most devastating of all brain tumors, with a five-year survival rate of 3.3 percent. One of the reasons for this poor prognosis is resistance of tumor cells to treatment with chemotherapy.

We have discovered a novel means by which GBMs become chemoresistant, based on inhibition of the redox/Fyn/c-Cbl pathway by overexpression of Cool-1. The protein c-Cbl, a receptor tyrosine kinase adaptor protein, is responsible for the ubiquitination and degradation of epidermal growth factor receptor (EGFR) and other receptor protein kinases critical in cell division and cell survival. c-Cbl is activated by Fyn kinase, which itself can be activated by agents that make cells more oxidized. In normal glia and glial progenitor cells of the CNS, exposure to chemotherapy makes cells more oxidized, leading to sequential activation of Fyn and c-Cbl. In GBMs, in contrast, exposure of GBM cells to BCNU or to chemical pro-oxidants does not lead to c-Cbl activation. Further studies demonstrated that these agents did cause Fyn activation, suggesting that GBMs inhibit Fyn-mediated c-Cbl activation. This would lead to decreased degradation of EGFR, thus enabling continued cell division and providing resistance to chemotherapy. We therefore set out to test the hypothesis that reversal of this inhibition would decrease cell division and enhance susceptibility to chemotherapy-induced cell death. In this work we discovered that oxidant-associated c-Cbl activation can be restored by suppressing expression of the protein Cool-1, which is over-expressed in many cancers including GBM. Our data further demonstrates that Cool-1 and Cbl interact, that genetic reduction in Cool-1 levels by expression of small inhibitory RNAs restores normal c-Cbl-mediated degradation of RTKs (including EGFR) in response to exposure to pro-oxidants and BCNU, and that restoration of normal c-Cbl activation also increases sensitivity to this and other chemotherapeutic agents.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A159.
Abstract A162: Inhibition of MEK sensitizes paclitaxel-induced apoptosis of human colorectal cancer cells by down-regulation of GRP78
Authors: Mhaidat Nizar M.
Published: June 2012

Here we report that paclitaxel induces variable degrees of apoptosis of human colorectal cancer cells. Paclitaxel induces multiple arms of the endoplasmic reticulum (ER) stress response, including up-regulation of 78-kDa glucose-regulatory protein (GRP78) and eukaryotic initiation factor α (eIF2) phosphorylation. Inhibition of MEK/ERK pathway sensitized colorectal cancer cells to paclitaxel-induced apoptosis. Similar result was obtained by inhibition of GRP78 using small interfering RNA molecules. Knockdown of MEK resulted in a significant down-regulation of paclitaxel-induced up-regulation of GRP78 indicating that activation of GRP78 is a downstream event of MEK/ERK pathway activation. These results indicate that GRP78 might be a novel mechanism underlying resistance of colorectal cancer cells to microtubule-targeting drugs. Combination of compounds capable of suppressing GRP78 might be a golden approach for improving the effectiveness of taxanes.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A162.
Abstract A177: Cetuximab resistance associated with dimerization-independence of oncogenic EGFR mutants
Authors: Cho Jeonghee , Chen Liang , Sangji Naveen , Du Jinyan , Okabe Takafumi , Yonesaka Kimio , Francis Joshua M. , Flavin Richard J. , Yu Soyoung , Greulich Heidi E. , Johnson Bruce E. , Eck Michael J. , Jänne Pasi A. , Wong Kwok-Kin , Meyerson Matthew
Published: June 2012

Asymmetric dimerization of the kinase domain is a key mechanism for activation of the epidermal growth factor receptor (EGFR). Here, we show that whereas wild-type EGFR and the L858R mutant require dimerization for activation and oncogenic transformation, the exon 19 deletion, exon 20 insertion, and L858R/T790M EGFR mutants do not require dimerization. Consistent with these findings, tyrosine phosphorylation of the carboxyl-terminus is not required for mutant EGFR-mediated cellular transformation. These differences in dimerization requirements may have clinical implications: treatment with the monoclonal antibody, cetuximab, shrinks mouse lung tumors induced by the dimerization-dependent L858R mutant, but exerts only a modest effect on tumors driven by dimerization-independent EGFR mutants. These data imply that disruption of dimerization is among the antitumor mechanisms of cetuximab. We therefore hypothesize that EGFR mutation status in lung cancers may serve as a marker for clinical response to cetuximab.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A177.
Abstract A18: The dual angiogenesis/heparanase inhibitor PG545, but not the tyrosine kinase inhibitor sorafenib, inhibits spontaneous metastasis in models of breast and lung cancer
Authors: Bytheway Ian , Hammond Edward , Handley Paul , Dredge Keith
Published: June 2012

PG545 is a fully synthetic heparan sulfate (HS) mimetic selected as the lead oncology candidate for formal preclinical development. PG545 inhibits key processes in tumor progression (a) neovascularization - by interfering with growth factor binding and (b) metastasis - presumably by inhibition of heparanase activity. PG545 was assessed for anti-angiogenic activity in vivo and for antitumor and anti-metastatic activity in the T41 breast cancer and the Lewis Lung Carcinoma (LL/2) models using the tyrosine kinase inhibitor sorafenib as an anti-angiogenic reference compound. Both PG545 (daily or twice weekly) and sorafenib (daily) significantly reduced CD31 staining in the AngioSponge™ model. Twice weekly treatment with 25 mg/kg PG545, but not daily treatment with 60mg/kg sorafenib, significantly inhibited solid tumor growth in the T41 model. Moreover, PG545 significantly inhibited spontaneous lung metastases in a dose-dependent manner, whereas sorafenib significantly increased the number of metastases. In the LL/2 model, once weekly treatment with PG545 at 20 mg/kg significantly reduced solid tumor growth to a similar extent as sorafenib while the 40mg/kg dose appeared more efficacious than sorafenib. A significant reduction in spontaneous lung metastases was again associated with PG545 following either a single injection or once weekly treatment while sorafenib had no appreciable effect on metastases. PG545 was well tolerated with no significant loss in bodyweight noted. Taken together, the data demonstrate that PG545 is an effective angiogenesis inhibitor with anti-metastatic activity - an envious property for an anti-cancer compound, allaying recently publicized concerns that angiogenesis inhibitors and even chemotherapeutic agents may have the potential to aggravate metastatic development.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A18.
Abstract A203: Heterogeneous nuclear ribonucleoprotein K (hnRNP K) binds to the vascular endothelial growth factor (VEGF) promoter and plays a role in its transcriptional control
Authors: Uribe Diana J. , Guo Kexiao , Shin Yoon-Joo , Hurley Laurence , Sun Daekyu
Published: June 2012

The vascular endothelial growth factor (VEGF) promoter is capable of forming secondary DNA structures, called G-quadruplex and i-motif, in its proximal promoter region (−85 to −50 from the transcription initiation site) that can mask transcription factor binding sites thereby inhibiting transcription. To understand this dynamic region and its implications in transcriptional control we studied protein-DNA interactions of this structurally versatile region, specifically those involving transcription factors. Our candidate transcription factor, heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a single-stranded DNA binding protein able to binding to cytosine-rich sequences such as the VEGF polypurine/polypyrimidine tract. We found that the cytosine-rich 24-bp oligomer has the potential of forming an i-motif at pH 6.5 and formed a complex with hnRNP K as shown by CD spectra analysis and electrophoretic mobility shift assay (EMSA), respectively. The binding of hnRNP K to the VEGF promoter was confirmed through chromatin immunoprecipitation (ChIP) assay, and its effect on transcriptional control was demonstrated through RT/PCR of hnRNP K siRNA KO and overexpression assays. We also observed through EMSA/Footprint that the hnRNP K protein changes the oligo conformation from an i-motif structure to a more unstructured linear conformation. In summary, this work is the first to show that hnRNP K serves a role in the transcriptional control of VEGF and that a bromine solution left to react to the protein-complex can be used to footprint its binding motif.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A203.
Abstract A205: Chk2 status (activation, proteomic, gene, and exon expression) and insights into the activity of its inhibitor PV1019 across the 60 cell lines from the NCI Screen
Authors: Zoppoli Gabriele M. , Connelly John W. , Reinhold William C. , Jobson Andrew G. , Solier Stephanie , Monks Anne , Shoemaker Robert H. , Pommier Yves
Published: June 2012

Chk2 is a multi-substrate kinase involved in the DNA damage response and genomic stability. Part of the ATM-Chk2-p53 axis, it is also activated in various malignant tumors, possibly in a “gene addiction” context. Chk2 inhibitors are in development as anticancer agents based on their selectivity for enhancing the activity of DNA targeting agents in p53-deficient tumors. Here we determined the activation of Chk2, its protein and gene expression levels, and the activity of PV1019 (a new and specific Chk2 inhibitor; see abstract by Jobson et al.) across the 60 lines of the NCI DTP screen. Chk2 expression data were obtained from five microarray platforms (Affymetrix HG-U95, U133, U133 Plus 2.0, HuEx 1.0, and Agilent WHG). Levels of total and activated Chk2 (i.e., phosphorylated on threonine 68) were analyzed by Western blotting. PV1019 was tested in duplicate, and GI50 was interpolated from five serial dilutions of the drug. Our analyses demonstrate that a number of cell lines have high endogenous Chk2 activation (ovarian OVCAR-3 and OVCAR-4, renal RFX-393, lung NCI-H322M and EKVX, melanoma UACC-62 and -257, leukemia RPMI-8226 and breast BT-549) whereas the wild-type p53 tumors all showed low Chk2 activation. Expression of total Chk2 protein and mRNA were generally positively correlated to each other and to the activity of PV1019. Exon array analyses across the NCI-60 suggest exon 3 splicing in approximately half of the cell lines and transcript interruption between exons 8 and 10 in the ovarian SKOV-3 cells, which could be related to the low level of Chk2 expression in this cell line. Together, these data demonstrate a complex phenotype, which underlies the susceptibility of tumor cell lines to Chk2 inhibitors. Such phenotype may relate to potential patient selection for the optimal use of Chk2 inhibitors as single agents or modulators of DNA targeting therapies.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A205.