bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B70: Design of the SHAPE-2 trial; Effects of equivalent weight loss, with and without exercise, on postmenopausal breast cancer risk
Authors: Gemert Willemijn AM van , Peeters Petra HM , Schuit Jantine A. , Monninkhof Evelyn M.
Published: January 2014

Background: Physical inactivity and overweight are two modifiable risk factors for breast cancer. These factors probably act through sex hormone-related pathways. The results of dietary intervention studies (mostly uncontrolled) suggest that diet-induced weight loss reduces postmenopausal sex hormone levels. The question remains if the beneficial effect of physical activity on breast cancer risk is fully explained by the accompanied weight loss. Three out of four exercise intervention studies showed that physical activity mainly influences hormone levels when concordant loss of body fat is achieved. One intervention study, however, suggests an effect of exercise on sex hormones independent of changes in adiposity.

Therefore, we set out to study the effect of weight loss mainly driven by exercise compared to equivalent diet induced weight loss only on sex hormone levels.

Methods/Design: We designed a three-armed, single blind, two-centre trial in 250 sedentary, postmenopausal women who are overweight/obese (BMI 25-35 kg/m2). Women are randomly allocated to a (1) Diet induced weight loss group, (2) Exercise induced weight loss group or (3) a stable weight Control group. The aim of both intervention groups is to loose an equivalent amount of 5-6 kg body weight in 10 to 14-week timeframe. The Diet-group will therefore follow an energy restricted diet. The Exercise-group will participate in a 16-week endurance and strength training programme (4 hours/week) combined with a slight caloric intake restriction. Measurements include blood sampling, questionnaires, anthropometrics, maximal exercise test, total body DEXA-scan (body (fat) composition) and MRI (abdominal fat). The main outcomes are endogenous serum levels of estradiol, estrone, testosterone and sex hormone binding globulin (SHBG).

Discussion: This study will give insight in the possible attributable effect, and the underlying mechanisms, of physical activity on endogenous sex hormone levels, directly and/or mediated by changes in body(fat) composition, in postmenopausal women.

Eventually this may lead to the design of more specific guidelines on lifestyle interventions and physical activity for prevention of breast cancer.

Citation Format: Willemijn AM van Gemert, Petra HM Peeters, Jantine A. Schuit, Evelyn M. Monninkhof. Design of the SHAPE-2 trial: Effects of equivalent weight loss, with and without exercise, on postmenopausal breast cancer risk. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B70.
Abstract B84: The association between germline genetic variants in the PI3K pathway and PI3K mutations in breast tumors.
Authors: Brewster Abenaa M. , Bondy Melissa , Do Kim-anh , Sahin Aysegul , Hale Katherine , Wei Caimiao , Mills Gordon , Thompson Patricia
Published: January 2014

Background: Gene mutations in the PI3K pathway in breast tumors are associated with resistance to tamoxifen and poorer prognosis. Differences in host susceptibility to developing breast cancers with PI3K pathway mutations may explain the heterogeneity in response to tamoxifen for chemoprevention and breast cancer outcomes. The objective of the study was to evaluate the association between host germline single nucleotide polymorphisms (SNPs) and activation of the PI3K pathway in breast tumors.

Methods: We extracted tumor and germline DNA from 386 women with stages I-II breast cancer treated at the MD Anderson Cancer Center. Nine PI3K mutation sites were evaluated using the Sequenom assay and 57 tagging single nucleotide polymorphisms (SNPs) of candidate genes in the PI3K pathway were genotyped using the Illumina Golden Gate Platform.

Results: 36 patients (10%) had at least one mutation in the PI3K pathway. There was no association between PI3K mutation status by age at diagnosis or ethnicity. In univariate analysis, there was a statistically significant association between PI3K gene mutation status and 3 tagging SNPs in the genes, PTEN (rs123421, rs1234213) and IGF-1 (rs2033178).

Conclusion: PI3K mutations are rare in breast tumors but represent a druggable target for prevention and treatment. Host genetics may play a role in contributing to tumor biology and serve to identify individuals at risk for tumors with PI3K pathway activation and tamoxifen resistance.

Citation Format: Abenaa M. Brewster, Melissa Bondy, Kim-anh Do, Aysegul Sahin, Katherine Hale, Caimiao Wei, Gordon Mills, Patricia Thompson. The association between germline genetic variants in the PI3K pathway and PI3K mutations in breast tumors. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B84.
Abstract B94: Hay fever and asthma as markers of atopic immune response and risk of colorectal cancer in three large cohort studies
Authors: Jacobs Eric J. , Gapstur Susan M. , Newton Christina C. , Turner Michelle C. , Campbell Peter T.
Published: January 2014

Background: In a previous analysis of the Cancer Prevention Study II (CPS-II) cohort that included follow-up from 1982-2000, having both hay fever and asthma was associated with lower colorectal cancer mortality. The combination of these allergy-related conditions may be a marker for allergy-related immune responses that could inhibit the development or progression of colorectal cancer.

Methods: We examined the association between having both hay fever and asthma and colorectal cancer mortality among 1,023,191 participants in Cancer Prevention Study I (CPS-I) followed-up from 1959-1972, and 1,102,092 participants in CPS-II, now followed-up from 1982 through 2008. We also examined associations with colorectal cancer incidence among 174,917 participants in the CPS-II Nutrition Cohort, a subgroup of CPS-II followed from 1992-2007. During follow-up, there were 5,644 colorectal cancer deaths in CPS-I, 13,558 colorectal cancer deaths in CPS-II, and 3,365 incident colorectal cancers in the CPS-II Nutrition Cohort. Cox proportional hazards regression models were used to calculate multivariable-adjusted relative risks (RRs).

Results: RRs for colorectal mortality associated with having both asthma and hay fever, compared to neither condition, were 0.90 (95% confidence interval (CI): 0.74-1.09) in CPS-I, 0.79 (95% CI: 0.69-0.91) in CPS-II, and 0.83 (95% CI: 0.74-0.92) when results from both cohorts were combined using a fixed-effects meta-analysis. The RR for colorectal cancer incidence in the CPS-II Nutrition Cohort was 0.90 (95% CI: 0.71-1.14).

Conclusion: These results are consistent with an association between having both hay fever and asthma and modestly lower colorectal cancer mortality.

Citation Format: Eric J. Jacobs, Susan M. Gapstur, Christina C. Newton, Michelle C. Turner, Peter T. Campbell. Hay fever and asthma as markers of atopic immune response and risk of colorectal cancer in three large cohort studies. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B94.
Abstract B99: Colon cancer treatment: Are there racial disparities in an equal-access healthcare system?
Authors: Andaya Abegail , Enewold Lindsey , Zahm Shelia H. , Shriver Craig D. , Warren Joan , Stojadinovic Alexander , McGlynn Katherine , Zhu Kangmin
Published: January 2014

Purpose: Accessibility to medical care may be the most important factor influencing differences in colon cancer treatment among whites and blacks. This study assessed whether racial disparities in colon cancer surgery and chemotherapy existed in an equal access healthcare system. Additionally, we sought to examine whether racial differences varied by tumor stage.

Methods: Patients included 2,570 non-Hispanic whites and non-Hispanic blacks with colon cancer diagnosed from 1998 to 2007. Logistic regression was used to assess the associations between race and the receipt of colon cancer surgery or chemotherapy, while controlling for available potential confounders, both overall and stratified by tumor stage.

Results: Univariate analysis revealed that there were no racial differences in surgery but that non-Hispanic blacks were more likely to receive chemotherapy than non-Hispanic whites. However, after multivariate adjustment, the odds of receiving colon cancer surgery and chemotherapy were similar between the two racial groups and did not vary by tumor stage.

Conclusion: When access to medical care is equal, racial disparities in the receipt of colon cancer surgery and chemotherapy were not apparent. Thus, it is possible that equal access to care is the driving force behind racial disparities in cancer treatment in the general population.

Citation Format: Abegail Andaya, Lindsey Enewold, Shelia H. Zahm, Craig D. Shriver, Joan Warren, Alexander Stojadinovic, Katherine McGlynn, Kangmin Zhu. Colon cancer treatment: Are there racial disparities in an equal-access healthcare system? [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B99.
Abstract CN01-03: Autoimmune rheumatic diseases and cancer: Not just chance?
Authors: Rosen Antony , Casciola-Rosen Livia
Published: January 2014

A relationship between cancer and autoimmune rheumatic diseases has been observed for many decades, although the relevance of, and mechanisms underlying this association remain unclear. Investigating this relationship has been extremely challenging, due to (i) the striking heterogeneity of the rheumatic diseases, (ii) the use of numerous pharmacologic agents which can be associated with cancer, (iii) the kinetic heterogeneity of cancer onset (some cancers precede the rheumatic disease; most follow diagnosis of cancer, but over a period which can vary from 0-25 years); and (iv) the large number of tumor types associated with rheumatic disease. Although >80% of rheumatic disease patients do not have any associated cancer, a striking temporal clustering of the onset of cancer and autoimmune rheumatic disease has been observed. This is true for Dermatomyositis and Polymyositis, where most cancers are diagnosed -1 to +1 years around the onset of the rheumatic syndrome. Cancer is diagnosed in ∼15% of all patients with DM (mostly adenocarcinomas). Interestingly, myositis autoantigens are expressed at very low levels in most normal tissues, but at increased levels in both tumors and inflamed muscle, where autoantigen expression is localized to regenerating muscle cells. Similar observations have been made in other rheumatic diseases including scleroderma. The available data suggest a model where autoantigen expression and inflammation in the tumor initiates a humoral and cellular immune response to autoantigens. In the setting of injury to a normal tissue (e.g. muscle), the precursors which differentiate to repair the injury express the same antigens, and become the target of the ongoing immune response, and drive tissue damage in a feedforward loop.

Citation Format: Antony Rosen, Livia Casciola-Rosen. Autoimmune rheumatic diseases and cancer: Not just chance? [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN01-03.
Abstract CN03-02: Is newer better? Use of technology to encourage cancer screening among various populations
Authors: Skinner Celette Sugg
Published: January 2014

Several major technological breakthroughs have greatly expanded our options for health behavior interventions. In the 1980s, we started being able to record our own videos through hand-held cameras, mass produce tailored print on micro-computers, and develop interactive computer programs. Now, all these interventions can be web-based and accessed through smart phones that can collect data and deliver tailored feedback in real time. In our fascination with new media and their capabilities, we have rushed to employ latest technologies for interventions for all kinds of people. But, is newer necessarily better? To suggest some answers to this question, the presentation will use qualitative data as well as main and interaction effects from some large behavioral intervention trials among African Americans and other population subgroups.

Citation Format: Celette Sugg Skinner. Is newer better? Use of technology to encourage cancer screening among various populations. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN03-02.
Abstract CN03-04: The effect of the new screening guidelines on uptake of screening tests
Authors: Taplin Stephen H.
Published: January 2014

National organizations funded through public and private dollars have been setting cancer screening guidelines for more than a generation. While guidelines are a lightning rod for practitioners and people at risk for cancer, their actual effect on behavior is unclear. In this presentation I will review what we can expect regarding the association between guidelines and behavior based on conceptual models. I will also review what we know from published work about the association between guideline changes and screening for breast, colon, cervical, and prostate cancer. Finally I will summarize changes in the USPSTF in the last 10 years and examine their association with changes in screening rates for breast, colorectal, cervical, and prostate cancer. To do the latter I will compare rates of screening as reported in the National Health Interview Survey (NHIS) using survey data from the following years 2000, 2003, 2005, 2008, 2010, 2011 and comparing screeing rates before and after significant USPSTF guideline changes in 2002 (breast), 2003 (cervix), and 2009 (breast, colorectal cancer). Lively discussion, insight, but no lightning will be sought.

Citation Format: Stephen H. Taplin. The effect of the new screening guidelines on uptake of screening tests. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN03-04.
Abstract CN05-01: Viral and Dietary Factors in Declining Liver Cancer Mortality in Qidong, China
Authors: Kensler Thomas W.
Published: January 2014

Liver cancer is the third leading cause of cancer mortality globally. In endemic areas of sub-Saharan Africa and southeast Asia liver cancer largely arises from both chronic infection with hepatitis B virus (HBV) and the ingestion of aflatoxin-contaminated foods such as corn and groundnuts. While synergistic interactions between these viral and chemical carcinogens have been observed in prospective cohort studies in China, the effects of primary prevention against both of these factors has not been examined. Mortality rates from liver cancer by birth cohort in Qidong, China were compared to timelines in the region for the introduction of HBV vaccination and to mandated, wholesale changes in staple foodstuffs from corn to rice. Levels of aflatoxin-albumin adducts in archived serum samples collected in Qidong from 1989 to 2012 were quantified by isotope dilution mass spectrometry as measures of carcinogen exposure. Halving of mortality rates from liver cancer are seen between birth cohorts from the 1960s and 1980s for residents 34 years old and younger. However, prevalence of HBsAg positivity was unchanged in these cohorts as all were born prior to implementation of universal HBV vaccination of newborns. Changing agricultural policies from a planned to a market-oriented economy in the early 1980s led from corn to rice based diets and dramatic decreases in aflatoxin exposures in Qidong. Substantial declines in liver cancer morality in birth cohorts occurring prior to the introduction of a universal HBV vaccination program in Qidong highlight the importance of altered food policies as a means for rapid risk reduction, especially amongst the ∼350 million HBV carriers, many of whom reside in endemic areas. Supported by NIEHS ES 006052 and National Science and Technology of China 2008ZX10002-015.

Citation Format: Thomas W. Kensler. Viral and dietary factors in declining liver cancer mortality in Qidong, China. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN05-01.
Abstract CN06-01: Induction of oral cavity cancer in rats by (S)-N'-nitrosonornicotine, a constituent of smokeless tobacco
Authors: Hecht Stephen S. , James-Yi Sandra , O'Sullivan Gerard , Stepanov Irina , Wang Mingyao , Kassie Fekadu , Carmella Steven , Upadhyaya Pramod , Balbo Silvia
Published: January 2014

Smokeless tobacco products such as moist oral snuff are being promoted by the tobacco industry with a half billion dollars per year in advertising. It is likely that the prevalence of smokeless tobacco use will continue to increase in the U.S. Smokeless tobacco products are widely used in other parts of the world and are considered by the International Agency for Research on Cancer as causes of cancer of the oral cavity, esophagus and pancreas in humans. However, no previous study has reported the presence of a strong oral cavity carcinogen in these products.

N'-Nitrosonornicotine (NNN) occurs in significant amounts in smokeless tobacco products, generally being found at levels of 1 - 10 μg/g tobacco. Since NNN has a chiral center, it exists as (S)- and (R)- enantiomers. (S)-NNN is the major enantiomer in smokeless tobacco products. While racemic NNN (a 50:50 mixture of (S)- and (R)-NNN) has been previously shown to cause esophageal tumors in rats, the carcinogenicity of the individual enantiomers has not been reported. Based on our published metabolism and DNA binding studies of (S)-NNN, we hypothesized that it might be a more powerful carcinogen than (R)-NNN and, furthermore, that it might cause oral cancer.

Groups of 24 male F-344 rats were treated with either (S)-NNN (15 ppm), (R)-NNN (15 ppm), or racemic NNN (30 ppm) in the drinking water for 15-20 months. Necropsy of 20 rats treated with (S)-NNN demonstrated a 100% incidence of oral cavity tumors. More than 60 oral cavity tumors were observed, including benign and malignant tumors of the buccal mucosa, soft and hard palate, tongue, and pharynx. All rats also had esophageal tumors. (R)-NNN was significantly less carcinogenic than (S)-NNN. Racemic NNN also induced a high incidence of oral cavity and esophageal tumors.

The results of this study demonstrate for the first time the presence of a strong oral cavity carcinogen in smokeless tobacco. (S)-NNN is a prime target for elimination from these products as a positive step toward cancer prevention.

Citation Format: Stephen S. Hecht, Sandra James-Yi, Gerard O'Sullivan, Irina Stepanov, Mingyao Wang, Fekadu Kassie, Steven Carmella, Pramod Upadhyaya, Silvia Balbo. Induction of oral cavity cancer in rats by (S)-N'-nitrosonornicotine, a constituent of smokeless tobacco. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN06-01.
Abstract CN07-01: Understanding the role of stem-like tumor cells in proneural glioma
Authors: Barrett Lindy Elise , Nam Hyung-song , Benezra Robert
Published: January 2014

The ID (Inhibitor of DNA-binding) gene family regulates self-renewal in adult neural stem cells. Cells expressing high levels of Id1 in the neurogenic niches of the adult brain define the B1 stem cell populations and Id proteins are essential for self-renewal and the maintenance of multipotency. A decline in Id1 levels is associated with the progression to a progenitor-like cell type in which the bHLH marker Olig2 becomes highly expressed. Since the discovery of stem-like and progenitor-like cell populations within high-grade gliomas, there has been a great deal of interest in elucidating their contributions to tumorigenesis. However, analyses are complicated by the lack of reliable marker sets to definitively isolate and characterize these distinct cell lineages. Using a genetically relevant mouse model of high-grade proneural glioma, we show that high Id1 expression (Id1high) identifies self-renewing, multipotent tumor cells, while low Id1 expression (Id1low) identifies progenitor-like cells characterized by Olig2 expression and limited self-renewal capacity, thus recapitulating what is observed in the normal neurogenic niche. Id1high cells generate tumors upon orthotopic transplantation, but surprisingly, Id1low cells do so with shorter latency and higher penetrance, despite their limited self-renewal capacity. Both Id1high and Id1low cells generate tumors with high-grade features and histopathology similar to the parental tumors. Purified Id1high cells give rise to Id1low cells during tumor formation thereby possibly fueling the generation of the more tumorigenic progenitor-like population. Targeting the more progenitor-like cells via knockdown of Olig2 results in a dramatic survival benefit. These data highlight an important distinction between self-renewal capacity and tumor initiation potential, underscoring the importance of non-stem cell lineages in brain tumor disease progression.

Citation Format: Lindy Elise Barrett, Hyung-song Nam, Robert Benezra. Understanding the role of stem-like tumor cells in proneural glioma. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN07-01.
Abstract CN07-02: Targeting tumor-initiating cells in medulloblastoma
Authors: Markant Shirley , Esparza Lourdes Adriana , Barton Kelly , Sun Jesse , Wechsler-Reya Robert
Published: January 2014

The growth of many tumors has been suggested to depend on a subset of tumor cells with an extensive capacity for self-renewal, termed cancer stem cells or tumor-initiating cells (TICs). These cells are not necessarily abundant or proliferative, but because they are long-lived and often resistant to conventional therapies, they are thought to contribute to tumor resistance and recurrence. Therefore, identifying these cells and finding approaches to targeting them has become an important goal in cancer research. We recently identified a population of TICs in a mouse model of medulloblastoma, the most common malignant brain tumor in children. These cells, marked by expression of the cell surface antigen CD15, are capable of propagating tumors following transplantation, whereas CD15– cells from the same donors cannot. To gain insight into the molecular mechanisms underlying the increased tumorigenic potential of CD15+ cells, we compared their gene expression profile to that of CD15– cells. Among the genes most consistently elevated in CD15+ cells were regulators of the G2/M phases of the cell cycle. This observation led us to hypothesize that CD15+ cells display altered cell cycle regulation, and that these cells might be particularly vulnerable to inhibitors of cell cycle progression. Here we show that CD15+ cells move more quickly through the G1 and S phases of the cell cycle, and as a result contain an increased proportion of cells in G2/M. Consistent with this cell cycle skewing, CD15+ cells express higher levels of the G2/M regulators Aurora Kinase (Aurk) and Polo-like Kinase (Plk). Treatment of tumor cells with small molecule antagonists of Aurk or Plk inhibits cell cycle progression, promotes apoptosis and enhances sensitivity to other modes of chemotherapy. Treatment of tumor-bearing mice with these agents also significantly inhibits tumor progression. Importantly, cells from medulloblastoma patient-derived xenografts are also sensitive to Aurk and Plk inhibitors. These findings suggest that inhibitors of Aurk and Plk may be useful for targeting TICs and may represent a novel avenue for therapy of human medulloblastoma.

Citation Format: Shirley Markant, Lourdes Adriana Esparza, Kelly Barton, Jesse Sun, Robert Wechsler-Reya,. Targeting tumor-initiating cells in medulloblastoma. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN07-02.
Abstract CN08-01: Computerized approaches to molecularly-designed drugs and target identification for cancer prevention
Authors: Dong Zigang
Published: January 2014

In the post-genomic era, computational modeling, simulations and genomics play a critical role in the next revolution in cancer research. Computational biology is an interdisciplinary field that uses the techniques of computer science, applied mathematics, and statistics to address problems in biology. The supercomputer is widely used in computational biology. We have applied supercomputers in cancer prevention research and have made progress in the following areas:

1) Mapping protein interaction networks in cancer cells (e.g., to study protein kinase interactions with other protein kinases, transcription factors, or other proteins)

2) Computational screening of chemical libraries against target proteins, identification of available chemical libraries (NCI; natural compounds, etc.), crystal structures or homology screening

3) Reverse docking and screening of protein structures against a chemical to identify its molecular target(s)

4) Drug target discovery by supercomputer and in vitro and in vivo validation of computer-identified potential targets using:

a) kinase assays

b) site mutagenesis

c) animal studies

5) Identifying key protein/DNA interactions

6) Modeling cancer promotion and progression in order to study cancer promotion, progression, and therapeutic effectiveness to predict success (i.e. predicting drug resistance)

Citation Format: Zigang Dong. Computerized approaches to molecularly designed drugs and target identification for cancer prevention. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN08-01.
Abstract CN08-02: New strategies for cancer chemoprevention
Authors: Steele Vernon E.
Published: January 2014

Chemoprevention research in animals and humans has revealed that pathways in the cancer process are amenable to inhibition, reversal or retardation at various stages. We must therefore identify the key pathways in the evolution of cancer that can be blocked to prevent this carcinogenesis process. Current mechanistic approaches include administering agents which block the activation of carcinogens, promote the detoxification of carcinogens (Phase II enzyme inducers), enhance glutathione, block the production of reactive oxygen species, antioxidants, inhibit carcinogen uptake, promote repair processes, and block cell cycle progression. Some of the more promising strategies to prevent breast cancer include selective estrogen receptor antagonists and aromatase inhibitors, while for colon, skin and urinary bladder NSAIDs and polyamine synthesis inhibitors are highly preventive. Many of these strategies have been validated in human cancer prevention studies. Retinoids are differentiation and apoptosis inducers primarily, but act as agonists to the RAR and RXR receptors with many downstream effects. Newer safer rexinoids can prevent both ER positive and ER negative breast cancers. Targeted mechanistic approaches are currently being investigated, such as inhibition of lipoxygenase, PI3K/AKT/mTOR pathway inhibitors, EGF receptor tyrosine kinase inhibitors, histone acetylation/deacetylation and methylation/demethylation inhibitors. Most recently immunoprevention approaches have shown exciting promise and are being developed into the clinic. Future strategies include possible miRNA or antisense miRNA administration to prevent cancers. To conquer this diverse disease, multiple key pathways must be attacked at once for a predetermined period of time. It is becoming clear that each organ-specific cancer type may require a custom combination of prevention strategies to be successful.

Citation Format: Vernon E. Steele. New strategies for cancer chemoprevention. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN08-02.
Abstract CN08-04: Novel Gemini vitamin D compounds for prevention of breast cancer by targeting stem cells
Authors: Suh Nanjoo
Published: January 2014

Identification and characterization of cancer stem cells in cancer development offers a new promising strategy in cancer prevention. Targeting cancer stem cells by novel cancer preventive agents may provide a new approach to blocking the progression of premalignant tumors into invasive cancer. CD44, a transmembrane glycoprotein, is a major receptor for extracellular proteins involved in invasion and metastasis of human cancers. CD44 has been recognized as one of the key cell surface markers for tumor-initiating cells in breast cancer. Our laboratory has demonstrated that the novel Gemini vitamin D analog BXL0124 [1α,25-dihydroxy-20R-21(3-hydroxy-3-deuteromethyl-4,4,4-trideuterobutyl)-23-yne-26,27-hexafluro-cholecalciferol] represses CD44 expression in MCF10DCIS.com basal-like human breast cancer cells and inhibits MCF10DCIS xenograft tumor growth. We have investigated potential factors downstream of CD44 and the biological role of CD44 repression by BXL0124 in MCF10DCIS cells. CD44 forms a complex with STAT3 and Janus kinase 2 (JAK2) to activate STAT3 signaling, which was inhibited by BXL0124 in MCF10DCIS cells. The knockdown of CD44 by small hairpin RNA significantly decreased mRNA expression levels of invasion markers in MCF10DCIS cells and decreased tumor size and weight as well as invasion markers in MCF10DCIS xenograft tumors. Repression of CD44-STAT3 signaling by the Gemini vitamin D analog BXL0124 appears to be a key molecular mechanism in the inhibition of breast cancer invasion. Identification of new targets and pathways in specific populations of cancer stem cells, such as those expressing CD44, may open a new direction in cancer prevention research. (Supported by NIH grant R01 CA127645).

Citation Format: Nanjoo Suh. Novel Gemini vitamin D compounds for prevention of breast cancer by targeting stem cells. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN08-04.
Abstract ED01-01: Report card for chemoprevention trials: The good, the bad and the ugly-How can we do better?
Authors: Lee J. Jack
Published: January 2014

There is no quarrel that prevention is preferable for fighting cancer compared to treating the disease in a late stage. Prevention studies, however, can be difficult and challenging to design and to conduct due to the low incidence rate, long process of cancer development, large sample size, extended study duration, cost, and the requirement of well tolerated or little toxicity of the chemopreventive agents. In the past 30 years, much effort has been devoted to chemoprevention in breast, colon, head/neck, lung, skin, and prostate cancers, etc. An overview of the successes and failures of the chemoprevention trials will be given. In order to do better, we must make improvements in the following areas: (1) Identify high risk individuals. Individual cancer risk models are available in breast and lung cancers for example but need to be refined. (2) Focus on subjects with premalignant lesions or intra-epithelial neoplasm as they are ideal candidates for prevention trials. (3) Identify subjects with molecular targets. For targeted agent trials, selecting subjects most likely to respond based on the agent's mechanism of action can dramatically increase the study efficiency. (4) Identify and validate the intermediate or surrogate endpoints for cancer development. (5) Apply efficient and flexible designs such that correct answers can be reached with a smaller number of patients in a shorter period of time. Adaptive randomization can also allow more subjects to be treated with better treatments in the trial based on cumulative information. (6) Balance the risk benefit ratio. It is evident that all treatments come with certain side effects. Seeking favorable efficacy and toxicity tradeoff is critically important for developing successful prevention strategies. More effective chemoprevention studies can be designed and implemented through the lessons learned.

Citation Format: J. Jack Lee. Report card for chemoprevention trials: The good, the bad and the ugly: How can we do better? [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr ED01-01.
Abstract ED03-02: Biomarker statistical design
Authors: Feng Ziding
Published: January 2014

Many cancer biomarkers were put into clinical use without a proper sequence of “level of evidence” evaluation (e.g., PSA for prostate cancer screening). Furthermore, most cancer biomarkers failed on their journey to clinic use. False positive findings are rampant. Better strategies are necessary for structured phase of development parallel to the phases for drug development, and rigorous study design standards to enhance the chance of producing biomarkers with clinical utility.

As the Coordinating Center for the Early Detection Research Network (EDRN), we have proposed a 5-phase biomarker development guideline and PRoBE study design standards to address the above issues. The key elements of PRoBE principles are: (i) the Clinical Context; (ii) Performance Criteria; (iii) the Biomarker test; and (iv) Study power and termination.

Two EDRN liver cancer biomarker validation studies, a completed Phase-2 and an on-going Phase-3, were used to illustrate how these concepts can guide a more structured and systematically development of cancer biomarkers with clinical goal in mind. The Phase-2 study identified promising candidate biomarkers and produced a specimen reference set to systematically evaluate new biomarkers. The Phase-3 study is set to address the clinical question of using biomarkers to improve the early detection of HCC and to reduce unnecessary CT/MRI for patients with liver cirrhosis.

Citation Format: Ziding Feng. Biomarker statistical design. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr ED03-02.
Abstract ED04-01: Defining and monitoring microbial networks
Authors: Braun Jonathan
Published: January 2014

The composition and function of the microbiome is emerging as a susceptibility factor affecting the tumor microenvironment locally and systemically. However, the high complexity and low inter-individual overlap of intestinal microbial composition are formidable barriers to identifying microbial taxa contributing to disease susceptibility. These difficulties might be overcome by an ecologic analytic strategy to identify modules of interacting bacteria (rather than individual bacteria) as quantitative reproducible features of microbial composition in normal and IBD mucosa. Using co-occurrence and network analysis of the intestinal mucosal bacterial microbiome, we have uncovered 5 microbial modules, each detectable in all individuals, and two modules were associated with colorectal susceptibility states such as inflammatory bowel disease. Network analysis of mucosal metabolites and proteins indicates that each microbial module is associated with a distinct functional mucosal community, which can be directly visualized forming a microgeographic distribution at the mucosal surface. Systemic products produced by certain mucosal functional communities also induce remote genotoxicity associated with lymphoma formation in susceptible individuals. Microbial modules thus provide an integrative view of microbial ecology relevant to cancer, and permit quantitative and reproducible microbial monitoring by minimally-invasive sampling of the readily accessible rectal mucosa.

Citation Format: Jonathan Braun. Defining and monitoring microbial networks. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr ED04-01.
Abstract ED05-01: Diet, physical activity and the prevention of obesity-related breast cancer: Lessons learned from transdisciplinary research
Authors: Hursting Stephen D.
Published: January 2014

Randomized clinical trials, observational epidemiologic studies, behavioral intervention studies, and basic animal and cellular/molecular research have complementary and synergistic roles in advancing knowledge on food, nutrition, physical activity and cancer prevention. In most cases, a single study (of any type) is unlikely to provide sufficient evidence of causal associations, and the entire available body of data from various perspectives and disciplines is necessary to provide the best evidence for the relationship between a dietary factor and cancer risk. One way to accelerate research progress in this area is to form transdisciplinary teams to approach a research problem on a multilevel basis. As but one example, the convergence of evidence supporting obesity and obesity-related biomarkers as risk factors for cancer, based on both human and animal studies, supports the recommendations from multiple agencies that persons “be as lean as possible, within the normal range of body weight”. However, with nearly 7 in 10 US adults currently at an unhealthy weight, and given the established associations between excess weight and many cancers s well as the difficulty many have in losing weight, new evidence-based targets and strategies are necessary to break obesity-cancer links. This presentation will discuss lessons learned from a transdiciplinary approach that bridges animal model and mechanistic studies with randomized breast cancer prevention trials.

Citation Format: Stephen D. Hursting. Diet, physical activity, and the prevention of obesity-related breast cancer: Lessons learned from transdisciplinary research. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr ED05-01.
Abstract FO02-02: What are the hurdles for moving approved drugs into the prevention setting?
Authors: Munster Pamela N.
Published: January 2014

Most anticancer agents are initially tested in patients with metastatic disease. Early dose finding studies evaluate the tolerability and safety of such agents, and the recommended Phase II dose is most commonly derived from toxicity assessments in the first 3-6 weeks of treatment. An acceptable maximally tolerated dose allows dose-limiting toxicities in at least one of 6 patients or <33% of the treated patients. Dose limiting toxicities are typically defined as grade 3 non-hematological toxicities and grade 4 hematological toxicities occurring in the first 3-4 weeks of treatment. Hence, most agents that receive approval from trials in metastatic patients are derived from studies with a relatively short exposure time and allow a considerable negative impact on quality of life. Similarly, novel anti-cancer agents that are tested and approved in the adjuvant setting are usually administered for a limited time span. Cytotoxic agents have therefore rarely been considered as chemopreventive agents.

The emergence of more effective targeted agents or biologics are of great interest as potential chemoprevention agents.

However, the motivation of treatment adherence and the acceptance of severe side effects of agents is higher when treating metastatic disease or when preventing a recurrence after a diagnosis of limited stage disease. Many of the targeted agents and biologics are developed similar to cytotoxic agents based on the maximally tolerated dose rather than optimal biological dose.

In contrast, cancer prevention agents may have to be given over prolonged periods to patients who have an elevated risk of developing cancer solely based on genomic testing or population studies. The uncertainty of the individual risk and potential benefit has to be weight against toxicities and impact on quality of life. The acceptance of grade 3 and 4 toxicities in this population is very limited.

The use of a targeted or biologic agent originally approved for metastatic disease in the prevention setting, will require a reassessment of what are acceptable doses for long-term use based on lower grade toxicities. Furthermore, a more in depth understanding of the effective biological and molecular concentrations and the development of predictive biomarker will be paramount.

Citation Format: Pamela N. Munster. What are the hurdles for moving approved drugs into the prevention setting? [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr FO02-02.
Abstract PL01-01: The role of telomeres and telomerase in aging and cancer
Authors: Shay Jerry W.
Published: January 2014

One of the fundamental differences in the behavior of human normal versus tumor cells is that most normal cells divide for a limited number of times (Hayflick Limit) whereas tumor cells can proliferate indefinitely (one of the hallmarks of cancer). It is widely believed that the biological function of cellular aging (senescence) is to serve as a mechanism for restricting cancer progression. It is now established that almost all advanced cancers express telomerase, and this provides the molecular mechanism for the bypass of both telomere-associated senescence. The following topics/questions will be discussed in this lecture.

1. Evidence that the telomere-based mechanism of cellular aging in human cells has held the test of time

2. The role of telomerase in bypassing telomere-based replicative senescence proves that the growth arrest of human cells with critically short telomeres is a key molecular basis of human cell aging

3. Progress in using telomerase inhibitors in targeting cancer

4. Development of accurate methods to quantitatively measure the shortest telomeres

5. Methods for safely using telomerase or telomerase activators for identifying and treating telomere diseases associated with aging?

Goals and Objectives

1. To review the evidence that telomeres are a biomarker that is important in human aging and cancer.

2. To review the evidence that introduction of telomerase into normal cells does not lead to an increased risk of cancer and inhibition of telomerase can lead to cancer cell death

3. To review human diseases associated with telomere dysfunction and approaches to identifying and treating telomeropathies

Citation Format: Jerry W. Shay. The role of telomeres and telomerase in aging and cancer. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr PL01-01.
Abstract PL02-02: Helicobacter gastritis, metaplasia, and gastric cancer
Authors: Merchant Juanita L.
Published: January 2014

Helicobacter pylori is one of the primary reasons that the gastric epithelium becomes chronically inflamed. As with other epithelial tissues, chronic inflammation can lead to hyperproliferation, metaplasia and eventually gastric cancer. The hedgehog (Hh) pathway is required for embryonic development including development of the gastrointestinal tract. In the pancreas, Hh signaling is extinguished after birth but becomes re-activated by chronic inflammation and when sustained contributes to pancreatic cancer. However, the contribution of Hh signaling in gastric cancer has been less clear. Components of the Hh pathway are elevated in human gastric cancer cell lines, and on this basis, its contribution to gastric cancers have been implicated. Unlike the pancreas, the gastric corpus produces abundant amounts of the Sonic Hedgehog (Shh) ligand. Recent studies have indicated that Shh expressed in the acid-producing parietal cells is required to recruit myeloid cells to the stomach during the initial phase of a Helicobacter infection. We will present evidence showing that the canonical Hh target gene Gli1 is required for the Helicobacter-induced inflammatory response as well as the subsequent development of mucous cell metaplasia, a pre-neoplastic lesion in the stomach.

Citation Format: Juanita L. Merchant. Helicobacter gastritis, metaplasia, and gastric cancer. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr PL02-02.