bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Trials and Tribulations of Interrogating Biomarkers to Define Efficacy of Cancer Risk Reductive Interventions
Authors: Brenner Dean E. , Hawk Ernest
Published: March 2024

Abstract
The challenges of clinical screening of cancer risk reductive interventions (“chemopreventive”) have slowed progress in deployment of therapeutics to reverse or delay the carcinogenesis process. The preoperative or window-of-opportunity design clinical trial design enrolls subjects rapidly, has short study periods, and quantifies tissue biomarkers that reflect both anti-carcinogenesis mechanism of the risk reductive intervention and key molecular events of the carcinogenesis process for a specific epithelial target. High subject screened to on study ratios reduce the efficiency and increase cost of this research strategy. Small-sized tissue samples obtained by minimally invasive endoscopic technologies limit the number of biomarkers that can be detected and quantified, forcing investigators into choosing either a broad-based but superficial multi-mechanism exploration of signaling intermediates or a more focused analysis of multiple molecular events in a linear signaling-specific pathway. More efficient strategies of the future might involve isolation and expansion of pluripotent cells from at-risk epithelium or intraepithelial neoplastic lesions. Such a strategy would allow interrogation of key carcinogenesis-associated pathways and mechanisms in representative primary single-cell cultures amenable to genomic, proteomics, or transfection-based technologies. Cancer Prev Res; 6(2); 71–3. ©2013 AACR.
Data from Chemoprevention of Pancreatic Cancer: Ready for the Clinic?
Authors: Logsdon Craig D. , Abbruzzese James L.
Published: March 2024

Abstract
Advances in our molecular, clinical, and epidemiologic understanding of the risk and development of pancreatic cancer offer hope for preventing this disease, which is largely intractable once developed. This perspective on provocative, genetically engineered mouse model work reported by Mohammed et al. (beginning on page 1417 in this issue of the journal) examines the prospects for pancreatic cancer chemoprevention with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). Despite having limited value in advanced pancreatic cancer, EGFR TKIs show promise in the setting of early pancreatic carcinogenesis. Cancer Prev Res; 3(11); 1375–8. ©2010 AACR.
Data from The Origins and Implications of Intratumor Heterogeneity
Authors: Michor Franziska , Polyak Kornelia
Published: March 2024

Abstract
Human tumors often display startling intratumor heterogeneity in various features including histology, gene expression, genotype, and metastatic and proliferative potential. This phenotypic and genetic heterogeneity plays an important role in neoplasia, cancer progression, and therapeutic resistance. In this issue of the journal (beginning on page 1388), Merlo et al. report their use of molecular data from 239 patients with Barrett's esophagus to evaluate the propensity of major diversity indices for predicting progression to esophageal adenocarcinoma. This work helps elucidate the implications of molecular heterogeneity for the evolution of neoplasia. Cancer Prev Res; 3(11); 1361–4. ©2010 AACR.
Data from Prevention of Colitis-Associated Colorectal Cancer with 8-Hydroxydeoxyguanosine
Authors: Ock Chan Young , Kim Eun-Hee , Hong Hua , Hong Kyung Sook , Han Young-Min , Choi Ki-Seok , Hahm Ki-Baik , Chung Myung-Hee
Published: March 2024

Abstract
Colitis-associated cancer (CAC) is one of clear examples of inflammation–carcinogenesis sequence, by which the strict control of colitis with potent anti-inflammatory or antioxidative agent offers the chance of cancer prevention. Supported with the facts that Rac1 binds and activates STAT3, which are significantly upregulated in inflammatory bowel disease (IBD) as well as CAC, but 8-hydroxydeoxyguanosine (8-oxo-7,8-dihydrodeoxyguanosine or 8-OHdG) paradoxically can block Rac1 activation and subsequent NADPH oxidase (NOX) inactivation in various inflammation models, we hypothesized that attenuated Rac1–STAT3 and COX–NF-κB pathway by exogenous 8-OHdG administration may ameliorate inflammatory signaling in dextran sodium sulfate (DSS)-induced colitis and can prevent CAC. Before commencing carcinogenesis model, we checked whether exogenous 8-OHdG can alleviate IBD, for which interleukin (IL)-10 knockout mice were designed to ingest 5% DSS for 1 week, and 8-OHdG is given through intraperitoneal route daily. 8-OHdG treatment groups significantly reduced pathologic grade of DSS-induced colitis as well as various inflammatory mediators such as TNF-α, IL-6, COX-2, and iNOS in a dose-dependent manner. To document the cancer prevention effects of 8-OHdG, mice were injected azoxymethane followed by drinking 2.5% DSS for 1 week, after which 8-OHdG–containing diets were given for 20 weeks. As results, mice that consumed 8-OHdG–containing diet significantly reduced both tumor incidence and multiplicity. Rac1 activity and phosphorylated STAT3 level were significantly attenuated in the 8-OHdG–treated group. Significantly decreased levels of malondialdehyde, monocyte chemotactic protein-1, matrix metalloproteinasess, COX-2, NOX4, and β-catenin nuclear accumulation were responsible for cancer prevention effects of exogenous 8-OHdG. In conclusion, we clearly showed cancer-preventive effect of exogenous 8-OHdG against CAC. Cancer Prev Res; 4(9); 1507–21. ©2011 AACR.
Data from Emergence of HPV16-Positive Oropharyngeal Cancer in Black Patients Over Time: University of Maryland 1992–2007
Authors: Zandberg Dan P. , Liu Sandy , Goloubeva Olga G. , Schumaker Lisa M. , Cullen Kevin J.
Published: March 2024

Abstract
While we previously reported a striking racial difference in the prevalence of human papilloma virus (HPV)–positive squamous cell carcinoma of the oropharynx (OPSCC), less is known about differences in outcomes and trends over time in OPSCC by HPV status and race. We conducted a retrospective analysis of 467 patients with OPSCC treated at the University of Maryland Greenebaum Cancer Center (Baltimore, MD) between 1992 and 2007, of which 200 had tissue available for HPV16 testing. HPV16-positive patients were significantly more likely to be white, with 45.5% of whites and 15.5% of blacks testing positive for HPV16. There was a significant increase in HPV16-positive OPSCC for all patients over time from 15.6% in 1992 to 1995 to 43.3% in 2004 to 2007 (P = 0.01). From 1992 to 1995, 33% of white patients were HPV16-positive, with no black patients positive. From 2004 to 2007, 17.7% of black patients and 54% of white patients were HPV16-positive. White and black patients with HPV16-positive tumors had an identical and favorable overall survival (OS; median, 8.1 and 8.1 years, respectively). However, among HPV16-negative patients, whites had an improved OS compared with blacks (median, 2.3 vs. 0.9 years, respectively; P = 0.02), including when analyzed in a multivariable Cox regression model. From 1992 to 2007, the percentage of HPV16-positive OPSCC increased for white patients and was seen for the first time in black patients. While survival for HPV-positive black and white patients was similar and favorable, outcomes for HPV-negative patients were poor, with blacks having worse survival even after controlling for baseline characteristics.Cancer Prev Res; 8(1); 12–19. ©2014 AACR.

See related article by E. Cohen and C. Fakhry, p. 9
Data from microRNA Portraits in Human Vulvar Carcinoma
Authors: de Melo Maia Beatriz , Lavorato-Rocha André Mourão , Rodrigues Lara Sant'Ana , Coutinho-Camillo Cláudia Malheiros , Baiocchi Glauco , Stiepcich Monica Maria , Puga Renato , de A. Lima Leandro , Soares Fernando Augusto , Rocha Rafael Malagoli
Published: March 2024

Abstract
Unregulated expression of microRNAs is well known and has already been demonstrated in many tumor types. However, in vulvar carcinoma this field has been unknown territory. Our study characterizes microRNA in vulvar tumors through an expression profile of 754 miRNAs, relating this with clinical and anatomopathologic data, and presence of HPV infection. Twenty HPV-negative and 20 HPV-positive samples, genotyped for high-risk HPVs (HPV16, 18, 31, 33) and a pool of seven normal vulvar skin samples were used for the identification of differentially expressed miRNAs by TLDA Quantitative Real Time PCR (qRT-PCR). Twenty-five differentially expressed microRNAs between HPV-positive and HPV-negative groups and 79 differentially expressed on the tumor compared with normal samples were obtained. A network between microRNA expression profiles and putative target mRNAs predicted by target prediction algorithms and previously demonstrated as relevant in vulvar carcinomas, such as TP53, RB, PTEN, and EGFR was constructed. Downregulation of both miR-223-5p and miR-19-b1-5p were correlated with the presence of lymph node metastasis; downregulation of miR-100-3p and miR-19-b1-5p were correlated with presence of vascular invasion; overexpression of miR-519b and miR-133a were associated with advanced FIGO staging. In conclusion, our study demonstrates that microRNAs may be clinically important in vulvar carcinomas and our findings may help for further studies on functional implications of miRNA deregulation in this type of cancer. Cancer Prev Res; 6(11); 1231–41. ©2013 AACR.
Data from Adaptor Proteins as Targets for Cancer Prevention
Authors: Yee Douglas
Published: March 2024

Abstract
This perspective on the report by McCampbell et al. in this issue of the journal (beginning on page 290) addresses the role of insulin receptor substrate (IRS) proteins in cancer progression. The IRS proteins link many cell-surface receptors to signal transduction pathways. Activation of the phosphoinositide-3 kinase/Akt/mammalian target of rapamycin axis normally results in serine phosphorylation and subsequent downregulation of these adaptor proteins. The authors show that changes in the negative feedback regulation of IRS proteins is associated with the progression of endometrial epithelial cells to hyperplasia and cancer. Therefore, understanding the function of adaptor proteins could provide additional strategies for cancer prevention and treatment. Cancer Prev Res; 3(3); 263–5
Data from Anthropometric Measures, Physical Activity, and Risk of Glioma and Meningioma in a Large Prospective Cohort Study
Authors: Michaud Dominique S. , Bové Gerald , Gallo Valentina , Schlehofer Brigitte , Tjønneland Anne , Olsen Anja , Overvad Kim , Dahm Christina C. , Teucher Brigit , Boeing Heiner , Steffen Annika , Trichopoulou Antonia , Bamia Christina , Kyrozis Andreas , Sacerdote Carlotta , Agnoli Claudia , Palli Domenico , Tumino Rosario , Mattiello Amalia , Bueno-de-Mesquita H. Bas , Peeters Petra H. M. , May Anne M. , Barricarte Aurelio , Chirlaque Maria-Dolores , Dorronsoro Miren , José Sánchez Maria , Rodríguez Laudina , Duell Eric J. , Hallmans Göran , Melin Beatrice S. , Manjer Jonas , Borgquist Signe , Khaw Kay-Tee , Wareham Nick , Allen Naomi E. , Travis Ruth C. , Romieu Isabelle , Vineis Paolo , Riboli Elio
Published: March 2024

Abstract
Body fatness has been associated with increased risk of a number of hormone-dependent cancers. Recent studies suggest that body mass index (BMI) may be related to meningiomas, which are more common in women than men, and for which estrogens are believed to play a role. Using data from a large European propective cohort, 203 incident cases of meningioma and 340 cases of glioma were included in the analysis for measures of body fat, height, and physical activity among 380,775 participants. All analyses were conducted using Cox proportional hazards model and controlling for age, sex, country, and education. A 71% increase in risk of meningioma was observed among men and women in the top quartile of waist circumference (HR = 1.71, 95% CI = 1.08–2.73, Ptrend = 0.01). A positive association was also observed for BMI and meningioma (HR = 1.48, 95% CI = 0.98–2.23, for BMI ≥30 compared with a BMI of 20–24.9, Ptrend = 0.05). An association with height and meningioma was also suggestive (HR = 1.24, 95% 0.96–1.51, for each 10 cm increase). In contrast, no associations were observed for height and different measures of body fat and risk of glioma. Physical activity was not related to either type of brain tumors. Results from this study support an increase in risk of meningioma with higher body fatness among both men and women. No association was observed between anthropometric measures and risk of glioma. Cancer Prev Res; 4(9); 1385–92. ©2011 AACR.
Data from The Sine Qua Non of Discovering Novel Biomarkers for Early Detection of Ovarian Cancer: Carefully Selected Preclinical Samples
Authors: Jacobs Ian , Menon Usha
Published: March 2024

Abstract
This perspective discusses reports by Cramer and colleagues (beginning on page 365 in this issue of the journal) and Zhu and colleagues (beginning on page 375), which provide the first systematic and reliable comparison of a large number of candidate biomarkers for the early detection of ovarian cancer in a sample set well-suited for this purpose. This research has important implications for the future design of cancer biomarker studies. Cancer Prev Res; 4(3); 299–302. ©2011 AACR.
Data from Chemoprevention of Endometrial Cancer in Lynch Syndrome: A Step Forward
Authors: Stoffel Elena M. , Walsh Christine
Published: March 2024

Abstract
Lynch syndrome is one of the most common hereditary cancer syndromes. Although Lynch syndrome is associated with increased risk for developing colorectal, endometrial, and other cancers specialized screening, risk-reducing surgery, and chemoprevention offer promise for reducing morbidity and mortality. Frequent colonoscopic surveillance has proven effective for early detection and prevention of Lynch syndrome-associated colorectal cancer; however, the optimal strategy for managing endometrial cancer risks in women with germline mutations in DNA mismatch repair genes has yet to be determined. In this issue of Cancer Prevention Research, Lu and colleagues report their findings of a phase II prospective, multicenter randomized trial comparing the effects of oral contraceptive pills and Depo-Provera on endometrial proliferation in women with Lynch syndrome. Although short-term hormonal treatment with either modality altered endometrial proliferation indices, it remains unknown whether hormonal suppression actually reduces endometrial cancer risk in women with Lynch syndrome. This trial represents the first of its kind in evaluating agents which might offer protection against Lynch syndrome-associated endometrial cancer and provides preliminary data regarding potential biomarkers for early detection of endometrial neoplasia. The investigators' experience with this trial also offers insights regarding the various technical and scientific challenges inherent in chemoprevention research. Cancer Prev Res; 6(8); 755–9. ©2013 AACR.
Data from Chemoprevention of Squamous Cell Carcinoma of the Head and Neck: No Time to Lose Momentum
Authors: Wirth Lori J.
Published: March 2024

Abstract
The prospects for chemoprevention to reduce the incidence of squamous cell carcinoma of the head and neck (SCCHN) are great. The tissue at risk for harboring disease is relatively accessible for examination and biopsy. Patients appropriate for study can be easily identified by their risk factors and the presence of premalignant lesions. Our understanding of the pathogenesis of SCCHN is ever increasing, and offers new opportunities to explore strategies for prevention therapies. In this issue of Cancer Prevention Research, Saba and colleagues report on a phase Ib trial of celecoxib plus erlotinib to prevent progression to higher-grade dysplasia or invasive carcinoma in patients with oral premalignant lesions. The overall response rate was 57%, though by the time of last analysis, 85% of patients relapsed. In this commentary, challenges to the success of chemoprevention clinical trials for SCCHN, such as pitfalls in using surrogate biomarkers and reversal of histologic premalignant changes as study endpoints, are discussed. In addition, strategies to help ensure further development in the field of head and neck cancer prevention are reviewed. These include focusing efforts on tobacco cessation and human papillomavirus vaccination, targeting key molecular drivers of head and neck carcinogenesis, and focusing on combination strategies that have the potential to eradicate premalignant clones, even if some toxicity is encountered. Cancer Prev Res; 7(3); 279–82. ©2014 AACR.
Data from Esculetin Suppresses Proliferation of Human Colon Cancer Cells by Directly Targeting β-Catenin
Authors: Lee Sung-Young , Lim Tae-Gyu , Chen Hanyong , Jung Sung Keun , Lee Hyo-Jeong , Lee Mee-Hyun , Kim Dong Joon , Shin Aram , Lee Ki Won , Bode Ann M. , Surh Young-Joon , Dong Zigang
Published: March 2024

Abstract
The Wnt pathway is a promising therapeutic and preventive target in various human cancers. The transcriptional complex of β-catenin–T-cell factor (Tcf), a key mediator of canonical Wnt signaling, has been implicated in human colon cancer development. Current treatment of colon cancer depends on traditional cytotoxic agents with limited effects. Therefore, the identification of natural compounds that can disrupt the β-catenin–TcF complex to suppress cancer cell growth with fewer adverse side effects is needed. To identify compounds that inhibit the association between β-catenin and Tcf, we used computer docking to screen a natural compound library. Esculetin, also known as 6,7-dihydroxycoumarin, is a derivative of coumarin and was identified as a potential small-molecule inhibitor of the Wnt–β-catenin pathway. We then evaluated the effect of esculetin on the growth of various human colon cancer cell lines and its effect on Wnt–β-catenin signaling in cells and in an embryonic model. Esculetin disrupted the formation of the β-catenin–Tcf complex through direct binding with the Lys312, Gly307, Lys345, and Asn387 residues of β-catenin in colon cancer cells. In addition, esculetin effectively decreased viability and inhibited anchorage-independent growth of colon cancer cells. Esculetin potently antagonized the cellular effects of β-catenin–dependent activity, and in vivo treatment with esculetin suppressed tumor growth in a colon cancer xenograft mouse model. Our data indicate that the interaction between esculetin and β-catenin inhibits the formation of the β-catenin–Tcf complex, which could contribute to esculetin's positive therapeutic and preventive effects against colon carcinogenesis. Cancer Prev Res; 6(12); 1356–64. ©2013 AACR.
Data from Inhibition of Lung Tumorigenesis by Metformin Is Associated with Decreased Plasma IGF-I and Diminished Receptor Tyrosine Kinase Signaling
Authors: Quinn Brendan J. , Dallos Matthew , Kitagawa Hiroshi , Kunnumakkara Ajaikumar B. , Memmott Regan M. , Hollander M. Christine , Gills Joell J. , Dennis Phillip A.
Published: March 2024

Abstract
Metformin is the most commonly prescribed drug for type II diabetes and is associated with decreased cancer risk. Previously, we showed that metformin prevented tobacco carcinogen (NNK)–induced lung tumorigenesis in a non-diabetic mouse model, which was associated with decreased IGF-I/insulin receptor signaling but not activation of AMPK in lung tissues, as well as decreased circulating levels of IGF-I and insulin. Here, we used liver IGF-I–deficient (LID) mice to determine the importance of IGF-I in NNK-induced lung tumorigenesis and chemoprevention by metformin. LID mice had decreased lung tumor multiplicity and burden compared with wild-type (WT) mice. Metformin further decreased lung tumorigenesis in LID mice without affecting IGF-I levels, suggesting that metformin can act through IGF-I–independent mechanisms. In lung tissues, metformin decreased phosphorylation of multiple receptor tyrosine kinases (RTK) as well as levels of GTP-bound Ras independently of AMPK. Metformin also diminished plasma levels of several cognate ligands for these RTKs. Tissue distribution studies using [14C]-metformin showed that uptake of metformin was high in liver but four-fold lower in lungs, suggesting that the suppression of RTK activation by metformin occurs predominantly via systemic, indirect effects. Systemic inhibition of circulating growth factors and local RTK signaling are new AMPK-independent mechanisms of action of metformin that could underlie its ability to prevent tobacco carcinogen–induced lung tumorigenesis. Cancer Prev Res; 6(8); 801–10. ©2013 AACR.
Data from Oral Contraceptives Decrease the Prevalence of Ovarian Cancer in the Hen
Authors: Treviño Lindsey S. , Buckles Elizabeth L. , Johnson Patricia A.
Published: March 2024

Abstract
Ovarian cancer is the leading cause of reproductive cancer death in U.S. women. This high mortality rate is due to the lack of early detection methods and ineffectiveness of therapy for advanced disease. Until more effective screening methods and therapies are developed, chemoprevention strategies are warranted. The hen has a high spontaneous prevalence of ovarian cancer and has been used as a model for studying ovarian cancer chemoprevention. In this study, we used the hen to determine the effect of progestin alone, estrogen alone, or progestin and estrogen in combination (as found in oral contraceptives) on ovarian cancer prevalence. We found that treatment with progestin alone and in combination with estrogen decreased the prevalence of ovarian cancer. A significant risk reduction of 91% was observed in the group treated with progestin alone (risk ratio = 0.0909; 95% CI: 0.0117–0.704) and an 81% reduction was observed in the group treated with progestin plus estrogen (risk ratio = 0.1916; 95% CI = 0.043–0.864). Egg production was also significantly reduced in these treatment groups compared with control. We found no effect of progestin, either alone or in combination with estrogen, on apoptosis or proliferation in the ovary, indicating that this is not the likely mechanism responsible for the protective effect of progestin in the hen. Our results support the use of oral contraceptives to prevent ovarian cancer and suggest that ovulation is related to the risk of ovarian cancer in hens and that other factors, such as hormones, more than likely modify this risk. Cancer Prev Res; 5(2); 343–9. ©2011 AACR.
Data from Mechanistic Contribution of Ubiquitous 15-Lipoxygenase-1 Expression Loss in Cancer Cells to Terminal Cell Differentiation Evasion
Authors: Moussalli Micheline J. , Wu Yuanqing , Zuo Xiangsheng , Yang Xiu L. , Wistuba Ignacio Ivan , Raso Maria G. , Morris Jeffrey S. , Bowser Jessica L. , Minna John D. , Lotan Reuben , Shureiqi Imad
Published: March 2024

Abstract
Loss of terminal cell differentiation promotes tumorigenesis. 15-Lipoxygenase-1 (15-LOX-1) contributes to terminal cell differentiation in normal cells. The mechanistic significance of 15-LOX-1 expression loss in human cancers to terminal cell differentiation suppression is unknown. In a screen of 128 cancer cell lines representing more than 20 types of human cancer, we found that 15-LOX-1 mRNA expression levels were markedly lower than levels in terminally differentiated cells. Relative expression levels of 15-LOX-1 (relative to the level in terminally differentiated primary normal human–derived bronchial epithelial cells) were lower in 79% of the screened cancer cell lines than relative expression levels of p16 (INK4A), which promotes terminal cell differentiation and is considered one of the most commonly lost tumor suppressor genes in cancer cells. 15-LOX-1 was expressed during terminal differentiation in three-dimensional air–liquid interface cultures, and 15-LOX-1 expression and terminal differentiation occurred in immortalized nontransformed bronchial epithelial but not in lung cancer cell lines. 15-LOX-1 expression levels were lower in human tumors than in paired normal lung epithelia. Short hairpin RNA–mediated downregulation of 15-LOX-1 in Caco-2 cells blocked enterocyte-like differentiation, disrupted tight junction formation, and blocked E-cadherin and ZO-1 localization to the cell wall membrane. 15-LOX-1 episomal expression in Caco-2 and HT-29 colon cancer cells induced differentiation. Our findings indicate that 15-LOX-1 downregulation in cancer cells is an important mechanism for terminal cell differentiation dysregulation and support the potential therapeutic utility of 15-LOX-1 reexpression to inhibit tumorigenesis. Cancer Prev Res; 4(12); 1961–72. ©2011 AACR.
Data from Curcumin Induces the Differentiation of Myeloid-Derived Suppressor Cells and Inhibits Their Interaction with Cancer Cells and Related Tumor Growth
Authors: Tu Shui Ping , Jin Huanyu , Shi Jin Dong , Zhu Li Ming , Suo Ya , Lu Gang , Liu Anna , Wang Timothy C. , Yang Chung S.
Published: March 2024

Abstract
Myeloid-derived suppressor cells (MDSC) accumulate in the spleen and tumors and contribute to tumor growth, angiogenesis, and progression. In this study, we examined the effects of curcumin on the activation and differentiation of MDSCs, their interaction with human cancer cells, and related tumor growth. Treatment with curcumin in the diet or by intraperitoneal injection significantly inhibited tumorigenicity and tumor growth, decreased the percentages of MDSCs in the spleen, blood, and tumor tissues, reduced interleukin (IL)-6 levels in the serum and tumor tissues in a human gastric cancer xenograft model and a mouse colon cancer allograft model. Curcumin treatment significantly inhibited cell proliferation and colony formation of cancer cells and decreased the secretion of murine IL-6 by MDSCs in a coculture system. Curcumin treatment inhibited the expansion of MDSCs, the activation of Stat3 and NF-κB in MDSCs, and the secretion of IL-6 by MDSCs, when MDSCs were cultured in the presence of IL-1β, or with cancer cell- or myofibroblast-conditioned medium. Furthermore, curcumin treatment polarized MDSCs toward a M1-like phenotype with an increased expression of CCR7 and decreased expression of dectin 1 in vivo and in vitro. Our results show that curcumin inhibits the accumulation of MDSCs and their interaction with cancer cells and induces the differentiation of MDSCs. The induction of MDSC differentiation and inhibition of the interaction of MDSCs with cancer cells are potential strategies for cancer prevention and therapy. Cancer Prev Res; 5(2); 205–15. ©2011 AACR.
Data from The Human Gut Microbiome as a Screening Tool for Colorectal Cancer
Authors: Zackular Joseph P. , Rogers Mary A.M. , Ruffin Mack T. , Schloss Patrick D.
Published: March 2024

Abstract
Recent studies have suggested that the gut microbiome may be an important factor in the development of colorectal cancer. Abnormalities in the gut microbiome have been reported in patients with colorectal cancer; however, this microbial community has not been explored as a potential screen for early-stage disease. We characterized the gut microbiome in patients from three clinical groups representing the stages of colorectal cancer development: healthy, adenoma, and carcinoma. Analysis of the gut microbiome from stool samples revealed both an enrichment and depletion of several bacterial populations associated with adenomas and carcinomas. Combined with known clinical risk factors of colorectal cancer (e.g., BMI, age, race), data from the gut microbiome significantly improved the ability to differentiate between healthy, adenoma, and carcinoma clinical groups relative to risk factors alone. Using Bayesian methods, we determined that using gut microbiome data as a screening tool improved the pretest to posttest probability of adenoma more than 50-fold. For example, the pretest probability in a 65-year-old was 0.17% and, after using the microbiome data, this increased to 10.67% (1 in 9 chance of having an adenoma). Taken together, the results of our study demonstrate the feasibility of using the composition of the gut microbiome to detect the presence of precancerous and cancerous lesions. Furthermore, these results support the need for more cross-sectional studies with diverse populations and linkage to other stool markers, dietary data, and personal health information. Cancer Prev Res; 7(11); 1112–21. ©2014 AACR.
Data from Lack of ABCG2 Shortens Latency of BRCA1-Deficient Mammary Tumors and This Is Not Affected by Genistein or Resveratrol
Authors: Zander Serge A.L. , Kersbergen Ariena , Sol Wendy , Gonggrijp Maaike , van de Wetering Koen , Jonkers Jos , Borst Piet , Rottenberg Sven
Published: March 2024

Abstract
In addition to their role in drug resistance, the ATP-binding cassette (ABC) transporters ABCG2 and ABCB1 have been suggested to protect cells from a broad range of substances that may foster tumorigenesis. Phytoestrogens or their metabolites are substrates of these transporters and the influence of these compounds on breast cancer development is controversial. Estrogen-like properties might accelerate tumorigenesis on the one hand, whereas their proposed health-protective properties might antagonize tumorigenesis on the other. To address this issue, we used a newer generation mouse model of BRCA1-mutated breast cancer and examined tumor latency in K14cre;Brca1F/F; p53F/F, Abcb1a/b−/−;K14cre;Brca1F/F; p53F/F, or Abcg2−/−;K14cre;Brca1F/F; p53F/F animals, fed with genistein- or resveratrol-supplemented diets. Ovariectomized K14cre;Brca1F/F; p53F/F animals were included to evaluate whether any estrogen-mimicking effects can restore mammary tumor development in the absence of endogenous estrogens. Compared with the ABC transporter proficient model, ABCG2-deficient animals showed a reduced median tumor latency of 17.5 days (P < 0.001), whereas no significant difference was observed for ABCB1-deficient animals. Neither genistein nor resveratrol altered this latency reduction in Abcg2−/−;K14cre;Brca1F/F; p53F/F animals. Ovariectomy resulted in nearly complete loss of mammary tumor development, which was not restored by genistein or resveratrol. Our results show that ABCG2 contributes to the protection of genetically instable epithelial cells against carcinogenesis. Diets containing high levels of genistein or resveratrol had no effect on mammary tumorigenesis, whether mice were lacking ABCG2 or not. Because genistein and resveratrol only delayed skin tumor development of ovariectomized animals, we conclude that these phytoestrogens are no effective modulators of mammary tumor development in our mouse model. Cancer Prev Res; 5(8); 1053–60. ©2012 AACR.
Data from Clinical Response to a Lapatinib-Based Therapy for a Li-Fraumeni Syndrome Patient with a Novel HER2V659E Mutation
Authors: Serra Violeta , Vivancos Ana , Puente Xose S. , Felip Enriqueta , Silberschmidt Daniel , Caratù Ginevra , Parra Josep-Lluís , De Mattos-Arruda Leticia , Grueso Judit , Hernández-Losa Javier , Arribas Joaquín , Prudkin Ludmila , Nuciforo Paolo , Scaltriti Maurizio , Seoane Joan , Baselga José
Published: March 2024

Abstract
Genomic characterization of recurrent breast and lung tumors developed over the course of 10 years in a 29-year-old patient with a germline TP53 mutation (Li-Fraumeni Syndrome) identified oncogenic alterations in the HER2 and EGFR genes across all tumors, including HER2 amplifications, an EGFR-exon 20 insertion, and the first-in-humans HER2V659E mutation showing a phenotypic convergent evolution toward HER2 and EGFR alterations. Following the identification of HER2-activating events in the most recent lung carcinoma and in circulating tumor cells, we treated the reminiscent metastatic lesions with a lapatinib-based therapy. A symptomatic and radiologic clinical response was achieved. HER2V659E sensitivity to lapatinib was confirmed in the laboratory.

Significance: The precise knowledge of the genomic alterations present in tumors is critical to selecting the optimal treatment for each patient. Here, we report the molecular characterization and clinical response to a lapatinib-based therapy for the tumors of a Li-Fraumeni patient showing prevalence of HER2 and EGFR genomic alterations. Cancer Discov; 3(11); 1238–44. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 1207
Data from Reactivation of ERK Signaling Causes Resistance to EGFR Kinase Inhibitors
Authors: Ercan Dalia , Xu Chunxiao , Yanagita Masahiko , Monast Calixte S. , Pratilas Christine A. , Montero Joan , Butaney Mohit , Shimamura Takeshi , Sholl Lynette , Ivanova Elena V. , Tadi Madhavi , Rogers Andrew , Repellin Claire , Capelletti Marzia , Maertens Ophélia , Goetz Eva M. , Letai Anthony , Garraway Levi A. , Lazzara Matthew J. , Rosen Neal , Gray Nathanael S. , Wong Kwok-Kin , Jänne Pasi A.
Published: March 2024

Abstract
The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here, we show, in multiple complementary models, that resistance to WZ4002 develops through aberrant activation of extracellular signal-regulated kinase (ERK) signaling caused by either an amplification of mitogen-activated protein kinase 1 (MAPK1) or by downregulation of negative regulators of ERK signaling. Inhibition of MAP–ERK kinase (MEK) or ERK restores sensitivity to WZ4002 and prevents the emergence of drug resistance. We further identify MAPK1 amplification in an erlotinib-resistant EGFR-mutant non–small cell lung carcinoma patient. In addition, the WZ4002-resistant MAPK1-amplified cells also show an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rational combination therapies that should be evaluated in clinical trials.

Significance: Our study identifies activated ERK signaling as a mediator of resistance to irreversible pyrimidine EGFR inhibitors in EGFR T790M-bearing cancers. We further provide a therapeutic strategy to both treat and prevent the emergence of this resistance mechanism. Cancer Discov; 2(10); 934–47. ©2012 AACR.

Read the Commentary on this article by Blakely and Bivona, p. 872.

This article is highlighted in the In This Issue feature, p. 857.
Data from BRAFL597 Mutations in Melanoma Are Associated with Sensitivity to MEK Inhibitors
Authors: Dahlman Kimberly Brown , Xia Junfeng , Hutchinson Katherine , Ng Charles , Hucks Donald , Jia Peilin , Atefi Mohammad , Su Zengliu , Branch Suzanne , Lyle Pamela L. , Hicks Donna J. , Bozon Viviana , Glaspy John A. , Rosen Neal , Solit David B. , Netterville James L. , Vnencak-Jones Cindy L. , Sosman Jeffrey A. , Ribas Antoni , Zhao Zhongming , Pao William
Published: March 2024

Abstract
Kinase inhibitors are accepted treatment for metastatic melanomas that harbor specific driver mutations in BRAF or KIT, but only 40% to 50% of cases are positive. To uncover other potential targetable mutations, we conducted whole-genome sequencing of a highly aggressive BRAF (V600) and KIT (W557, V559, L576, K642, and D816) wild-type melanoma. Surprisingly, we found a somatic BRAFL597R mutation in exon 15. Analysis of BRAF exon 15 in 49 tumors negative for BRAFV600 mutations as well as driver mutations in KIT, NRAS, GNAQ, and GNA11, showed that two (4%) harbored L597 mutations and another two involved BRAF D594 and K601 mutations. In vitro signaling induced by L597R/S/Q mutants was suppressed by mitogen-activated protein (MAP)/extracellular signal–regulated kinase (ERK) kinase (MEK) inhibition. A patient with BRAFL597S mutant metastatic melanoma responded significantly to treatment with the MEK inhibitor, TAK-733. Collectively, these data show clinical significance to BRAFL597 mutations in melanoma.

Significance: This study shows that cells harboring BRAFL597 mutants are sensitive to MEK inhibitor treatment, providing a rationale for routine screening and therapy of BRAFL597-mutant melanoma. Cancer Discov; 2(9); 791–7. ©2012 AACR.

Read the Commentary on this article by Garraway and Baselga, p. 766.

This article is highlighted in the In This Issue feature, p. 753.
Data from Genotype-Selective Combination Therapies for Melanoma Identified by High-Throughput Drug Screening
Authors: Held Matthew A. , Langdon Casey G. , Platt James T. , Graham-Steed Tisheeka , Liu Zongzhi , Chakraborty Ashok , Bacchiocchi Antonella , Koo Andrew , Haskins Jonathan W. , Bosenberg Marcus W. , Stern David F.
Published: March 2024

Abstract
Resistance and partial responses to targeted monotherapy are major obstacles in cancer treatment. Systematic approaches to identify efficacious drug combinations for cancer are not well established, especially in the context of genotype. To address this, we have tested pairwise combinations of an array of small-molecule inhibitors on early-passage melanoma cultures using combinatorial drug screening. Results reveal several inhibitor combinations effective for melanomas with activating RAS or BRAF mutations, including mutant BRAF melanomas with intrinsic or acquired resistance to vemurafenib. Inhibition of both EGF receptor and AKT sensitized treatment-resistant BRAF mutant melanoma cultures to vemurafenib. Melanomas with RAS mutations were more resistant to combination therapies relative to BRAF mutants, but were sensitive to combinations of statins and cyclin-dependent kinase inhibitors in vitro and in vivo. These results show the use of combinatorial drug screening for discovering unique treatment regimens that overcome resistance phenotypes of mutant BRAF- and RAS-driven melanomas.

Significance: We have used drug combinatorial screening to identify effective combinations for mutant BRAF melanomas, including those resistant to vemurafenib, and mutant RAS melanomas that are resistant to many therapies. Mechanisms governing the interactions of the drug combinations are proposed, and in vivo xenografts show the enhanced benefit and tolerability of a mutant RAS-selective combination, which is currently lacking in the clinic. Cancer Discov; 3(1); 52–67. ©2012 AACR.

See related commentary by Al-Lazikani and Workman, p. 14

This article is highlighted in the In This Issue feature, p. 1
Data from Cell-Selective Inhibition of NF-κB Signaling Improves Therapeutic Index in a Melanoma Chemotherapy Model
Authors: Enzler Thomas , Sano Yasuyo , Choo Min-Kyung , Cottam Howard B. , Karin Michael , Tsao Hensin , Park Jin Mo
Published: March 2024

Abstract
The transcription factor NF-κB promotes the survival of cancer cells exposed to doxorubicin and other chemotherapeutic agents. IκB kinase is essential for chemotherapy-induced NF-κB activation and considered a prime target for anticancer treatment. An IκB kinase inhibitor sensitized human melanoma xenografts in mice to killing by doxorubicin yet also exacerbated treatment toxicity in the host animals. By using mouse models that simulate cell-selective targeting, we found that impaired NF-κB activation in melanoma and host myeloid cells accounts for therapeutic and adverse effects, respectively. Ablation of tumor-intrinsic NF-κB activity resulted in apoptosis-driven tumor regression after treatment with doxorubicin. By contrast, chemotherapy in mice with myeloid-specific loss of NF-κB activation led to a massive intratumoral recruitment of interleukin-1β–producing neutrophils and necrotic tumor lesions, a condition associated with increased host mortality but not accompanied by tumor regression. Therefore, a molecular target-based therapy may be steered toward different clinical outcomes depending on the drug's cell-specific effects.

Significance: Our findings show that the IκB kinase–NF-κB signaling pathway is important for both promoting treatment resistance and preventing host toxicity in cancer chemotherapy; however, the two functions are exerted by distinct cell type–specific mechanisms and can therefore be selectively targeted to achieve an improved therapeutic outcome. Cancer Discovery; 1(6); 496–507. ©2011 AACR.

Read the Commentary on this article by Aggarwal and Sung, p. 469

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Data from Janus Kinase 3–Activating Mutations Identified in Natural Killer/T-cell Lymphoma
Authors: Koo Ghee Chong , Tan Soo Yong , Tang Tiffany , Poon Song Ling , Allen George E. , Tan Leonard , Chong Soo Ching , Ong Whee Sze , Tay Kevin , Tao Miriam , Quek Richard , Loong Susan , Yeoh Kheng-Wei , Yap Swee Peng , Lee Kuo Ann , Lim Lay Cheng , Tan Daryl , Goh Christopher , Cutcutache Ioana , Yu Willie , Young Ng Cedric Chuan , Rajasegaran Vikneswari , Heng Hong Lee , Gan Anna , Ong Choon Kiat , Rozen Steve , Tan Patrick , Teh Bin Tean , Lim Soon Thye
Published: March 2024

Abstract
The molecular pathogenesis of natural killer/T-cell lymphoma (NKTCL) is not well understood. We conducted whole-exome sequencing and identified Janus kinase 3 (JAK3) somatic–activating mutations (A572V and A573V) in 2 of 4 patients with NKTCLs. Further validation of the prevalence of JAK3 mutations was determined by Sanger sequencing and high-resolution melt (HRM) analysis in an additional 61 cases. In total, 23 of 65 (35.4%) cases harbored JAK3 mutations. Functional characterization of the JAK3 mutations support its involvement in cytokine-independent JAK/STAT constitutive activation leading to increased cell growth. Moreover, treatment of both JAK3-mutant and wild-type NKTCL cell lines with a novel pan-JAK inhibitor, CP-690550, resulted in dose-dependent reduction of phosphorylated STAT5, reduced cell viability, and increased apoptosis. Hence, targeting the deregulated JAK/STAT pathway could be a promising therapy for patients with NKTCLs.

Significance: Gene mutations causing NKTCL have not been fully identified. Through exome sequencing, we identified activating mutations of JAK3 that may play a significant role in the pathogenesis of NKTCLs. Our findings have important implications for the management of patients with NKTCLs. Cancer Discov; 2(7); 591–7. ©2012 AACR.

This article is highlighted in the In This Issue feature, p. 569.
Data from Functional Viability Profiles of Breast Cancer
Authors: Brough Rachel , Frankum Jessica R. , Sims David , Mackay Alan , Mendes-Pereira Ana M. , Bajrami Ilirjana , Costa-Cabral Sara , Rafiq Rumana , Ahmad Amar S. , Cerone Maria Antonietta , Natrajan Rachael , Sharpe Rachel , Shiu Kai-Keen , Wetterskog Daniel , Dedes Konstantine J. , Lambros Maryou B. , Rawjee Teeara , Linardopoulos Spiros , Reis-Filho Jorge S. , Turner Nicholas C. , Lord Christopher J. , Ashworth Alan
Published: March 2024

Abstract
The design of targeted therapeutic strategies for cancer has largely been driven by the identification of tumor-specific genetic changes. However, the large number of genetic alterations present in tumor cells means that it is difficult to discriminate between genes that are critical for maintaining the disease state and those that are merely coincidental. Even when critical genes can be identified, directly targeting these is often challenging, meaning that alternative strategies such as exploiting synthetic lethality may be beneficial. To address these issues, we have carried out a functional genetic screen in >30 commonly used models of breast cancer to identify genes critical to the growth of specific breast cancer subtypes. In particular, we describe potential new therapeutic targets for PTEN-mutated cancers and for estrogen receptor–positive breast cancers. We also show that large-scale functional profiling allows the classification of breast cancers into subgroups distinct from established subtypes.

Significance: Despite the wealth of molecular profiling data that describe breast tumors and breast tumor cell models, our understanding of the fundamental genetic dependencies in this disease is relatively poor. Using high-throughput RNA interference screening of a series of pharmacologically tractable genes, we have generated comprehensive functional viability profiles for a wide panel of commonly used breast tumor cell models. Analysis of these profiles identifies a series of novel genetic dependencies, including that of PTEN-null breast tumor cells upon mitotic checkpoint kinases, and provides a framework upon which additional dependencies and candidate therapeutic targets may be identified. Cancer Discovery; 1(3); 260–73. © 2011 AACR.

Read the Commentary on this article by Beijersbergen and Bernards, p. 205

This article is highlighted in the In This Issue feature, p. 189
Data from Reversing Resistance to Vascular-Disrupting Agents by Blocking Late Mobilization of Circulating Endothelial Progenitor Cells
Authors: Taylor Melissa , Billiot Fanny , Marty Virginie , Rouffiac Valérie , Cohen Patrick , Tournay Elodie , Opolon Paule , Louache Fawzia , Vassal Gilles , Laplace-Builhé Corinne , Vielh Philippe , Soria Jean-Charles , Farace Françoise
Published: March 2024

Abstract
The prevailing concept is that immediate mobilization of bone marrow–derived circulating endothelial progenitor cells (CEP) is a key mechanism mediating tumor resistance to vascular-disrupting agents (VDA). Here, we show that administration of VDA to tumor-bearing mice induces 2 distinct peaks in CEPs: an early, unspecific CEP efflux followed by a late yet more dramatic tumor-specific CEP burst that infiltrates tumors and is recruited to vessels. Combination with antiangiogenic drugs could not disrupt the early peak but completely abrogated the late VDA-induced CEP burst, blunted bone marrow–derived cell recruitment to tumors, and resulted in striking antitumor efficacy, indicating that the late CEP burst might be crucial to tumor recovery after VDA therapy. CEP and circulating endothelial cell kinetics in VDA-treated patients with cancer were remarkably consistent with our preclinical data. These findings expand the current understanding of vasculogenic “rebounds” that may be targeted to improve VDA-based strategies.

Significance: Our findings suggest that resistance to VDA therapy may be strongly mediated by late, rather than early, tumor-specific recruitment of CEPs, the suppression of which resulted in increased VDA-mediated antitumor efficacy. VDA-based therapy might thus be significantly enhanced by combination strategies targeting late CEP mobilization. Cancer Discov; 2(5); 434–49. ©2012 AACR.

Read the Commentary on this article by De Palma and Nucera, p. 395.

This article is highlighted in the In This Issue feature, p. 377.
Data from Imaging Androgen Receptor Signaling with a Radiotracer Targeting Free Prostate-Specific Antigen
Authors: Ulmert David , Evans Michael J. , Holland Jason P. , Rice Samuel L. , Wongvipat John , Pettersson Kim , Abrahamsson Per-Anders , Scardino Peter T. , Larson Steven M. , Lilja Hans , Lewis Jason S. , Sawyers Charles L.
Published: March 2024

Abstract
Despite intense efforts to develop radiotracers to detect cancers or monitor treatment response, few are widely used as a result of challenges with demonstrating clear clinical use. We reasoned that a radiotracer targeting a validated clinical biomarker could more clearly assess the advantages of imaging cancer. The virtues and shortcomings of measuring secreted prostate-specific antigen (PSA), an androgen receptor (AR) target gene, in patients with prostate cancer are well documented, making it a logical candidate for assessing whether a radiotracer can reveal new (and useful) information beyond that conferred by serum PSA. Therefore, we developed 89Zr-labeled 5A10, a novel radiotracer that targets “free” PSA. 89Zr–5A10 localizes in an AR-dependent manner in vivo to models of castration-resistant prostate cancer, a disease state in which serum PSA may not reflect clinical outcomes. Finally, we demonstrate that 89Zr–5A10 can detect osseous prostate cancer lesions, a context where bone scans fail to discriminate malignant and nonmalignant signals.

Significance: This report establishes that AR-dependent changes in PSA expression levels can be quantitatively measured at tumor lesions using a radiotracer that can be rapidly translated for human application and advances a new paradigm for radiotracer development that may more clearly highlight the unique virtues of an imaging biomarker. Cancer Discov; 2(4); 320–7. ©2012 AACR.

Read the Commentary on this article by Herschman and Czernin, p. 301

This article is highlighted in the In This Issue feature, p. 288