Derrick Beech

Leptin-Notch signaling axis is involved in pancreatic cancer progression.

Pancreatic cancer (PC) shows a high death rate. PC incidence and prognosis are affected by obesity, a pandemic characterized by high levels of leptin. Notch is upregulated by leptin in breast cancer. Thus, leptin and Notch crosstalk could influence PC progression. Here we investigated in PC cell lines (BxPC-3, MiaPaCa-2, Panc-1, AsPC-1), derived tumorspheres and xenografts whether a functional leptin-Notch axis affects PC progression and expansion of pancreatic cancer stem cells (PCSC). PC cells and tumorspheres were treated with leptin and inhibitors of Notch (gamma-secretase inhibitor, DAPT) and leptin (iron oxide nanoparticle-leptin peptide receptor antagonist 2, IONP-LPrA2). Leptin treatment increased cell cycle progression and proliferation, and the expression of Notch receptors, ligands and targeted molecules (Notch1-4, DLL4, JAG1, Survivin and Hey2), PCSC markers (CD24/CD44/ESA, ALDH, CD133, Oct-4), ABCB1 protein, as well as tumorsphere formation. Leptin-induced effects on PC and tumorspheres were decreased by IONP-LPrA2 and DAPT. PC cells secreted leptin and expressed the leptin receptor, OB-R, which indicates a leptin autocrine/paracrine signaling loop could also affect tumor progression. IONP-LPrA2 treatment delayed the onset of MiaPaCa-2 xenografts, and decreased tumor growth and the expression of proliferation and PCSC markers. Present data suggest that leptin-Notch axis is involved in PC. PC has no targeted therapy and is mainly treated with chemotherapy, whose efficiency could be decreased by leptin and Notch activities. Thus, the leptin-Notch axis could be a novel therapeutic target, particularly for obese PC patients.

CCR6 expression in colon cancer is associated with advanced disease and supports epithelial-to-mesenchymal transition

Background:Adjuvant chemotherapy offered to treat colon cancer is based on the TNM staging system, which often fails due to molecular heterogeneity and undefined molecular mechanisms independent of TNM. Therefore, identification of markers to better predict therapeutic option and outcome is needed. In this study we have characterised the clinical association of CCR6 with colon cancer and defined CCR6-mediated molecular pathway.Methods:Immunohistochemistry, RT-qPCR, western blot and FACS were used to determine expression of CCR6 and/or EMT markers in colon tissues/cells. BrdU assay and trans-well system were used to determine cell proliferation, migration and invasion in response to CCL20.Results:CCR6 was higher in cancer cases compared to normal adjacent tissue and expression was associated with nodal status and distant metastasis. Similarly, CCR6 expression was higher in cells derived from node-positive cases and highest expression was in cells derived from metastatic cases. Significant changes in EMT markers, that is, E-cadherin, vimentin, β-catenin, N-cadherin, α-SMA, SNAILl and ZEB1 were observed in response to CCL20 along with decreased proliferation, increased migratory and invasive potential.Conclusions:Results suggest CCR6 as a potential therapeutic target as well as biomarker in addition to nodal status for predicting therapeutic option.

Implementing the Prospective Surveillance Model (PSM) of Rehabilitation for Breast Cancer Patients with 1-Year Postoperative Follow-up, a Prospective, Observational Study.

BackgroundThe Prospective Surveillance Model (PSM) of rehabilitation for patients with breast cancer aims for early identification, treatment, and support of physical impairments postoperatively. The purpose of this study was to describe the incidence of impairments during the first postoperative year and the differences between the patients requiring rehabilitation intervention versus those not requiring intervention.MethodsA total of 120 patients were enrolled. Impairment measures included: pain, range of motion, and self-reported measures of function using the Upper Extremity Functional Index (UEFI) and Quick Disability of the Arm, Shoulder and Hand (QuickDASH) questionnaires. These measures were performed at designated intervals during the first postoperative year. All patients received exercise and education, and patients with identified impairments underwent individualized rehabilitation intervention. Clinical factors associated with need for intervention were determined using univariate analysis.ResultsThirty-six patients required rehabilitation intervention. There were no statistically significant differences between intervention and no-intervention groups for body mass index, breast surgery type, reconstruction type, or radiotherapy. Statistically significant differences were found between intervention and no-intervention groups in early postoperative UEFI, QuickDASH, pain scores, age, number of lymph nodes removed [9.3 (intervention) vs. 5.6 (no-intervention)], axillary surgery type, chemotherapy, and breast cancer stage.ConclusionsSurvivorship practitioners should have heightened awareness for rehabilitation intervention in patients with greater axillary surgery and burden of disease. Patients with more activity restriction and lower levels of function in the early postoperative period may benefit from rehabilitation intervention. Future studies should focus on implementing a screening tool to identify patients in need of rehabilitation referral.

Abstract B26: Leptin affects proliferation, stem cells and chemotherapeutic treatment outcome of pancreatic cancer: A link to health disparity

Background: Pancreatic cancer (PC) is an aggressive disease that is in most cases advanced at the time of diagnosis. The overall 5-year survival rate for PC patients is less than 5 %. African-Americans show the highest incidence of obesity and PC as well as mortality rate. How obesity is associated to PC incidence and health disparity is still an unanswered question. High levels of leptin shown by obese African American patients could impact negatively on PC. We hypothesize that leptin signaling induces PC proliferation, stem cells (PCSC) and drug resistance. Methods: Human PC cell lines derived from primary pancreatic adenocarcinoma (Panc-1 and MiaPaCa-2-highly aggressive, BxPC-3-less aggressive) and from metastatic tumor (AsPC-1) were challenged with leptin and chemotherapeutic agents. Cell proliferation, apoptosis rate, and the expression levels of molecular markers were analyzed. PCSC markers were determined in cell lines and tumor biopsies. Effects of leptin and chemotherapeutics on PC-tumorsphere formation were also determined. Results: Leptin stimulated proliferation of PC cells, induced the expression of PCSC markers and increased tumorsphere formation. Moreover, leptin impaired the efficacy of chemotherapeutics on PC cells. Conclusions: Present data suggest leptin is a proliferative and survival factor for PC that reduces chemotherapeutic effectiveness. These observations are of paramount importance for obese African American PC patients, who show the highest levels of leptin, poor prognosis and outcome of chemotherapeutic treatment. Acknowledgements: this work was supported by the DOD W81XWH-13-1-0382; NIH/SBIR 1R41CA183399-01A1; Pilot Project Award from MSM/Tuskegee University/UAB Cancer Center Partnership grant 5U54CA118638; PC SPORE Grant from UAB to RRGP, and facilities and support services at Morehouse School of Medicine (1G12RR026250-03; NIH RR03034 and 1C06 RR18386). Citation Format: Adriana Harbuzariu, Danielle S. Daley-Brown, Tia L. Harmon, Robin C. Garrison, Derrick J. Beech, Frederick D. Cason, Christopher Klug, Ruben R. Gonzalez-Perez. Leptin affects proliferation, stem cells and chemotherapeutic treatment outcome of pancreatic cancer: A link to health disparity. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B26.

Molecular Mechanism Linking BRCA1 Dysfunction to High Grade Serous Epithelial Ovarian Cancers with Peritoneal Permeability and Ascites

Ovarian cancer constitutes the second most common gynecological cancer with a five-year survival rate of 40%. Among the various histotypes associated with hereditary ovarian cancer, high-grade serous epithelial ovarian carcinoma (HGSEOC) is the most predominant and women with inherited mutations in BRCA1 have a lifetime risk of 40-60%. HGSEOC is a challenge for clinical oncologists, due to late presentation of patient, diagnosis and high rate of relapse. Ovarian tumors have a wide range of clinical presentations including development of ascites as a result of deregulated endothelial function thereby causing increased vascular permeability of peritoneal vessels. The molecular mechanisms remain elusive. Studies have shown that fallopian tube cancers develop in women with BRCA1 gene mutations more often than previously suspected. Recent studies suggest that many primary peritoneal cancers and some high-grade serous epithelial ovarian carcinomas actually start in the fallopian tubes. In this article we have addressed the molecular pathway of a recently identified potential biomarker Ubc9 whose deregulated expression due to BRCA1 dysfunction can result in HGSEOC with peritoneal permeability and formation of ascites. We also discuss the role of downstream targets Caveolin-1 and Vascular Endothelial Growth Factor (VEGF) in the pathogenesis of ascites in ovarian carcinomas. Finally we hypothesize a signaling axis between Ubc9 over expression, loss of Caveolin-1 and induction of VEGF in BRCA1 mutant HGSEOC cells. We suggest that Ubc9-mediated stimulation of VEGF as a novel mechanism underlying ovarian cancer aggressiveness and ascites formation. Agents that target Ubc9 and VEGF signaling may represent a novel therapeutic strategy to impede peritoneal growth and spread of HGSEOC.

Hospital-based, Multidisciplinary, youth mentoring and medical exposure program positively influences and reinforces health care career choice: “The Reach One Each One Program early Experience”

BACKGROUND According to the National Center for Educational Statistics, underrepresented minorities (URMs) are more likely to leave science, technology, engineering and mathematics (STEM) fields at higher rates than their peers during undergraduate studies. Many institutions of higher learning have implemented pipeline programs aimed at preparing and inspiring high school and college aged students in select careers in health sciences with varying levels of success. Research has shown that a health care workforce that mirrors the community they serve is more effective in reducing health disparities and increasing positive health outcomes. We hypothesize that a hospital-based, multidisciplinary youth mentoring and medical exposure program will enhance the decision of URM high school students to choose healthcare careers. MATERIALS AND METHOD A retrospective analysis of the Reach One Each One Program (ROEO) was performed. ROEO is a hospital based, 11-week multidisciplinary youth mentoring and medical exposure program for inner-city high school students. The analysis was based on a phone survey of the twenty-six (26) seniors who completed the program and subsequently graduated from high school between May 2013 and May 2015 to assess the following: 1) College enrollment/attendance, 2) Health profession majors, and 3) Pre-med status. The study was approved by the Morehouse School of Medicine Institutional Review Board. RESULTS Of the twenty-six students, 23 were female and 3 were male; 25 (96%) of the students were African American and one student was a Caucasian female. Twenty-four (92.3%) of the students were enrolled in college and 2 (7.7%) were scheduled to begin in the spring semester of 2016. Twenty-one of the 24 attending college at the time of the survey (87.5%) were enrolled in a health science degree program and 16 (66.7%) confirmed that they were enrolled in pre-medical (Pre-med) curriculum. CONCLUSION Hospital-based, multidisciplinary medical mentoring programs can have a positive impact on the lives and health care career decisions of aspiring URM high school students. Further study will be necessary to validate the most influential components needed for the success of such programs.

Building Diversity Initiatives in Academic Medicine

The changing landscape in the healthcare environment has presented unique challenges for Academic Medical Centers (AMCs) to transition to “value-based” health services. Shifting demographics with increased ethnic, religious, and gender diversity have made the need for enhancing programs focused on diversity essential in academic medicine. Identifying and replicating effective programs of this nature will be of vital importance as we move into the next generation of healthcare delivery. The value proposition of enhanced diversity in healthcare and academic medicine has been outlined in previous chapters. This overview will focus on initiatives that promote diversity within and associated with AMCs and their ultimate objective of addressing the needs of the present day community. In this chapter, we will explore the importance of diversity in modern healthcare, review the innovative role of pipeline programs in helping to create a diverse healthcare workforce, and discuss the vital impact diversity mentoring in AMCs can have on the development of future healthcare trainees and practitioners.

Abstract 1701: CCR6 associates with colon cancer metastasis

Despite established benefits of screening, colon cancer remains a leading cause of cancer death in the U.S. Majority of colon cancer deaths result from metastasis. Effective treatments are not available for advanced disease because molecular mechanisms of initiation and progression of this disease are yet to be defined. Chemokine-chemokine receptor interaction plays an important role in cancer progression. In this study, using colon cancer tissue microarray, we have shown that expression of CCR6 was significantly higher in advanced colon cancer (p Citation Format: Neeraj Kapur, Hina Mir, Clarence E. Clark, Uma Krishnamurti, Derrick J. Beech, James W. Lillard, Shailesh Singh. CCR6 associates with colon cancer metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1701.

Abstract 1901: Leptin modulation of PCSC, HDAC, and microRNA in pancreatic adenocarcinoma

Background: Obesity is an important risk factor of Pancreatic Adenocarcinoma (PA) and it is characterized by the accumulation of excessive body fat and a Body Mass Index (BMI) value greater than 30. Obesity is also characterized by high levels of leptin, which has been consistently associated with the development of many different cancer including PA. Leptin can induce the proliferation of Pancreatic Cancer Stem Cells (PCSC), which are responsible for chemoresistance, invasiveness and reoccurrence of PA. PCSC express specific cell markers and can form tumorspheres in vitro. Obesity can alter the DNA acetylation and microRNA activity which are also linked to PA progression. We hypothesized that high level of leptin could modulate Histone Deacetylase (HDAC) and microRNA activity in PA cells, which induce PCSC changes and tumor progression. Methods: The PA cell lines were cultured in mammocult media that contained heparin and hydrocortisone, which will allow the proliferation of tumorspheres enriched with PCSCs. The cells were cultured with leptin, chemotherapeutic drug, and leptin signaling inhibitor IONP-LPrA2. Tumorspheres formation (number and size) was determined after 1 week of treatment. Additionally, the levels of PCSC markers, HDAC1, HDAC2, HDAC3, and HDAC8 in tumorspheres were determined using flow cytometry, western blot, and RT-PCR. In addition, the effects of treatments on miR21 and miR200a/c levels were determined using RT-PCR. Results: Leptin induced PA tumorspheres formation and size, which was accompanied by higher level of PCSC markers (CD24, CD44, ESA, and ALDH1). Moreover, leptin affected the level of HDACs, miR21 and miR200a/c in PA tumorspheres. IONP-LPrA2 abrogated leptin effects and decreased PCSC which were spared by chemotherapeutics. Conclusion: Obesity signals via leptin could be involved in the increase PA aggressiveness and chemoresistance, which may be linked to the increase of PCSC. Leptin could induce PA progression and chemoresistance via modulation of HDAC and miRNA. Acknowledgement: This work was supported by the DOD W81XWH-13-1-0382; NIH/SBIR1R41CA183399-01A1; Pilot Project Award from MSM/Tuskegee University/UAB Cancer Center Partnership grant 5U54CA118638; PC SPORE Grant from UAB to RRGP; Calvin Johnson Jr. Foundation Pancreatic Cancer Research Scholarship to CITM, and facility and support services at Morehouse School of Medicine (1G12RR026250-03; NIH RR03034 and 1C06 RR18386). Citation Format: Cynthia M. Tchio, Adriana Harbuzariu, Tia Harmon, Derrick Beech, Ruben Gonzalez-Perez. Leptin modulation of PCSC, HDAC, and microRNA in pancreatic adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1901.

Abstract 1034: Leptin induces early onset and aggressiveness of pancreatic cancer

Background: During the past 30 years, pancreatic cancer (PC) has constantly been the fourth leading cause of cancer death. PC is usually advanced at the time of diagnosis, with an overall five years survival rate of less than 5%. Obesity, characterized by high levels of leptin, is pandemic in United States and a risk factor for PC. Notch abnormal signaling is linked to carcinogenesis, tumor angiogenesis and self renewal capacity of PC stem cells (PCSC). We have previously shown that leptin induces proliferation of PC cell lines, increases Notch expression, PCSC and tumorsphere formation. To test leptin effects in a PC mouse model, a specific and potent signaling inhibitor bound to nanoparticles, IONP-LPrA2 was produced by us. Hypothesis: High levels of leptin induce early onset and multiplicity of PC xenografts, which is abrogated by IONP-LPrA2 treatment. Methods: Human PC cell line MiaPaCa-2 was challenged with leptin or IONP-LPrA2. The expression of pluripotency associated genes (STAT3, Oct4, Sox2 and NANOG) was evaluated. MiaPaCa-2 cells forming tumorspheres were treated with leptin or IONP-LPrA2 and inoculated into CD1 nu/nu mice. Untreated tumorspheres were inoculated as controls. A group of mice were injected twice a week with IONP-LPrA2. Tumor onset and growth were assessed. PC xenografts were analyzed for expression of Ki67 (proliferation marker), leptin targeted molecules (Notch), PCSC markers etc. Results: Leptin induced the expression of PCSC pluripotency markers. Moreover, leptin treatment of tumorspheres induced early tumor onset and multiplicity. Also, leptin increased proliferation, PCSC and oncogenic markers in PC xenografts. IONP-LPrA2 reduced leptin effects. No changes of mice food intake and body weight were observed. Conclusions: This observation might imply that obese patients are at high risk to develop PC. Inhibition of leptin signaling may be used as preventative or therapeutic strategy for PC, especially in obese patients. Acknowledgements: this work was supported by DOD W81XWH-13-1-0382; NIH/SBIR 1R41CA183399-01A1; Pilot Project Award from MSM/Tuskegee University/UAB Cancer Center partnership grant 5U54CA118638; PC SPORE Grant from UAB to RRGP, and facilities and support services at Morehouse School of Medicine (1G12RR026250-03; NIH RR 03034 and 1C06 RR18386). Citation Format: Adriana Harbuzariu, Antonio Rampoldi, Danielle S. Daley-Brown, Tia L. Harmon, Derrick J. Beech, Gabriela Oprea-Ilies, Ruben R. Gonzalez-Perez. Leptin induces early onset and aggressiveness of pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1034.