bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B92: Metabolomic landscape of African American prostate cancer: Insights into the biologic basis of the racial disparity
Authors: Lloyd Stacy M. , Gohlke Jie H. , Basu Sumanta , Putluri Vasanta , Vareed Shaiju K , Martin Rebeca San , Rajendiran Thekkelnaycke , Dorsey Tiffany A. , Prasad Bandana , Sonavane Rajni , Rasaily Uttam , Henderson James , Karanam Balasubramanyam , Venghatakrishnan Harene , Bhowmik Salil , Zaslavsky Alexander , Guha Nilanjan , Kittles Rick , Ambs Stefan , Ittmann Michael , Rowley David , Palapattu Ganesh , Putluri Nagireddy , Michailidis George , Sreekumar Arun
Published: February 2019

African American (AA) men have an approximately 60% higher incidence of prostate cancer (PCa) and have about two times greater risk of dying of the disease than their European American (EA) counterparts. Despite this staggeringly unequal burden of PCa incidence and outcome between AA and EA men, there is limited insight into the molecular mechanisms associated with this racial disparity. Using state-of-the-art mass spectrometry platform, we uncovered the very first metabolic and lipidomics landscape in PCa/benign adjacent tissue pairs and paired plasma and urine containing epidemiologic meta-data from ancestry-typed AA and EA men. A total of 190 polar and mid-polar metabolites and 495 lipids were measured in tissues and 183 metabolites and lipids were examined in the plasma and urine samples. AA PCa tissue and plasma signatures had unique alterations in metabolites and key enzymes associated with the methionine-homocysteine pathway, including adenosine and inosine levels, compared to corresponding tissues and plasma from EA case controls and EA PCa tissues. Intriguingly, methionine levels in AA PCa were also portrayed by distinct dietary practices in these patients. In addition, AA PCa tissues demonstrated unique patterns of bioenergetic metabolites and accumulated lipids reflecting impaired mitochondrial activity and TCA cycle. Further characterization of these first-in-the-field findings demonstrating reprogrammed metabolism in AA PCa relative to EA tumors could reveal insights into the biologic basis of PCa disparities and novel areas for therapeutic intervention.

Citation Format: Stacy M. Lloyd*, Jie H. Gohlke*, Sumanta Basu*, Vasanta Putluri,Shaiju K Vareed, Rebeca San Martin, Thekkelnaycke Rajendiran, Tiffany A. Dorsey, Bandana Prasad, Rajni Sonavane, Uttam Rasaily, James Henderson, Balasubramanyam Karanam, Harene Venghatakrishnan, Salil Bhowmik, Alexander Zaslavsky,Nilanjan Guha, Rick Kittles, Stefan Ambs, Michael Ittmann,David Rowley, Ganesh Palapattu, Nagireddy Putluri,George Michailidis, Arun Sreekumar. Metabolomic landscape of African American prostate cancer: Insights into the biologic basis of the racial disparity [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B92.
Abstract C02: The real cost. Preventing smokeless tobacco usage among rural adolescents and teens.
Authors: Carothers Sharon
Published: February 2019

Smokeless tobacco use is woven into the culture of rural communities, particularly among white males aged 12 to 18. There are few, if any, sources in these areas providing a steady message about the dangers of smokeless tobacco use. Instead it is glorified and seen as a rite of passage for this particular demographic.

The FDA's Center for Tobacco Products engaged the cross-cultural agency, Sensis, to establish and, in 2016, launch the first nationwide campaign to prevent smokeless tobacco use. The campaign targeted those most vulnerable to initiation of use: rural, white male youth. Sensis utilized its experienced researchers and campaign strategists to conduct formative research that would shape campaign strategy, test creative concepts, and develop all aspects of the campaign creative.

The goals/objectives of The Real Cost Rural Smokeless Campaign set by Sensis were to:

Educate the target audience by increasing awareness and understanding of the dangers of smokeless tobacco use.

Create cognitive dissonance that prompts the audience to rethink their relationship with smokeless tobacco and decrease their intent to use.

Those who attend this presentation can expect to learn:

1. The extent of the formative research conducted to learn about the target audience and their views of the product.

2. The tactics used to help change behaviors that had been culturally ingrained for decades, often passed through the generations.

3. How Sensis was able to educate about the potential dangers without attacking a cultural norm woven into the rural lifestyle.

Citation Format: Sharon Carothers. The real cost. Preventing smokeless tobacco usage among rural adolescents and teens. [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr C02.
Abstract C19: [Advocate Abstract:] Patient advocate program
Authors: Stanford Sandi
Published: February 2019

The poster will be the history, education, qualifications, scholarships for the Patient Advocate Program. It will include how it was developed, education programs, mentor program, qualifications, and responsibilities.

Citation Format: Sandi Stanford. [Advocate Abstract:] Patient advocate program [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr C19.
Abstract C26: Associations Between race/ethnicity and enrollment in cancer research protocols
Authors: Ezeoke Ogochukwu Marietta , Brooks Gary , Postow Michael A. , Baxi Shrujal , Diamond Lisa
Published: February 2019

Background: There is evidence of racial and ethnic disparities in clinical trial participation in oncology, but the studies reporting disparities tend to be small and specific to certain cancers. We aimed to use the experience of a large cancer center to investigate diverse participation in oncology research.

Methods: We performed a retrospective cross-sectional analysis of all adult patients seen at Memorial Sloan Kettering Cancer Center (MSK) from 2005-2015. We examined if enrollment, defined as consent and registration to a research study, varied by race/ethnicity, a variable derived from the combination of self-reported values at MSK, gender, age, cancer type, and preferred language. Cancer type was determined by site and histology and designated as either common or rare, based on NCI criteria. Language preference was dichotomized to English and non-English. Descriptive and chi-square analyses examined bivariate associations between race/ethnicity and other characteristics, and research protocol enrollment. Due to large numbers of participants, associations were also assessed for clinical importance using standardized, chi-square residuals.

Results: A total of 233,599 patients were available for analysis. 93,276 (39.9%) were enrolled in a research protocol. The mean + SD age of the enrolled observations was 57.7+13.7 and for those not enrolled, was 58.9+14.6 (Mann-Whitney U Test, p<.0001). Clinically meaningful associations were seen for “other” race/ethnicity, English language preference, and common cancer diagnosis.

Conclusion: Patients who reported “other” race/ethnicity, whose preferred language was English, or who had common cancer diagnoses were more likely to be enrolled into a research protocol. Differences in enrollment on research protocols due to the additional race/ethnicity categories or gender were minimal. Further research is needed to understand the impact of these findings on diversity in oncology research protocols and to design interventions to reduce disparities in oncology trial enrollment.

Citation Format: Ogochukwu Marietta Ezeoke, Gary Brooks, Michael A. Postow, Shrujal Baxi, Lisa Diamond. Associations Between race/ethnicity and enrollment in cancer research protocols [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr C26.
Abstract C30: Coping strategies in cancer: A systematic review of African American women with breast cancer
Authors: McFall Jeanette Renay , McFall Jeanette Renay , McFall Jeanette Renay , McFall Jeanette Renay
Published: February 2019

Introduction: African American women (AAW) have lower mortality rates for breast cancer compared to non-Hispanic white women. Late-stage diagnosis contributes to these lower mortality rates in AAW. AAW who are diagnosed with breast cancer and receive treatment report a disconnect in provider and patient communication. This disconnect leads to poor outcomes in survivorship. Understanding coping strategies in cancer for AAW diagnosed with breast cancer can help improve provider-patient communication and overall survivorship for patients.

Methods: The systematic review included an electronic search of PubMed and EBSCOHost databases. A search of terms “coping with cancer” and “African American women with breast cancer” yielded results of 35 articles. 14 of 35 articles were used in this review. Articles included in this study were screened for information related to spirituality, coping, and knowledge about cancer.

Results: The 14 studies reviewed all contained qualitative data. Common themes among all 14 studies were that spirituality and religion were the main sources for support for AAW with breast cancer. AAW reported feeling mistrust with health care providers, limited access to health care, and educational providers as barriers in physician-patient communication.

Discussion: Based on the results of this study, AAW use religion and spirituality to cope with cancer diagnosis and treatments. More AAW felt a disconnect with their providers because they felt neglected after completion of treatment. AAW credited medical mistrust to strained communication with health care providers. This information could be helpful to nurses and medical professionals to improve treatment for AAW with breast cancer.

Note: This abstract was not presented at the conference.

Citation Format: Jeanette Renay McFall, Jeanette Renay McFall, Jeanette Renay McFall, Jeanette Renay McFall. Coping strategies in cancer: A systematic review of African American women with breast cancer [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr C30.
Abstract C40: Employment participation after early-stage breast cancer: Patterns and determinants
Authors: Ekenga Christine C. , Perez Maria , Margenthaler Julie A. , Jeffe Donna B.
Published: February 2019

Background: Employment is a social determinant of health. However, few longitudinal studies have examined employment outcomes in women with early-stage breast cancer. The purpose of this study was to examine employment trajectories in a cohort of early-stage breast cancer patients from treatment to 2-year follow-up, and evaluate relationships between sociodemographic, clinical/treatment, and psychosocial factors and employment outcomes.

Methods: Data from a cohort study of newly diagnosed early-stage breast cancer patients were used to examine employment outcomes among 347 working-age patients, 40-64 years old. We examined patients' employment trajectories after definitive surgical treatment, using a multivariable logistic regression model to identify factors associated with diminished (versus sustained) employment at 2-year follow-up.

Results: A total of 245 patients (71%) were employed at least part-time at the time of definitive surgical treatment. 50 patients (20%) reported diminished employment over the 2-year follow-up period. After adjusting for covariates (age, marital status, education, household income, insurance status, depression history, social support, comorbidity, and surgery alone or surgery with chemotherapy, radiation therapy, or both), we observed that fatigue, assessed as SF-36 vitality subscale score below the median (OR=5.50, 95%CI=2.41, 12.56), and African-American race (versus white race, OR=4.23, 95%CI=1.66, 10.76) were associated with diminished employment.

Conclusions: Patients with elevated fatigue and African Americans patients were more likely to experience diminished employment participation after definitive surgical treatment. Further research is warranted to identify factors associated with these disparities and strategies to improve workforce participation after breast cancer.

Citation Format: Christine C. Ekenga, Maria Perez, Julie A. Margenthaler, Donna B. Jeffe. Employment participation after early-stage breast cancer: Patterns and determinants [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr C40.
Abstract C56: An online-based storytelling video intervention on promoting Korean American female college students' HPV vaccine uptake
Authors: Kim Minjin , Lee Haeok , Aronowitz Teri , Sheldon Lisa Kennedy , Kiang Peter , Allison Jeroan , Shi Ling
Published: February 2019

Introduction: Korean American (KA) women are at high risk for human papillomavirus (HPV) infection and cervical cancer, yet they have low awareness and knowledge about HPV vaccine, and subsequently have low HPV vaccine uptake rates. Therefore, it is imperative to develop culturally appropriate education interventions to reduce the health disparities.

Objective: This study aimed to evaluate the effects of an online storytelling intervention to promote HPV vaccine uptake by conducting a pilot randomized controlled trial (RCT).

Method: We recruited 104 participants from multiple sites in six different states in Northeast.

Participants were eligible if they were current KA female college students between the ages of 18-26 and who have not been vaccinated for HPV. This study was implemented in an innovative online laboratory from data collection to experimentation. Participants were randomly assigned to the experimental group (a storytelling video) or control group (written information). The effects of the intervention were assessed at post-intervention and 2-month follow-up.

Results: Both experimental group and control group improved in knowledge and attitudes from baseline to post-intervention. However, the experimental group had higher overall knowledge score, satisfaction with the education program, and intention to get the HPV vaccine within 1 year and was twice as likely to receive or schedule an appointment for the HPV vaccine compared with the control group (15.6% vs. 7.1%).

Conclusion: This pilot study provides evidence in support of the effectiveness of the storytelling video intervention in using an innovative online laboratory setting aimed at HPV and HPV-related cancer prevention.

Citation Format: Minjin Kim, Haeok Lee, Teri Aronowitz, Lisa Kennedy Sheldon, Peter Kiang, Jeroan Allison, Ling Shi. An online-based storytelling video intervention on promoting Korean American female college students' HPV vaccine uptake [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr C56.
Abstract IA03: Breast cancer disparities: Progress, challenges, and opportunities
Authors: Li Christopher I.
Published: February 2019

Breast cancer remains the most commonly diagnosed cancer among women in the United States and worldwide. Important disparities in breast cancer incidence and mortality persist. African American, Hispanic, and American Indian/Alaska Native women are more commonly diagnosed with aggressive forms of breast cancer (including advanced stage disease and triple-negative breast cancer) and experience lower 5-year survival rates. While survival rates have improved across all races/ethnicities, the disparity gap between different races/ethnicities has held essentially constant. Underlying these disparities are a host of factors related to access to care, socioeconomic status, lifestyle/cultural factors, and systems-level factors. For example, mammography utilization varies considerably by education and insurance status, and African American and Hispanic women are less like to receive guideline-concordant treatment for their breast cancers compared to non-Hispanic whites. Additionally, several risk factors that are more common among African American and Hispanic women (including parity, early age at first pregnancy, and obesity) have been shown to be associated with risk of triple-negative breast cancer, potentially accounting for the greater frequency of this aggressive subtype that they experience. Contributors to breast cancer disparities occur on multiple levels and span the entire breast cancer continuum from prevention to screening to diagnosis/treatment and to survivorship. Continued research on all fronts is necessary to address these persistent disparities.

Citation Format: Christopher I. Li. Breast cancer disparities: Progress, challenges, and opportunities [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr IA03.
Abstract IA14: Not the same everywhere: The moderating role of context on cancer disparities
Authors: Pruitt Sandi L.
Published: February 2019

In the emerging field of multilevel cancer disparities research, investigators typically examine the independent contribution of factors such as individual- and neighborhood-level race/ethnicity and socioeconomic status. The moderating role of context is often neglected. In the real world, people interact with and are nested within multiple contexts that may influence the processes whereby disparities are generated and reinforced. The moderating role of context will be explored using two illustrative examples drawn from colorectal cancer screening and breast cancer mortality. Specific contexts explored include patient residence, neighborhood, health care system, and state. In the first example, expected patterns of individual- and neighborhood- level disparity were not evident in colorectal cancer screening among patients of an urban safety-net health care system. For example, neighborhood disparity was limited and the expected pattern of patient-level racial and ethnic disparity (i.e., advantage of white patients as compared to African American and Hispanic patients) was not observed. In the second example, differences in neighborhood context between Texas and California are explored in a study of breast cancer mortality. State-level differences in both neighborhood socioeconomic status and density of Hispanic residents are explored as potential moderators of the association between patient ethnicity, birthplace, and mortality. To conclude the discussion, contextual variables potentially influencing cancer behaviors and outcomes will be identified and described in regard to existing evidence about their influence, methods, and datasets for their analysis, and opportunities for future research.

Citation Format: Sandi L. Pruitt. Not the same everywhere: The moderating role of context on cancer disparities [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr IA14.
Abstract IA17: The tobacco environment at the point of sale and the effects on vulnerable populations
Authors: A Lourdes
Published: February 2019

This presentation will cover findings from a project in the tobacco retail environment of the Tobacco Center for Regulatory Sciences in Vulnerable Populations at USC. Qualitative and survey research was conducted among over 700 retailers and in retail outlets that sell tobacco products in vulnerable ethnic communities, including among American Indian tribal lands, in African American, Hispanic/Latino, Korean, and low-SES non-Hispanic White neighborhoods. Findings show violations to tobacco rulings as well as identify potential areas of concern and viable targeted and culturally tailored solutions to reducing exposure to environmental influences that foster and encourage the use of tobacco products in vulnerable communities.

Citation Format: Lourdes A. The tobacco environment at the point of sale and the effects on vulnerable populations [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr IA17.
Abstract IA25: Disparities in survivors of pediatric, adolescent, and young adult cancers
Authors: Bhatia Smita
Published: February 2019

Outcome disparities in pediatric, adolescent, and young adult cancer are multifaceted. While disparities are commonly described along racial/ethnic lines, the underlying causes of these differences in outcome are often rooted in socioeconomic status, host genetics, disease biology, health literacy lifestyle factors, health behaviors, and comorbidities. Nonetheless, by the middle of this century, racial/ethnic minority populations will collectively constitute 50% of the U.S. population. This temporal shift in the racial/ethnic composition of the U.S. population demands a close examination of the observed disparities in both the quality and quantity of survival in pediatric, adolescent, and young adult cancer. In this talk we describe the differences in overall and event-free survival by race/ethnicity as well as by age (children vs. adolescent and young adult) across a variety of cancer types. We examine the causes of the difference in these outcomes. We describe the burden of morbidity carried by cancer survivors across racial/ethnic and socioeconomic lines and present the current evidence for the causes of observed differences in morbidity. We speculate that any racial/ethnic differences in outcome are likely to be multifactorial, and draw on extant literature to illustrate the various contributors (socioeconomic characteristics, health behaviors, disease biology, and comorbidities) that could explain any observed differences in key treatment-related complications. Finally, we outline challenges in conducting race/ethnicity-specific survivorship research, demonstrating that there are limited absolute numbers who are diagnosed and survive histologically distinct cancers in any one racial/ethnic minority population, thereby precluding a rigorous evaluation of adverse events among specific primary cancer diagnoses and treatment exposure groups.

Citation Format: Smita Bhatia. Disparities in survivors of pediatric, adolescent, and young adult cancers [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr IA25.
Abstract IA32: Building and sustaining partnerships in cancer health disparities research
Authors: Halbert Chanita Hughes
Published: February 2019

Partnerships between academic institutions, public health agencies, and community-based organizations are critical to addressing racial and ethnic disparities in cancer outcomes. However, developing and sustaining these partnerships may be challenging because of differences in organizational missions, priorities, and infrastructure for conducting research. While these issues can be addressed by establishing a shared vision and mission for the partnership using principles of community-based participatory research, it is also critical to establish an effective administrative structure that centralizes and integrates activities across research and outreach efforts. This presentation will use two case examples of building and sustaining partnerships for cancer health disparities research. The first example is the process that was used to develop and manage the West Philadelphia Consortium to Address Disparities that was established to address minority health and health disparities in chronic diseases among African Americans in the Philadelphia, PA metropolitan area. The second example will focus on describing the Consortium Core that is a component of the Medical University of South Carolina Transdisciplinary Collaborative Center in Precision Medicine and Minority Men's Health.

Citation Format: Chanita Hughes Halbert. Building and sustaining partnerships in cancer health disparities research [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr IA32.
Plasminogen Activator Inhibitor 1 (PAI1) Promotes Actin Cytoskeleton Reorganization and Glycolytic Metabolism in Triple-Negative Breast Cancer
Authors: Humphries Brock A. , Buschhaus Johanna M. , Chen Yu-Chih , Haley Henry R. , Qyli Tonela , Chiang Benjamin , Shen Nathan , Rajendran Shrila , Cutter Alyssa , Cheng Yu-Heng , Chen Yu-Ting , Cong Jason , Spinosa Phillip C. , Yoon Euisik , Luker Kathryn E. , Luker Gary D.
Published: February 2019

Migration and invasion of cancer cells constitute fundamental processes in tumor progression and metastasis. Migratory cancer cells commonly upregulate expression of plasminogen activator inhibitor 1 (PAI1), and PAI1 correlates with poor prognosis in breast cancer. However, mechanisms by which PAI1 promotes migration of cancer cells remain incompletely defined. Here we show that increased PAI1 drives rearrangement of the actin cytoskeleton, mitochondrial fragmentation, and glycolytic metabolism in triple-negative breast cancer (TNBC) cells. In two-dimensional environments, both stable expression of PAI1 and treatment with recombinant PAI1 increased migration, which could be blocked with the specific inhibitor tiplaxtinin. PAI1 also promoted invasion into the extracellular matrix from coculture spheroids with human mammary fibroblasts in fibrin gels. Elevated cellular PAI1 enhanced cytoskeletal features associated with migration, actin-rich migratory structures, and reduced actin stress fibers. In orthotopic tumor xenografts, we discovered that TNBC cells with elevated PAI1 show collagen fibers aligned perpendicular to the tumor margin, an established marker of invasive breast tumors. Further studies revealed that PAI1 activates ERK signaling, a central regulator of motility, and promotes mitochondrial fragmentation. Consistent with known effects of mitochondrial fragmentation on metabolism, fluorescence lifetime imaging microscopy of endogenous NADH showed that PAI1 promotes glycolysis in cell-based assays, orthotopic tumor xenografts, and lung metastases. Together, these data demonstrate for the first time that PAI1 regulates cancer cell metabolism and suggest targeting metabolism to block motility and tumor progression.

Implications:

We identified a novel mechanism through which cancer cells alter their metabolism to promote tumor progression.
Abstract A06: LINC00261 acts as a tumor suppressor in lung adenocarcinoma
Authors: Castillo Jonathan , Shahabi Shandy , Kumaran Vishaly , Marconett Crystal
Published: February 2019

Lung cancer is the leading cause of cancer-related mortality, with a 5-year mortality rate approaching 85%. My lab focuses on the major histologic subtype, lung adenocarcinoma (LUAD). Using a combination of bioinformatics and biologic analyses, we have uncovered a role for novel regulatory RNAs in the etiology of LUAD development. Our current research focuses primarily on a long noncoding RNA with effects on proliferation and metastasis of lung cancer cells. It is our hope to identity key regulators of cancer development and progression, so that targeted therapeutics can be developed to help improve the overall survival rate for this deadly disease.

Citation Format: Jonathan Castillo, Shandy Shahabi, Vishaly Kumaran, Crystal Marconett. LINC00261 acts as a tumor suppressor in lung adenocarcinoma [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A06.
Abstract A37: Tobacco smoke increases lung adenocarcinoma risk by downregulating TGF-beta and AhR-regulated focal adhesion proteins involved in injury resolution
Authors: Stueve Theresa Ryan , Yang Chenchen , Marconett Crystal N. , Yan Chunli , Zhou Beiyun , Borok Zea , Laird-Offringa Ite A.
Published: February 2019

Background: The most prevalent type of lung cancer—lung adenocarcinoma—arises from the most distal reaches of the lung in the alveolar epithelium. The alveolar epithelium consists of two cell types: (i) thin type I alveolar epithelial cells (AT1) that facilitate gas exchange and constitute more than 90% of the alveolar surface, and (ii) cuboidal surfactant-producing type II (AT2) cells. Following injury, dynamic interactions between extracellular matrix components, integrins, focal adhesion proteins, and cytoskeletal components allow AT2 progenitor cells to migrate, spread, and transdifferentiate into AT1 cells to restore the denuded epithelial barrier.

Methods: Utilizing primary human AT2 cells isolated from lung transplant remnants, our lab has established and extensively profiled an in vitro model of epithelial restitution, wherein AT2 cells differentiate over a period of six days into terminally differentiated AT1-like cells. Because cigarette smoking is the most recognized risk factor for lung adenocarcinoma (LUAD), and because the alveolar space is the primary target of tobacco smoke, we also compared the RNA-seq profiles of AT2>AT1 differentiation to those of A549 LUAD cells exposed to cigarette smoke condensate (CSC).

Results: We find that CSC downregulates many factors that are upregulated in the AT2>AT1 restitution model, particularly integrins, extracellular matrix components, and novel focal adhesion proteins that are also downregulated in LUAD relative to adjacent normal tissue. We describe regulation of four such novel focal adhesion proteins, specifically by TGF-β and aryl hydrocarbon receptor (AhR)-mediated mechanisms.

Conclusions: Our findings shed light on early mechanisms in the carcinogenic process, and support the notion that alveolar cells engaged in repeated cycles of injury and repair are critical actors in LUAD risk trajectories.

Note: This abstract was not presented at the conference.

Citation Format: Theresa Ryan Stueve, Chenchen Yang, Crystal N. Marconett, Chunli Yan, Beiyun Zhou, Zea Borok, Ite A. Laird-Offringa. Tobacco smoke increases lung adenocarcinoma risk by downregulating TGF-beta and AhR-regulated focal adhesion proteins involved in injury resolution [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A37.
Abstract B13: The impact of combined CDK9 inhibition and TRAIL treatment on NSCLC
Authors: Zubiaur Itziar Areso , Montinaro Antonella , Karstedt Silvia von , Lemke Johannes , Hartwig Torsten , Taraborelli Lucia , Surinova Silvia , El-Bahrawy Mona A. , Walczak Henning
Published: February 2019

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been shown to specifically kill cancer cells in vivo. On the basis of this, TRAIL-receptor (TRAIL-R) agonists were devised for clinical use. However, to date, TRAIL-R agonists have only shown limited therapeutic benefit in clinical trials. This can most likely be attributed to the fact that most primary human cancers are TRAIL resistant. It is therefore important to identify potent and cancer-selective TRAIL-sensitizers that overcome TRAIL resistance. Recently, the combination of CDK9 inhibition with TRAIL was found to effectively induce apoptosis in a panel of TRAIL-resistant non-small cell lung cancer (NSCLC) cell lines. Furthermore, tumors from NSCLC patients show high expression levels of CDK9, providing a rationale for targeting CDK9 in lung cancer. Here, we evaluate how effective the new TRAIL/CDK9 inhibition combination therapy is in treating lung cancer in an autochthonous mouse model (the KrasG12D/p53R172H) that closely recapitulates the human disease. We found that this combination was highly effective in vivo and led to a significant tumor regression and prolonged the survival of these mice. Our most recent results regarding these effects will be presented.

Citation Format: Itziar Areso Zubiaur, Antonella Montinaro, Silvia von Karstedt, Johannes Lemke, Torsten Hartwig, Lucia Taraborelli, Silvia Surinova, Mona A. El-Bahrawy, Henning Walczak. The impact of combined CDK9 inhibition and TRAIL treatment on NSCLC [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B13.
Abstract B24: Differential sensitivity to Aurora kinase inhibition in RIT1- and KRAS-mutant lung adenocarcinoma
Authors: Holmes Kristin D. , Mundt Filip , Mertins Phillip , Carr Steve , Berger Alice
Published: February 2019

Mutations in Ras-family genes Kirsten rat sarcoma viral oncogene (KRAS) and Ras-like in all tissues (RIT1) occur in 30% and 2% of lung adenocarcinomas, respectively. Targeted therapies have shown promise in lung adenocarcinomas and other cancers; however, there are currently no FDA-approved drugs that directly target RIT1 or KRAS. To identify critical effector pathways and/or genetic dependencies that might be targeted for clinical benefit in these cancers, we undertook complementary proteomic and small-molecule screens in multiple human lung cancer models.

To better understand the signaling networks modulated by RIT1 and KRAS, we performed deep characterization of total protein and phosphoproteins in non-transformed human lung epithelial cells engineered to express mutant or wild-type RIT1 or KRAS. 10,131 proteins were detected across all samples, 9,001 of which were detected in every sample. 29,172 phosphorylated sites were detected with 14,769 of these identified in every sample. Gene set enrichment analysis (GSEA) identified pathways significantly modulated by RIT1 M90I, KRAS G12V, or KRAS Q61H mutations. Whereas some pathways, such as MYC, were commonly activated by both mutant RIT1 and KRAS, others, such as Aurora kinase signaling, were specifically perturbed by RIT1.

Previously, we found that mutant RIT1 and KRAS can transform human lung epithelial cells and confer resistance to EGFR blockade in EGFR-dependent lung adenocarcinoma. To identify opportunities for therapeutic intervention of RIT1- and KRAS-mutant tumors, we screened a collection of 160 small molecules for their ability to block RIT1/KRAS-induced drug resistance in PC9 cells, an EGFR-mutant lung adenocarcinoma cell line. Interestingly, RIT1 M90I-expressing cells were selectively killed as a result of treatment with the Aurora kinase inhibitors, alisertib and barasertib, while KRAS G12V cells were resistant to these inhibitors. The specific effect of Aurora kinase inhibition on RIT1 mutant cells was also confirmed in a fibroblast transformation assay and could not be attributed to proliferation rate, which was similar between RIT1- and KRAS-expressing cells. Moreover, Aurora kinase B (AURKB) was among the most differentially expressed transcripts when comparing RIT1- or KRAS-expressing cells, suggesting differential effects of RIT1 and KRAS on Aurora kinase activity.

These findings nominate Aurora kinase inhibition as a potential therapeutic strategy in RIT1- , but not KRAS-mutant, lung cancer.

Citation Format: Kristin D. Holmes, Filip Mundt, Phillip Mertins, Steve Carr, Alice Berger. Differential sensitivity to Aurora kinase inhibition in RIT1- and KRAS-mutant lung adenocarcinoma [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B24.
Abstract B28: Targeted inhibition of EGFR and glutaminase induces metabolic crisis in EGFR-mutant lung cancer
Authors: Momcilovic Milica , Bailey Sean T. , Lee Jason T. , Magyar Clara , Braas Daniel , Graeber Thomas , Parlati Francesco , Demo Susan , Krysan Konstyantyn , Walser Tonya C. , Dubinett Steven M. , Sadeghi Saman , Christofk Heather R. , Shackelford David B.
Published: February 2019

Cancer cells exhibit increased use of nutrients, including glucose and glutamine, to support the bioenergetic and biosynthetic demands of proliferation. We tested the small-molecule inhibitor of glutaminase CB-839 in combination with erlotinib on epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) as a therapeutic strategy to simultaneously impair cancer glucose and glutamine utilization and thereby suppress tumor growth. Here, we show that CB-839 cooperates with erlotinib to drive energetic stress and activate the AMP-activated protein kinase (AMPK) pathway in EGFR (del19) lung tumors. Tumor cells undergo metabolic crisis and cell death, resulting in rapid tumor regression in vivo in mouse NSCLC xenografts. Consistently, positron emission tomography (PET) imaging with 18F-fluoro-2-deoxyglucose (18F-FDG) and 11C-glutamine (11C-Gln) of xenografts indicated reduced glucose and glutamine uptake in tumors following treatment with CB-839 + erlotinib. Therefore, PET imaging with 18F-FDG and 11C-Gln tracers can be used to noninvasively measure metabolic response to CB-839 and erlotinib combination therapy.

Citation Format: Milica Momcilovic, Sean T. Bailey, Jason T. Lee, Clara Magyar, Daniel Braas, Thomas Graeber, Francesco Parlati, Susan Demo, Konstyantyn Krysan, Tonya C. Walser, Steven M. Dubinett, Saman Sadeghi, Heather R. Christofk, David B. Shackelford. Targeted inhibition of EGFR and glutaminase induces metabolic crisis in EGFR-mutant lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B28.
Abstract B30: Three-dimensional organoid model for acquired drug resistance in non-small cell lung cancer
Authors: Shukla Navika D. , Salahudeen Ameen A. , Padda Sukhmani K. , Neal Joel W. , Wakelee Heather A. , Kuo Calvin J.
Published: February 2019

Background: Targeted therapies against specific driver mutations of cancer progression have been used to improve survival of lung adenocarcinoma patients. In KRAS mutant NSCLC specifically, however, after some initial improvement in lung cancer patients, targeted therapies often fail due to acquired drug resistance. To uncover mechanisms of resistance and to discover new drivers, genome-scale sequencing of lung cancers has identified candidate genes, but these data have not rapidly translated in preclinical validation. A major obstacle in lung cancer research has been the deficiencies of standard in vitro models.

Methods: To address the deficiencies within standard models we have developed an in vitro 3-dimensional, KRAS-mutated “organoid” model of lung adenocarcinoma that surpasses both in vitro and in vivo models by possessing the tractability of cell lines and the 3-dimensional architecture and morphology of animal models. We have engineered a p53 knockout and KRAS mutation on top of normal wild-type lung epithelium to achieve oncogenicity.

Result: Through an optimized growth period in the presence of drug, an organoid model of resistance has been developed through which de novo genetic events underlying acquired resistance can be studied.

Conclusion: The highly defined genetic background of the KRAS-mutated 3-D organoid model serves as a tabula rasa upon which stochastic secondary genetic and epigenetic changes can be identified and mechanistically studied by forward and reverse genetics approaches in order to rapidly identify mechanisms of acquired drug resistance and validate therapeutic options.

Citation Format: Navika D. Shukla, Ameen A. Salahudeen, Sukhmani K. Padda, Joel W. Neal, Heather A. Wakelee, Calvin J. Kuo. Three-dimensional organoid model for acquired drug resistance in non-small cell lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B30.
Abstract B34: Safety and activity of the IL-15/sIL-15Rα complex ALT-803 in combination with the anti-PD1 mAb nivolumab in metastatic non-small cell lung cancer
Authors: Wrangle John , Velchetti Vamshidar , Patel Manish , Suriano Samantha , Swiderska-syn Marzena , Anderton Kate , Ravenel James , Hill Elisabeth , Rock Amy , Wong Hing , Rubinstein Mark
Published: February 2019

This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR05) of the Conference Proceedings.

Citation Format: John Wrangle, Vamshidar Velchetti, Manish Patel, Samantha Suriano, Marzena Swiderska-syn, Kate Anderton, James Ravenel, Elisabeth Hill, Amy Rock, Hing Wong, Mark Rubinstein. Safety and activity of the IL-15/sIL-15Rα complex ALT-803 in combination with the anti-PD1 mAb nivolumab in metastatic non-small cell lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B34.
Abstract IA09: Inflammation and immunity in pulmonary premalignancy
Authors: Krysan Kostyantyn , Tran Linh M. , Grimes Brandon S. , Dubinett Steven M.
Published: February 2019

Unleashing the immune response against pulmonary premalignancy could transform therapy and outcomes. We are evaluating the mutational landscape of pulmonary premalignancy and the associated premalignant microenvironment by whole-exome DNA sequencing and immunohistochemistry. Remarkably, we find putative neoepitopes and frequent immune-effector cell infiltration as well as evidence of immune suppression in pulmonary premalignancy. These findings suggest that premalignant-associated antigens are recognized and elicit immune responses at the earliest points of lung adenocarcinoma development. Identification of neoepitopes that can be targeted before the development of invasive lung cancer could eventually shift the approach to disease interception through immunoprevention and treatment of the very earliest phase of the disease.

Citation Format: Kostyantyn Krysan, Linh M. Tran, Brandon S. Grimes, Steven M. Dubinett. Inflammation and immunity in pulmonary premalignancy [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA09.
Abstract IA11: Gene networks, airway smoke injury, and cancer risk
Authors: Ponder Bruce A.J.
Published: February 2019

Background: Fifteen percent of smokers and former smokers develop lung cancer. This might be chance; an alternative is that some are at greater risk because of different individual responses to airway smoke injury. Several groups have investigated gene expression in normal airway epithelium as a readout of smoke injury and as a stratifier for risk. Questions include, but are not limited to: i) Can nasal epithelium provide a useful and accessible surrogate for bronchial? ii) Is there an inherited component to the injury-related risk? iii) What components of the injury response contribute most to increased risk in current and in former smokers? iv) What is the distribution of injury response in the healthy current and former smoker populations, rather than symptomatic patients, and how does this relate to risk?

Results and Work in Progress: We, like others, have based our analysis on gene expression in normal bronchial and nasal epithelium. We use transcription factor-centered gene regulatory networks, derived from normal bronchial and nasal epithelium, to identify the overlying cellular regulatory mechanisms that differ between injury responses. We identify transcriptional “master regulators” (MRs), the activity of which differs between cancer and benign, and confirm the overlap of MRs between nasal and bronchial epithelium. A preliminary pathway analysis suggests the involvement of these MRs in oxidative stress response, DNA repair, immune responses, and developmental processes. Using data from the TRICL consortium, we show that the regulons of a subset of these MRs are enriched in genes located at lung GWAS loci. This suggests that the observed gene expression differences between cancer and benign are in part causal, related to inherited variation rather than secondary to the cancer.

Using samples from the Cambridge Bioresource volunteers, we are analyzing data from nasal samples to compare healthy current and former smokers with healthy never-smokers, and so obtain a “smoke injury response.” We will use this to describe the distribution of injury response in the healthy smoker/former smoker populations. Our aim is to test what component of risk-related gene response may be apparent in this healthy asymptomatic smoker population rather than at the “later” symptomatic stages of hospital investigation, and to find which genes or regulatory processes contribute most to this. The results may have implications both for risk prediction and possible interventions in these populations.

My talk will be a “work in progress” aimed at stimulating discussion about questions and approaches, rather than a presentation of finished results.

Citation Format: Bruce A.J. Ponder. Gene networks, airway smoke injury, and cancer risk [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA11.