bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Prediction Models for Gastric Cancer Risk in the General Population: A Systematic Review
Authors: Gu Jianhua , Chen Ru , Wang Shao-Ming , Li Minjuan , Fan Zhiyuan , Li Xinqing , Zhou Jiachen , Sun Kexin , Wei Wenqiang
Published: March 2024

Abstract
Risk prediction models for gastric cancer could identify high-risk individuals in the general population. The objective of this study was to systematically review the available evidence about the construction and verification of gastric cancer predictive models. We searched PubMed, Embase, and Cochrane Library databases for articles that developed or validated gastric cancer risk prediction models up to November 2021. Data extracted included study characteristics, predictor selection, missing data, and evaluation metrics. Risk of bias (ROB) was assessed using the Prediction model Risk Of Bias Assessment Tool (PROBAST). We identified a total of 12 original risk prediction models that fulfilled the criteria for analysis. The area under the receiver operating characteristic curve (AUC) ranged from 0.73 to 0.93 in derivation sets (n = 6), 0.68 to 0.90 in internal validation sets (n = 5), 0.71 to 0.92 in external validation sets (n = 7). The higher-performing models usually include age, salt preference, Helicobacter pylori, smoking, body mass index, family history, pepsinogen, and sex. According to PROBAST, at least one domain with a high ROB was present in all studies mainly due to methodologic limitations in the analysis domain. In conclusion, although some risk prediction models including similar predictors have displayed sufficient discriminative abilities, many have a high ROB due to methodologic limitations and are not externally validated efficiently. Future prediction models should adherence to well-established standards and guidelines to benefit gastric cancer screening.
Prevention Relevance:
Through systematical reviewing available evidence about the construction and verification of gastric cancer predictive models, we found that most models have a high ROB due to methodologic limitations and are not externally validated efficiently. Future prediction models are supposed to adherence to well-established standards and guidelines to benefit gastric cancer screening.
Data from “Rescue” of Nonparticipants in Colorectal Cancer Screening: A Randomized Controlled Trial of Three Noninvasive Test Options
Authors: Young Graeme Paul , Chen Gang , Wilson Carlene J. , McGrane Ellen , Hughes-Barton Donna Lee-Ann , Flight Ingrid Helen K. , Symonds Erin Leigh
Published: March 2024

Abstract
Few studies have directly targeted nonparticipants in colorectal cancer screening to identify effective engagement strategies. We undertook a randomized controlled trial that targeted nonparticipants in a previous trial of average-risk subjects which compared participation rates for mailed invitations offering a fecal test, a blood test or a choice of either. Nonparticipants (n = 899) were randomized to be offered a kit containing a fecal immunochemical test (FIT), directions on how to arrange a blood DNA test, or the option of doing either. Screening participation was assessed 12 weeks after the offer. To assess the cognitive and attitudinal variables related to participation and invitee choice, invitees were surveyed after 12 weeks, and associations were investigated using multinomial logistic regression. Participation rates were similar between groups (P = 0.88): 12.0% for FIT (35/292), 13.3% for the blood test (39/293), and 13.4% for choice (39/290). Within the choice group, participation was significantly higher with FIT (9.7%, 28/290) compared with the blood test (3.8%, 11/290, P = 0.005). The only variable significantly associated with participation was socioeconomic status when offered FIT, and age when offered choice but there was none when offered the blood test. Survey respondents indicated that convenience, time-saving, comfort, and familiarity were major influences on participation. There was no clear advantage between a fecal test, blood test, or choice of test although, when given a choice, the fecal test was preferred. Differences in variables associated with participation according to invitation strategy warrant consideration when deciding upon an invitation strategy for screening nonparticipants.
Prevention Relevance:
This trial of screening for those at average risk for colorectal cancer targeted past fecal-test nonparticipants and compared participation rates for mailed invitations offering a fecal test, blood test, or choice of either. Although there was no clear advantage between strategies, factors associated with participation differed between each strategy.
Data from δ-Tocotrienol is the Most Potent Vitamin E Form in Inhibiting Prostate Cancer Cell Growth and Inhibits Prostate Carcinogenesis in Ptenp−/− Mice
Authors: Wang Hong , Yan William , Sun Yuhai , Yang Chung S.
Published: March 2024

Abstract
Vitamin E compounds, consisting of α, β, γ, and δ forms of tocopherols and tocotrienols, display different cancer preventive activities in experimental models. Tocotrienols may have higher potential for clinical use due to their lower effective doses in laboratory studies. However, most studies on tocotrienols have been carried out using cancer cell lines. Strong data from animal studies may encourage the use of tocotrienols for human cancer prevention research. To examine the cancer inhibitory activity of different vitamin E forms, we first investigated their inhibitory activities of different vitamin E forms in prostate cancer cell lines. We found that δ-tocotrienol (δT3) was the most effective form in inhibiting cell growth at equivalent doses. Because of this in vitro potency, δT3 was further studied using prostate-specific Pten−/− (Ptenp−/−) mice. We found that 0.05% δT3 in diet reduced prostate adenocarcinoma multiplicity by 32.7%, featuring increased apoptosis and reduced cell proliferation. The inhibitory effect of 0.05% δT3 in diet was similar to that of 0.2% δ-tocopherol (δT) in diet reported previously. Our further study on the δT3-induced transcriptome changes indicated that δT3 inhibited genes in blood vessel development in the prostate of Ptenp−/− mice, which was confirmed by IHC. Together, our results demonstrate that δT3 effectively inhibits the development of prostate adenocarcinoma in Ptenp−/− mice, which involves inhibition of proliferation and angiogenesis and promotion of apoptosis.
Prevention Relevance:
We demonstrated that δ-tocotrienol is the most active vitamin E form in inhibiting the growth of several prostate cancer cell lines. In transgenic Ptenp−/− mice, δ-tocotrienol inhibited the formation of prostate cancer. This result would encourage and help design clinical studies for the application of δ-tocotrienol for prostate cancer prevention.
Data from Prevention of Skin Carcinogenesis by the Non-β-blocking R-carvedilol Enantiomer
Authors: Liang Sherry , Shamim Md Abdullah , Shahid Ayaz , Chen Mengbing , Cleveland Kristan H. , Parsa Cyrus , Orlando Robert , Andresen Bradley T. , Huang Ying
Published: March 2024

Abstract
Skin cancer is the most common malignancy worldwide and is rapidly rising in incidence, representing a significant public health challenge. The β-blocker, carvedilol, has shown promising effects in preventing skin cancer. However, as a potent β-blocker, repurposing carvedilol to an anticancer agent is limited by cardiovascular effects. Carvedilol is a racemic mixture consisting of equimolar S- and R-carvedilol, whereas the R-carvedilol enantiomer does not possess β-blocking activity. Because previous studies suggest that carvedilol's cancer preventive activity is independent of β-blockade, we examined the skin cancer preventive activity of R-carvedilol compared with S-carvedilol and the racemic carvedilol. R- and S-carvedilol were equally effective in preventing EGF-induced neoplastic transformation of the mouse epidermal JB6 Cl 41-5a (JB6 P+) cells and displayed similar attenuation of EGF-induced ELK-1 activity. R-carvedilol appeared slightly better than S-carvedilol against UV-induced intracellular oxidative stress and release of prostaglandin E2 from the JB6 P+ cells. In an acute UV-induced skin damage and inflammation mouse model using a single irradiation of 300 mJ/cm2 UV, topical treatment with R-carvedilol dose dependently attenuated skin edema and reduced epidermal thickening, Ki-67 staining, COX-2 protein, and IL6 and IL1β mRNA levels similar to carvedilol. In a chronic UV (50–150 mJ/cm2) induced skin carcinogenesis model in mice with pretreatment of test agents, topical treatment with R-carvedilol, but not racemic carvedilol, significantly delayed and reduced skin squamous cell carcinoma development. Therefore, as an enantiomer present in an FDA-approved agent, R-carvedilol may be a better option for developing a safer and more effective preventive agent for skin carcinogenesis.
Prevention Relevance:
In this study, we demonstrated the skin cancer preventive activity of R-carvedilol, the non-β-blocking enantiomer present in the racemic β-blocker, carvedilol. As R-carvedilol does not have β-blocking activity, such a preventive treatment would not lead to common cardiovascular side effects of β-blockers.
Data from Dietary Intake of Branched-Chain Amino Acids and Risk of Colorectal Cancer
Authors: Katagiri Ryoko , Song Mingyang , Zhang Xuehong , Lee Dong Hoon , Tabung Fred K. , Fuchs Charles S. , Meyerhardt Jeffrey A. , Nishihara Reiko , Chan Andrew T. , Joshi Amit D. , Iwasaki Motoki , Ogino Shuji , Willett Walter C. , Giovannucci Edward , Wu Kana
Published: March 2024

Abstract
Branched-chain amino acids (BCAA) are essential amino acids, and emerging evidence suggests that BCAAs may mediate pathways related to cancer progression, possibly due to their involvement in insulin metabolism. We investigated the association between dietary intake of BCAAs with colorectal cancer risk in three prospective cohorts: the Nurses' Health Study I [(NHS), number of participants (n) at baseline = 77,017], NHS II (n = 92,984), and the Health Professionals Follow-up Study [(HPFS) n = 47,255]. Validated food frequency questionnaires were administered every 4 years and follow-up questionnaires on lifestyle biennially. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards regression models. Pooled HRs were obtained using random effect models. After up to 28 years of follow-up, 1,660 cases were observed in NHS, 306 in NHS II, and 1,343 in HPFS. In multivariable adjusted models, we observed a weak inverse association between BCAA intake and colorectal cancer [highest vs. lowest quintile, pooled HR including all three cohorts (95% CI): 0.89 (0.80–1.00), Ptrend = 0.06, HR per standard deviation (SD) increment 0.95 (0.92–0.99)]. However, after including dairy calcium to the models, BCAA intake was no longer associated with risk of colorectal cancer [HR 0.96 (0.85–1.08), Ptrend = 0.50, HR per SD increment 0.97 (0.93–1.01)]. We did not find evidence that higher dietary BCAA intake is associated with higher risk of colorectal cancer. As this is the first prospective study to examine the association between BCAA intake and colorectal cancer, our findings warrant investigation in other cohorts.
Data from Targeting of CD40 and PD-L1 Pathways Inhibits Progression of Oral Premalignant Lesions in a Carcinogen-induced Model of Oral Squamous Cell Carcinoma
Authors: Monteiro de Oliveira Novaes Jose A. , Hirz Taghreed , Guijarro Irene , Nilsson Monique , Pisegna Marlese A. , Poteete Alissa , Barsoumian Hampartsoum B. , Fradette Jared J. , Chen Limo N. , Gibbons Don L. , Tian Xiangjun , Wang Jing , Myers Jeffrey N. , McArthur Mark J. , Bell Diana , William William N. , Heymach John V.
Published: March 2024

Abstract
We have previously demonstrated that PD-1 blockade decreased the incidence of high-grade dysplasia in a carcinogen-induced murine model of oral squamous cell carcinoma (OSCC). It remains unknown, however, whether there are additional factors involved in escape from immune surveillance that could serve as additional targets for immunoprevention. We performed this study to further characterize the immune landscape of oral premalignant lesions (OPL) and determine the impact of targeting of the PD-1, CTLA-4, CD40, or OX40 pathways on the development of OPLs and oral carcinomas in the 4-nitroquinoline 1-oxide model. The immune pathways were targeted using mAbs or, in the case of the PD-1/PD-L1 pathway, using PD-L1–knockout (PD-L1ko) mice. After intervention, tongues and cervical lymph nodes were harvested and analyzed for malignant progression and modulation of the immune milieu, respectively. Targeting of CD40 with an agonist mAb was the most effective treatment to reduce transition of OPLs to OSCC; PD-1 alone or in combination with CTLA-4 inhibition, or PD-L1ko, also reduced progression of OPLs to OSCC, albeit to a lesser extent. Distinct patterns of immune system modulation were observed for the CD40 agonists compared with blockade of the PD-1/PD-L1 axis with or without CTLA-4 blockade; CD40 agonist generated a lasting expansion of experienced/memory cytotoxic T lymphocytes and M1 macrophages, whereas PD-1/CTLA-4 blockade resulted in a pronounced depletion of regulatory T cells among other changes. These data suggest that distinct approaches may be used for targeting different steps in the development of OSCC, and that CD40 agonists merit investigation as potential immunoprevention agents in this setting.
Prevention Relevance:
PD-1/PD-L1 pathway blockade, as well as activation of the CD40 pathway, were able to prevent OPL progression into invasive OSCC in a murine model. A distinct pattern of immune modulation was observed when either the CD40 or the PD-1/PD-L1 pathways were targeted.
Data from Diallyl Disulfide (DADS), a Constituent of Garlic, Inactivates NF-κB and Prevents Colitis-Induced Colorectal Cancer by Inhibiting GSK-3β
Authors: Saud Shakir M. , Li Weidong , Gray Zane , Matter Matthias S. , Colburn Nancy H. , Young Matthew R. , Kim Young S.
Published: March 2024

Abstract
There is a strong belief that garlic has medicinal properties and may even reduce the risk of developing certain cancers including those of the gastrointestinal tract. The chemopreventive effects of garlic may be attributed to the anti-inflammatory properties of the sulfur-containing constituents of garlic, which includes diallyl disulfide (DADS). Here, we demonstrate that DADS prevented colorectal tumorigenesis in a mouse model of colitis-induced colorectal cancer. Supplementation with 85 ppm of DADS (60 mg daily human equivalent dose) in the diet of FVB/N mice treated with chemical carcinogen azoxymethane (AOM) and colonic irritant dextran sodium sulfate (DSS) resulted in the reduction in tumor incidence, tumor number, and tumor burden by 21.54%, 47.3%, and 66.4%, respectively. Further analysis revealed that mice fed the DADS-supplemented diet resolved the initial DSS-induced inflammation faster than those on the control diet, preventing prolonged inflammation and cellular transformation. Subsequent mechanistic studies in vitro suggest that DADS chemopreventive effects are mediated through NF-κB signaling. When SW480 colorectal cancer cells were treated with DADS, NF-κB nuclear localization and activity were diminished. Interestingly, NF-κB suppression was found to be dependent on DADS inhibition of GSK-3β, a positive regulator of NF-κB. Inhibition of GSK-3β and loss of nuclear NF-κB activity were also observed in vivo in AOM/DSS-treated mice fed a diet supplemented with 85 ppm DADS. Our results indicate that DADS can prevent tumorigenesis by suppressing inflammation, a process largely involving GSK-3β inhibition and consequential reduction in NF-κB nuclear localization. Cancer Prev Res; 9(7); 607–15. ©2016 AACR.
Data from Expression of miR-18a and miR-210 in Normal Breast Tissue as Candidate Biomarkers of Breast Cancer Risk
Authors: Shidfar Ali , Costa Fabricio F. , Scholtens Denise , Bischof Jared M. , Sullivan Megan E. , Ivancic David Z. , Vanin Elio F. , Soares Marcelo B. , Wang Jun , Khan Seema A.
Published: March 2024

Abstract
miRNAs are noncoding RNAs with abnormal expression in breast cancer; their expression in high-risk benign breast tissue may relate to breast cancer risk. We examined miRNA profiles in contralateral unaffected breasts (CUB) of patients with breast cancer and validated resulting candidates in two additional sample sets. Expression profiles of 754 mature miRNAs were examined using TaqMan Low Density Arrays in 30 breast cancer samples [15 estrogen receptor (ER)-positive and 15 ER-negative] and paired CUBs and 15 reduction mammoplasty controls. Pairwise comparisons identified miRNAs with significantly differential expression. Seven candidate miRNAs were examined using qRT-PCR in a second CUB sample set (40 cases, 20 ER+, 20 ER−) and 20 reduction mammoplasty controls. Further validation was performed in 80 benign breast biopsy (BBB) samples; 40 from cases who subsequently developed breast cancer and 40 from controls who did not. Logistic regression, using tertiles of miRNA expression, was used to discriminate cases from controls. Seven miRNAs were differentially expressed in tumors and CUBs versus reduction mammoplasty samples. Among them, miR-18a and miR-210 were validated in the second CUB set, showing significantly higher expression in tumor and CUBs than in reduction mammoplasty controls. The expression of miR-18a and miR-210 was also significantly higher in BBB cases than in BBB controls. When both miR-18a and miR-210 were expressed in the upper tertiles in BBB, OR for subsequent cancer was 3.20, P = 0.023. miR-18a and miR-210 are expressed at higher levels in CUBs of patients with breast cancer, and in BBB prior to cancer development, and are therefore candidate breast cancer risk biomarkers. Cancer Prev Res; 10(1); 89–97. ©2016 AACR.
Data from DNA Methylation in Peripheral Blood and Risk of Gastric Cancer: A Prospective Nested Case–control Study
Authors: Chamberlain James A , Dugué Pierre-Antoine , Bassett Julie K. , Milne Roger L. , Joo Jihoon E. , Wong Ee Ming , Brinkman Maree T. , Stuart Geoffrey W. , Boussioutas Alex , Southey Melissa C. , Giles Graham G. , Mitchell Hazel , English Dallas R. , Hodge Allison M.
Published: March 2024

Abstract
DNA methylation in peripheral blood is a potential biomarker of gastric cancer risk which could be used for early detection. We conducted a prospective case–control study nested within the Melbourne Collaborative Cohort Study. Genomic DNA was prepared from blood samples collected a median of 12 years before diagnosis for cases (N = 168). Controls (N = 163) were matched to cases on sex, year of birth, country of birth, and blood sample type using incidence density sampling. Genome-wide DNA methylation was measured using the Infinium HumanMethylation450K Beadchip. Global measures of DNA methylation were defined as the median methylation M value, calculated for each of 13 CpG subsets representing genomic function, mean methylation and location, and reliability of measurement. Conditional logistic regression was conducted to assess associations between these global measures of methylation and gastric cancer risk, adjusting for Helicobacter pylori and other potential confounders. We tested nonlinear associations using quintiles of the global measure distribution. A genome-wide association study of DNA methylation and gastric cancer risk was also conducted (N = 484,989 CpGs) using conditional logistic regression, adjusting for potential confounders. Differentially methylated regions (DMR) were investigated using the R package DMRcate. We found no evidence of associations with gastric cancer risk for individual CpGs or DMRs (P > 7.6 × 10−6). No evidence of association was observed with global measures of methylation (OR 1.07 per SD of overall median methylation; 95% confidence interval, 0.80–1.44; P = 0.65). We found no evidence that blood DNA methylation is prospectively associated with gastric cancer risk.

Prevention Relevance: We studied DNA methylation in blood to try and predict who was at risk of gastric cancer before symptoms developed, by which stage survival is poor. We did not find any such markers, but the importance of early diagnosis in gastric cancer remains, and the search for markers continues.
Data from A Phase II Randomized Placebo-Controlled Trial of Oral N-acetylcysteine for Protection of Melanocytic Nevi against UV-Induced Oxidative Stress In Vivo
Authors: Cassidy Pamela B. , Liu Tong , Florell Scott R. , Honeggar Matthew , Leachman Sancy A. , Boucher Kenneth M. , Grossman Douglas
Published: March 2024

Abstract
Oxidative stress plays a role in UV-induced melanoma, which may arise from melanocytic nevi. We investigated whether oral administration of the antioxidant N-acetylcysteine (NAC) could protect nevi from oxidative stress in vivo in the setting of acute UV exposure. The minimal erythemal dose (MED) was determined for 100 patients at increased risk for melanoma. Patients were randomized to receive a single dose (1,200 mg) of NAC or placebo, in double-blind fashion, and then one nevus was irradiated (1–2 MED) using a solar simulator. One day later, the MED was redetermined and the irradiated nevus and a control unirradiated nevus were removed for histologic analysis and examination of biomarkers of NAC metabolism and UV-induced oxidative stress. Increased expression of 8-oxoguanine, thioredoxin reductase-1, and γ-glutamylcysteine synthase modifier subunit were consistently seen in UV-treated compared with unirradiated nevi. However, no significant differences were observed in these UV-induced changes or in the pre- and postintervention MED between those patients receiving NAC versus placebo. Similarly, no significant differences were observed in UV-induced changes between subjects with germline wild-type versus loss-of-function mutations in the melanocortin-1 receptor. Nevi showed similar changes of UV-induced oxidative stress in an open-label post-trial study in 10 patients who received NAC 3 hours before nevus irradiation. Thus, a single oral dose of NAC did not effectively protect nevi from UV-induced oxidative stress under the conditions examined. Cancer Prev Res; 10(1); 36–44. ©2016 AACR.
Data from Telomeric Allelic Imbalance Indicates Defective DNA Repair and Sensitivity to DNA-Damaging Agents
Authors: Birkbak Nicolai J. , Wang Zhigang C. , Kim Ji-Young , Eklund Aron C. , Li Qiyuan , Tian Ruiyang , Bowman-Colin Christian , Li Yang , Greene-Colozzi April , Iglehart J. Dirk , Tung Nadine , Ryan Paula D. , Garber Judy E. , Silver Daniel P. , Szallasi Zoltan , Richardson Andrea L.
Published: March 2024

Abstract
DNA repair competency is one determinant of sensitivity to certain chemotherapy drugs, such as cisplatin. Cancer cells with intact DNA repair can avoid the accumulation of genome damage during growth and also can repair platinum-induced DNA damage. We sought genomic signatures indicative of defective DNA repair in cell lines and tumors and correlated these signatures to platinum sensitivity. The number of subchromosomal regions with allelic imbalance extending to the telomere (NtAI) predicted cisplatin sensitivity in vitro and pathologic response to preoperative cisplatin treatment in patients with triple-negative breast cancer (TNBC). In serous ovarian cancer treated with platinum-based chemotherapy, higher levels of NtAI forecast a better initial response. We found an inverse relationship between BRCA1 expression and NtAI in sporadic TNBC and serous ovarian cancers without BRCA1 or BRCA2 mutation. Thus, accumulation of telomeric allelic imbalance is a marker of platinum sensitivity and suggests impaired DNA repair.

Significance: Mutations in BRCA genes cause defects in DNA repair that predict sensitivity to DNA damaging agents, including platinum; however, some patients without BRCA mutations also benefit from these agents. NtAI, a genomic measure of unfaithfully repaired DNA, may identify cancer patients likely to benefit from treatments targeting defective DNA repair. Cancer Discov; 2(4); 366–75. ©2012 AACR.

This article is highlighted in the In This Issue feature, p. 288
Data from Inherited Variation at Chromosome 12p13.33, Including RAD52, Influences the Risk of Squamous Cell Lung Carcinoma
Authors: Shi Jianxin , Chatterjee Nilanjan , Rotunno Melissa , Wang Yufei , Pesatori Angela C. , Consonni Dario , Li Peng , Wheeler William , Broderick Peter , Henrion Marc , Eisen Timothy , Wang Zhaoming , Chen Wei , Dong Qiong , Albanes Demetrius , Thun Michael , Spitz Margaret R. , Bertazzi Pier Alberto , Caporaso Neil E. , Chanock Stephen J. , Amos Christopher I. , Houlston Richard S. , Landi Maria Teresa
Published: March 2024

Abstract
Although lung cancer is largely caused by tobacco smoking, inherited genetic factors play a role in its etiology. Genome-wide association studies in Europeans have only robustly demonstrated 3 polymorphic variations that influence the risk of lung cancer. Tumor heterogeneity may have hampered the detection of association signal when all lung cancer subtypes were analyzed together. In a genome-wide association study of 5,355 European ever-smoker lung cancer patients and 4,344 smoking control subjects, we conducted a pathway-based analysis in lung cancer histologic subtypes with 19,082 single-nucleotide polymorphisms mapping to 917 genes in the HuGE-defined “inflammation” pathway. We identified a susceptibility locus for squamous cell lung carcinoma at 12p13.33 (RAD52, rs6489769) and replicated the association in 3 independent studies totaling 3,359 squamous cell lung carcinoma cases and 9,100 controls (OR = 1.20, Pcombined = 2.3 × 10−8).

Significance: The combination of pathway-based approaches and information on disease-specific subtypes can improve the identification of cancer susceptibility loci in heterogeneous diseases. Cancer Discovery; 2(2); 131–9. © 2011 AACR.

Read the Commentary on this article by Sellers and Chen, p. 110.

This article is highlighted in the In This Issue feature, p. 95.
Data from Combination Epigenetic Therapy Has Efficacy in Patients with Refractory Advanced Non–Small Cell Lung Cancer
Authors: Juergens Rosalyn A. , Wrangle John , Vendetti Frank P. , Murphy Sara C. , Zhao Ming , Coleman Barbara , Sebree Rosa , Rodgers Kristen , Hooker Craig M. , Franco Noreli , Lee Beverly , Tsai Salina , Delgado Igor Espinoza , Rudek Michelle A. , Belinsky Steven A. , Herman James G. , Baylin Stephen B. , Brock Malcolm V. , Rudin Charles M.
Published: March 2024

Abstract
Epigenetic alterations are strongly associated with the development of cancer. We conducted a phase I/II trial of combined epigenetic therapy with azacitidine and entinostat, inhibitors of DNA methylation and histone deacetylation, respectively, in extensively pretreated patients with recurrent metastatic non–small cell lung cancer. This therapy is well tolerated, and objective responses were observed, including a complete response and a partial response in a patient who remains alive and without disease progression approximately 2 years after completing protocol therapy. Median survival in the entire cohort was 6.4 months (95% CI 3.8–9.2), comparing favorably with existing therapeutic options. Demethylation of a set of 4 epigenetically silenced genes known to be associated with lung cancer was detectable in serial blood samples in these patients and was associated with improved progression-free (P = 0.034) and overall survival (P = 0.035). Four of 19 patients had major objective responses to subsequent anticancer therapies given immediately after epigenetic therapy.

Significance: This study demonstrates that combined epigenetic therapy with low-dose azacitidine and entinostat results in objective, durable responses in patients with solid tumors and defines a blood-based biomarker that correlates with clinical benefit. Cancer Discovery; 1(7); 598–607. ©2011 AACR.

Read the Commentary on this article by Rodríguez-Paredes and Esteller, p. 557

This article is highlighted in the In This Issue feature, p. 539
Data from Androgen Receptor Signaling Regulates DNA Repair in Prostate Cancers
Authors: Polkinghorn William R. , Parker Joel S. , Lee Man X. , Kass Elizabeth M. , Spratt Daniel E. , Iaquinta Phillip J. , Arora Vivek K. , Yen Wei-Feng , Cai Ling , Zheng Deyou , Carver Brett S. , Chen Yu , Watson Philip A. , Shah Neel P. , Fujisawa Sho , Goglia Alexander G. , Gopalan Anuradha , Hieronymus Haley , Wongvipat John , Scardino Peter T. , Zelefsky Michael J. , Jasin Maria , Chaudhuri Jayanta , Powell Simon N. , Sawyers Charles L.
Published: March 2024

Abstract
We demonstrate that the androgen receptor (AR) regulates a transcriptional program of DNA repair genes that promotes prostate cancer radioresistance, providing a potential mechanism by which androgen deprivation therapy synergizes with ionizing radiation. Using a model of castration-resistant prostate cancer, we show that second-generation antiandrogen therapy results in downregulation of DNA repair genes. Next, we demonstrate that primary prostate cancers display a significant spectrum of AR transcriptional output, which correlates with expression of a set of DNA repair genes. Using RNA-seq and ChIP-seq, we define which of these DNA repair genes are both induced by androgen and represent direct AR targets. We establish that prostate cancer cells treated with ionizing radiation plus androgen demonstrate enhanced DNA repair and decreased DNA damage and furthermore that antiandrogen treatment causes increased DNA damage and decreased clonogenic survival. Finally, we demonstrate that antiandrogen treatment results in decreased classical nonhomologous end-joining.

Significance: We demonstrate that the AR regulates a network of DNA repair genes, providing a potential mechanism by which androgen deprivation synergizes with radiotherapy for prostate cancer. Cancer Discov; 3(11); 1245–53. ©2013 AACR.

See related commentary by Bartek et al., p. 1222

This article is highlighted in the In This Issue feature, p. 1207
Data from The OPCML Tumor Suppressor Functions as a Cell Surface Repressor–Adaptor, Negatively Regulating Receptor Tyrosine Kinases in Epithelial Ovarian Cancer
Authors: McKie Arthur B. , Vaughan Sebastian , Zanini Elisa , Okon Imoh S. , Louis Louay , de Sousa Camila , Greene Mark I. , Wang Qiang , Agarwal Roshan , Shaposhnikov Dmitry , Wong Joshua L. C. , Gungor Hatice , Janczar Szymon , El-Bahrawy Mona , Lam Eric W-F. , Chayen Naomi E. , Gabra Hani
Published: March 2024

Abstract
Epithelial ovarian cancer is the leading cause of death from gynecologic malignancy, and its molecular basis is poorly understood. We previously demonstrated that opioid binding protein cell adhesion molecule (OPCML) was frequently epigenetically inactivated in epithelial ovarian cancers, with tumor suppressor function in vitro and in vivo. Here, we further show the clinical relevance of OPCML and demonstrate that OPCML functions by a novel mechanism in epithelial ovarian cancer cell lines and normal ovarian surface epithelial cells by regulating a specific repertoire of receptor tyrosine kinases: EPHA2, FGFR1, FGFR3, HER2, and HER4. OPCML negatively regulates receptor tyrosine kinases by binding their extracellular domains, altering trafficking via nonclathrin-dependent endocytosis, and promoting their degradation via a polyubiquitination-associated proteasomal mechanism leading to signaling and growth inhibition. Exogenous recombinant OPCML domain 1–3 protein inhibited the cell growth of epithelial ovarian cancers cell in vitro and in vivo in 2 murine ovarian cancer intraperitoneal models that used an identical mechanism. These findings demonstrate a novel mechanism of OPCML-mediated tumor suppression and provide a proof-of-concept for recombinant OPCML protein therapy in epithelial ovarian cancers.

Significance: The OPCML tumor suppressor negatively regulates a specific spectrum of receptor tyrosine kinases in ovarian cancer cells by binding to their extracellular domain and altering trafficking to a nonclathrin, caveolin-1–associated endosomal pathway that results in receptor tyrosine kinase polyubiquitination and proteasomal degradation. Recombinant OPCML domain 1–3 recapitulates this mechanism and may allow for the implementation of an extracellular tumor-suppressor replacement strategy. Cancer Discovery; 2(2); 156–71. © 2012 AACR.

Read the Commentary on this article by Wu and Sood, p. 115.

This article is highlighted in the In This Issue feature, p. 95.
Data from Opposing Effects of Androgen Deprivation and Targeted Therapy on Prostate Cancer Prevention
Authors: Jia Shidong , Gao Xueliang , Lee Sang Hyun , Maira Sauveur-Michel , Wu Xiaoqiu , Stack Edward C. , Signoretti Sabina , Loda Massimo , Zhao Jean J. , Roberts Thomas M.
Published: March 2024

Abstract
Prostate cancer is an ideal target for chemoprevention. To date, chemoprevention clinical trials with 5α-reductase inhibitors have yielded encouraging yet ultimately confounding results. Using a preclinical mouse model of high-grade prostatic intraepithelial neoplasia (HG-PIN) induced by PTEN loss, we observed unprecedented deteriorating effects of androgen deprivation, in which surgical castration or MDV3100 treatment accelerated disease progression of the otherwise stable HG-PIN to invasive castration-resistant prostate cancer (CRPC). As an alternative, targeting the phosphoinositide 3-kinase (PI3K) signaling pathway via either genetic ablation of genes encoding PI3K components or pharmacologic inhibition of the PI3K pathway reversed the PTEN loss–induced HG-PIN phenotype. Finally, concurrent inhibition of the PI3K and mitogen-activated protein kinase (MAPK) pathways was effective in blocking the growth of PTEN-null CRPC. Together, these data have revealed the potential adverse effects of antiandrogen chemoprevention in certain genetic contexts (such as PTEN loss) while showing the promise of targeted therapy in the clinical management of this complex and prevalent disease.

Significance: Chemoprevention with antiandrogen therapies is attractive for prostate cancer, given its prevalence and established hormonally mediated pathogenesis. However, because PTEN loss has been found in 9% to 45% of HG-PIN in the clinic, the current findings suggest that patients with PTEN-deficient prostate tumors might be better treated with PI3K-targeted therapies. Cancer Discov; 3(1); 44–51. ©2012 AACR.

This article is highlighted in the In This Issue feature, p. 1
Data from Antagonism of Inhibitor of Apoptosis Proteins Increases Bone Metastasis via Unexpected Osteoclast Activation
Authors: Yang Chang , Davis Jennifer L. , Zeng Rong , Vora Paras , Su Xinming , Collins Lynne I. , Vangveravong Suwanna , Mach Robert H. , Piwnica-Worms David , Weilbaecher Katherine N. , Faccio Roberta , Veis Novack Deborah
Published: March 2024

Abstract
Inhibitor of apoptosis (IAP) proteins play a central role in many types of cancer, and IAP antagonists are in development as anticancer agents. IAP antagonists cause apoptosis in many cells, but they also activate alternative NF-κB signaling through NF-κB–inducing kinase (NIK), which regulates osteoclasts. In bone metastasis, a positive feedback loop between tumors and osteoclasts promotes tumor growth and osteolysis. We therefore tested the effect of IAP antagonists on the bone microenvironment for metastasis. In both drug-sensitive and drug-resistant tumors, growth in bone was favored, as compared with other sites during IAP antagonist treatment. These drugs also caused osteoporosis and increased osteoclastogenesis, mediated by NIK, and enhanced tumor-associated osteolysis. Cotreatment with zoledronic acid, a potent osteoclast inhibitor, reduced IAP antagonist–enhanced tumor growth in bone and osteolysis. Thus, IAP antagonist–based cancer treatment may be compromised by osteoporosis and enhanced skeletal metastasis, which may be prevented by antiresorptive agents.

Significance: Although IAP antagonists are a class of anticancer agents with proven efficacy in multiple cancers, we show that these agents can paradoxically increase tumor growth and metastasis in the bone by stabilizing NIK and activating the alternative NF-κB pathway in osteoclasts. Future clinical trials of IAP antagonist–based therapy may require detailed examination of this potential for enhanced bone metastasis and osteoporosis, as well as possible combination with antiresorptive agents. Cancer Discov; 3(2); 212–23. ©2012 AACR.

This article is highlighted in the In This Issue feature, p. 125
Data from The Vigorous Immune Microenvironment of Microsatellite Instable Colon Cancer Is Balanced by Multiple Counter-Inhibitory Checkpoints
Authors: Llosa Nicolas J. , Cruise Michael , Tam Ada , Wicks Elizabeth C. , Hechenbleikner Elizabeth M. , Taube Janis M. , Blosser Richard L. , Fan Hongni , Wang Hao , Luber Brandon S. , Zhang Ming , Papadopoulos Nickolas , Kinzler Kenneth W. , Vogelstein Bert , Sears Cynthia L. , Anders Robert A. , Pardoll Drew M. , Housseau Franck
Published: March 2024

Abstract
We examined the immune microenvironment of primary colorectal cancer using immunohistochemistry, laser capture microdissection/qRT-PCR, flow cytometry, and functional analysis of tumor-infiltrating lymphocytes. A subset of colorectal cancer displayed high infiltration with activated CD8+ cytotoxic T lymphocyte (CTL) as well as activated Th1 cells characterized by IFNγ production and the Th1 transcription factor TBET. Parallel analysis of tumor genotypes revealed that virtually all of the tumors with this active Th1/CTL microenvironment had defects in mismatch repair, as evidenced by microsatellite instability (MSI). Counterbalancing this active Th1/CTL microenvironment, MSI tumors selectively demonstrated highly upregulated expression of multiple immune checkpoints, including five—PD-1, PD-L1, CTLA-4, LAG-3, and IDO—currently being targeted clinically with inhibitors. These findings link tumor genotype with the immune microenvironment, and explain why MSI tumors are not naturally eliminated despite a hostile Th1/CTL microenvironment. They further suggest that blockade of specific checkpoints may be selectively efficacious in the MSI subset of colorectal cancer.

Significance: The findings reported in this article are the first to demonstrate a link between a genetically defined subtype of cancer and its corresponding expression of immune checkpoints in the tumor microenvironment. The mismatch repair–defective subset of colorectal cancer selectively upregulates at least five checkpoint molecules that are targets of inhibitors currently being clinically tested. Cancer Discov; 5(1); 43–51. ©2014 AACR.

See related commentary by Xiao and Freeman, p. 16

This article is highlighted in the In This Issue feature, p. 1
Data from HIF2α-Dependent Lipid Storage Promotes Endoplasmic Reticulum Homeostasis in Clear-Cell Renal Cell Carcinoma
Authors: Qiu Bo , Ackerman Daniel , Sanchez Danielle J. , Li Bo , Ochocki Joshua D. , Grazioli Alison , Bobrovnikova-Marjon Ekaterina , Diehl J. Alan , Keith Brian , Simon M. Celeste
Published: March 2024

Abstract
Two hallmarks of clear-cell renal cell carcinoma (ccRCC) are constitutive hypoxia-inducible factor (HIF) signaling and abundant intracellular lipid droplets (LD). However, regulation of lipid storage and its role in ccRCC are incompletely understood. Transcriptional profiling of primary ccRCC samples revealed that expression of the LD coat protein gene PLIN2 was elevated in tumors and correlated with HIF2α, but not HIF1α, activation. HIF2α-dependent PLIN2 expression promoted lipid storage, proliferation, and viability in xenograft tumors. Mechanistically, lipid storage maintained integrity of the endoplasmic reticulum (ER), which is functionally and physically associated with LDs. Specifically, PLIN2-dependent lipid storage suppressed cytotoxic ER stress responses that otherwise result from elevated protein synthetic activity characteristic of ccRCC cells. Thus, in addition to promoting ccRCC proliferation and anabolic metabolism, HIF2α modulates lipid storage to sustain ER homeostasis, particularly under conditions of nutrient and oxygen limitation, thereby promoting tumor cell survival.

Significance: We demonstrate that HIF2α promotes lipid storage, ER homeostasis, and cell viability in ccRCC via upregulation of the LD coat protein PLIN2, revealing a novel function for the well-documented “clear-cell” phenotype and identifying ER stress as a targetable vulnerability created by HIF2α/PLIN2 suppression in this common renal malignancy. Cancer Discov; 5(6); 652–67. ©2015 AACR.

See related commentary by Sim and Johnson, p. 584.

This article is highlighted in the In This Issue feature, p. 565
Data from Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLC
Authors: Walter Annette O. , Sjin Robert Tjin Tham , Haringsma Henry J. , Ohashi Kadoaki , Sun Jing , Lee Kwangho , Dubrovskiy Aleksandr , Labenski Matthew , Zhu Zhendong , Wang Zhigang , Sheets Michael , St Martin Thia , Karp Russell , van Kalken Dan , Chaturvedi Prasoon , Niu Deqiang , Nacht Mariana , Petter Russell C. , Westlin William , Lin Kevin , Jaw-Tsai Sarah , Raponi Mitch , Van Dyke Terry , Etter Jeff , Weaver Zoe , Pao William , Singh Juswinder , Simmons Andrew D. , Harding Thomas C. , Allen Andrew
Published: March 2024

Abstract
Patients with non–small cell lung cancer (NSCLC) with activating EGF receptor (EGFR) mutations initially respond to first-generation reversible EGFR tyrosine kinase inhibitors. However, clinical efficacy is limited by acquired resistance, frequently driven by the EGFRT790M mutation. CO-1686 is a novel, irreversible, and orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR, including T790M, while exhibiting minimal activity toward the wild-type (WT) receptor. Oral administration of CO-1686 as single agent induces tumor regression in EGFR-mutated NSCLC tumor xenograft and transgenic models. Minimal activity of CO-1686 against the WT EGFR receptor was observed. In NSCLC cells with acquired resistance to CO-1686 in vitro, there was no evidence of additional mutations or amplification of the EGFR gene, but resistant cells exhibited signs of epithelial–mesenchymal transition and demonstrated increased sensitivity to AKT inhibitors. These results suggest that CO-1686 may offer a novel therapeutic option for patients with mutant EGFR NSCLC.

Significance: We report the preclinical development of a novel covalent inhibitor, CO-1686, that irreversibly and selectively inhibits mutant EGFR, in particular the T790M drug-resistance mutation, in NSCLC models. CO-1686 is the first drug of its class in clinical development for the treatment of T790M-positive NSCLC, potentially offering potent inhibition of mutant EGFR while avoiding the on-target toxicity observed with inhibition of the WT EGFR. Cancer Discov; 3(12); 1404–15. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 1317
Data from Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a Target in LKB1-Mutant Lung Cancer
Authors: Liu Yan , Marks Kevin , Cowley Glenn S. , Carretero Julian , Liu Qingsong , Nieland Thomas J.F. , Xu Chunxiao , Cohoon Travis J. , Gao Peng , Zhang Yong , Chen Zhao , Altabef Abigail B. , Tchaicha Jeremy H. , Wang Xiaoxu , Choe Sung , Driggers Edward M. , Zhang Jianming , Bailey Sean T. , Sharpless Norman E. , Hayes D. Neil , Patel Nirali M. , Janne Pasi A. , Bardeesy Nabeel , Engelman Jeffrey A. , Manning Brendan D. , Shaw Reuben J. , Asara John M. , Scully Ralph , Kimmelman Alec , Byers Lauren A. , Gibbons Don L. , Wistuba Ignacio I. , Heymach John V. , Kwiatkowski David J. , Kim William Y. , Kung Andrew L. , Gray Nathanael S. , Root David E. , Cantley Lewis C. , Wong Kwok-Kin
Published: March 2024

Abstract
The LKB1/STK11 tumor suppressor encodes a serine/threonine kinase, which coordinates cell growth, polarity, motility, and metabolism. In non–small cell lung carcinoma, LKB1 is somatically inactivated in 25% to 30% of cases, often concurrently with activating KRAS mutations. Here, we used an integrative approach to define novel therapeutic targets in KRAS-driven LKB1-mutant lung cancers. High-throughput RNA interference screens in lung cancer cell lines from genetically engineered mouse models driven by activated KRAS with or without coincident Lkb1 deletion led to the identification of Dtymk, encoding deoxythymidylate kinase (DTYMK), which catalyzes dTTP biosynthesis, as synthetically lethal with Lkb1 deficiency in mouse and human lung cancer lines. Global metabolite profiling showed that Lkb1-null cells had a striking decrease in multiple nucleotide metabolites as compared with the Lkb1–wild-type cells. Thus, LKB1-mutant lung cancers have deficits in nucleotide metabolism that confer hypersensitivity to DTYMK inhibition, suggesting that DTYMK is a potential therapeutic target in this aggressive subset of tumors.

Significance: Using cell lines derived from the lung cancers occurring in genetically engineered mice, we conducted an integrative genome-wide short hairpin RNA and metabolite screen to identify DTYMK as a potential therapeutic target in Kras/Lkb1–mutant lung cancer. We believe that DTYMK is tractable for the development of novel therapeutics, and show an integrative approach to target identification that reduces false-positive candidates and should have broad applicability for the development of targeted therapeutics. Cancer Discov; 3(8); 870–9. ©2013 AACR.

See related commentary by Marcus and Khuri, p. 843

This article is highlighted in the In This Issue feature, p. 826
Data from Biallelic Mutations in BRCA1 Cause a New Fanconi Anemia Subtype
Authors: Sawyer Sarah L. , Tian Lei , Kähkönen Marketta , Schwartzentruber Jeremy , Kircher Martin , Majewski Jacek , Dyment David A. , Innes A. Micheil , Boycott Kym M. , Moreau Lisa A. , Moilanen Jukka S. , Greenberg Roger A.
Published: March 2024

Abstract
Deficiency in BRCA-dependent DNA interstrand crosslink (ICL) repair is intimately connected to breast cancer susceptibility and to the rare developmental syndrome Fanconi anemia. Bona fide Fanconi anemia proteins, BRCA2 (FANCD1), PALB2 (FANCN), and BRIP1 (FANCJ), interact with BRCA1 during ICL repair. However, the lack of detailed phenotypic and cellular characterization of a patient with biallelic BRCA1 mutations has precluded assignment of BRCA1 as a definitive Fanconi anemia susceptibility gene. Here, we report the presence of biallelic BRCA1 mutations in a woman with multiple congenital anomalies consistent with a Fanconi anemia–like disorder and breast cancer at age 23. Patient cells exhibited deficiency in BRCA1 and RAD51 localization to DNA-damage sites, combined with radial chromosome formation and hypersensitivity to ICL-inducing agents. Restoration of these functions was achieved by ectopic introduction of a BRCA1 transgene. These observations provide evidence in support of BRCA1 as a new Fanconi anemia gene (FANCS).

Significance: We establish that biallelic BRCA1 mutations cause a distinct FA-S, which has implications for risk counselling in families where both parents harbor BRCA1 mutations. The genetic basis of hereditary cancer susceptibility syndromes provides diagnostic information, insights into treatment strategies, and more accurate recurrence risk counseling to families. Cancer Discov; 5(2); 135–42. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 97