Z01 BC 011136 (Z01) | |||
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Title | The CCR/Walter Reed Army Medical Center (WRAMC) Gynecologic Cancer Program Resear | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Kohn, Elise | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $55,714 | Project Dates | 10/01/2007 - N/A |
Fiscal Year | 2008 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) |
Cervical Cancer (20.0%) Ovarian Cancer (20.0%) Uterine (20.0%) |
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Research Type | |||
Resources and Infrastructure Related to Etiology Technology and/or Marker Testing in a Clinical Setting |
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Abstract | |||
1. Stage I Endometrial Cancer (EC): Over the past year, we have developed standard operating procedures for analyzing small tissue specimens using laser capture microscopy (LCM) techniques for both gene expression analysis using oligonucleotide array in the CRC/WRAMC GCPRL as well as liquid chromatography (nanoRPLC) and mass spectrometry (linear ion trap-Orbitrap) methods of proteomics analysis with our collaborator, Dr Conrads at the UPitt Cancer Institute (UPCI). Innovative bioinformatic methods of integrated analysis of gene and protein expression data have been developed that enable us to identify differentially expressed transcripts as well as the corresponding differentially expressed proteins. We identified 132 molecules differentially expressed in 92 stage I ECs and 12 postmenopausal endometria using genomic and proteomic methods. Multiple molecules associated with inflammation and oxidative processes were found to be differentially expressed and provide the basis for an investigation of previously unrecognized novel pathways involved in early stage EC and identifying targets for prevention strategies for endometrioid and serous histologic subtypes. Our group has recently developed collaborations with Dr Annunziata MOB/CCR to investigate NF-kB pathway alterations in endometrial cancer. 2. Racial Disparities in Endometrial Cancer: Our group has focused on investigation of racial disparities in outcome among African American (AA) patients with EC. Our analysis of Gynecologic Oncology Group (GOG) Phase III EC clinical trials over the past decade demonstrated worse outcome for AA with EC compared to Caucasians even when treated in a clinical trial environment where all patients receive similar care irrespective of their racial status. We acknowledge that the racial disparities in outcome for AA patient with EC is multi-factorial (inequalities to access to care, differences in care rendered, social and cultural barriers to care, etc), and our clinical data has prompted hypothesis that there may be underlying biologic origins for the differences in outcome. We have demonstrated an increased frequency of PTEN (typically associated with favorable prognosis cancer) and lower frequency of p53 (poor prognostic factor) mutations among tumors from Caucasians versus AAs suggesting these alterations may in part explain the differences in clinical outcome. We subsequently compared tumor pairs from AAs and Caucasians (matched for stage, grade and histology) from Duke Univ using oligonucleotide array and found statistically significant global gene expression profiles associated with ECs from minority patients. Over the past year, we have further validated our hypothesis that biological etiologies contribute to this outcome racial disparity. In collaboration with investigators at Ohio State Univ, the UPCI, Roswell Park Cancer Center and the GOG, we have correlated our genomic data with proteomics, methylation specific array and genomic hybridization array data to further identify unique molecular alterations associated with EC from AA compared to Caucasians. These analyses have been complemented by additional clinical studies performed in collaboration with the GOG. In two meta-analyses (n>1100 advanced stage EC and n>1400 advanced stage ovarian cancer pts), we have confirmed AA have significantly more gastrointestinal toxicity despit similar chemotherapy dose intensity. In addition, AA with advanced stage endometrial cancer are less chemosensitive than Caucasians despite receiving similar regimens of therapy. In a separate analysis of 1800 stage I EC patients (GOG137, double blinded randomized controlled trial of Estrogen Replacement Therapy [ERT] or placebo in EC), we found higher recurrence rates in AA compared to Caucasians taking ERT. The rates of recurrence were similar in the two groups that received placebo. The data from these 3 clinical studies suggest a biologic etiology for outcome differences observed among AAs with EC and have prompted further validation of selected differentially expressed molecules identified in our discovery analyses. We are currently collaborating with the GOG in the creation of a tissue microarray (TMA) containing 200 ECs from AA and Caucasians, matched by stage and histology. This resource will enable us to further confirm differentially expressed molecules that can then be assessed for oncologic relevance. Our group will comprehensively investigate the associations between 128 African specific mtDNA polymorphisms/haplogroups and clinical and pathological characteristics of EC within and between Caucasian and AA women to help elucidate the similarities and differences in the genetic etiology of EC. This will in turn provide us with a method of objectively defining AA status (based on one of three known mtDNA haplotypes) instead of using self described racial status for future experiments using high throughput techniques. 3. Obesity and EC: The relationship between obesity and EC is more significant than for any other cancer type. Obese women have a 3-5 fold increased risk of developing EC and up to a 6 fold increased risk of cancer related mortality. Our data have recently shown an apparent significant global gene expression profiles differing between ECs from lean patients versus obese women. Several of these molecules are associated with inflammatory processes suggesting that anovulation may promote an inflammatory microenvironment conducive to carcinogenesis. A validation study is currently underway aimed at evaluating these preliminary findings in a larger sample set provided by colleagues at Duke Univ. Dr. Linkov at UPCI has preliminary data demonstrating differences in serum inflammatory cytokines in lean versus obese patients with EC. Recent data have shown that bariatric surgery is associated with a decreased incidence of EC and we aim to identify what proteomic changes occur in association with the transition in EC risk (analysis at baseline and at yearly intervals in association with weight loss). We are currently submitting an application to the scientific review committee for the NIH sponsored Longitudinal Assessment of Bariatric Surgery (LABS) study. Other members of our consortia are planning to collaborate with one of the LAPS sites to collect endometrial biopsies before bariatric surgery and in follow-up as part of a prospective ancillary study. We will analyze those samples at the GCPRL and correlate these data with the proteomic serum analysis. Our collaborator Dr Conrad is analyzing 15 estrogen metabolites in a serum sample set that we obtained from the former M.D. Anderson Endometrial Cancer SPORE, evaluating differences in circulating estrogen among EC patients according to BMI. We plan to use these preliminary data to justify a definitive metabolomic analysis of estrogen in tumor/urine/serum/blood correlated with gene expression analysis in tumor through GOG 210. Previous work by our group in collaboration with the CDC has shown that higher higher progestin- potency OCs may be more protective than lower progestin potency OCs among women with a larger body habitus. We have further shown using macaque models in collaboration with Mark Cline at Wake Forest that these protective effects may be in part due to progestin mediated induction of apoptosis and TGF mediated pathways. Recent data from our group have also shown that a combination of vitamin D and progestin offer a greater protective effect than progestin alone in prevention of hyperplasia among PTEN +/- mice. |