Therapeutic reduction of cell-mediated immunosuppression in mycosis fungoides and Sézary syndrome

Abstract

Tumor progression is associated with progressive immunosuppression mediated in part by T regulatory cell(s) (Treg) and/or myeloid-derived suppressor cell(s) (MDSC). Development of strategies to reduce populations of immune cells with suppressive function in cancer patients may enable the induction or recovery of immunity against tumor cells, which may limit or reverse disease progression. With a goal of developing Treg and MDSC neutralizing strategies to treat mycosis fungoides (MF) and Sézary syndrome (SzS), we determined the association between disease stage and suppressor cell populations in patients with MF/SzS, including those responding to therapy. We found elevations in Treg populations, across Treg subtypes, in patients with SzS, and these Treg markedly suppressed proliferation of autologous CD4⁺CD25⁻ responder T cells. Interestingly, while MDSC numbers were not increased in MF/SzS patients, MDSC from patients with stage IB and above produced significantly more reactive oxygen species than those from stage IA MF patients and control cohorts. Therapy with the CD25-targeting agent denileukin diftitox or IFN-α2b was associated with a reduction in Treg numbers or MDSC function, respectively. These studies identify potential mechanisms of action for these therapies and support the development of coordinated strategies targeting both Treg and MDSC activities in patients with MF/SzS.

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Selection of reference groups in the Life Span Study of atomic bomb survivors

Abstract

In cohort studies, unbiased estimation of exposure-outcome associations requires selection of an appropriate reference group of unexposed individuals. We illustrate strategies for analyzing cohort data with multiple potential reference groups. We analyzed the association between radiation exposure and incidence of first primary solid cancer among 105,444 participants of the Life Span Study (Hiroshima and Nagasaki, Japan, 1958–2009). Potential reference groups included zero-dose survivors at different ground distances from the hypocenter (internal) and city residents who were not in either city at the time of the bombings (external). DS02R1 weighted absorbed colon doses were estimated by the DS02 dosimetry system. Piecewise constant hazard models estimated excess relative risks of first primary solid cancer. We focused on sex-averaged excess relative risks and the shape of the dose–response curve. A model with internal standardization provided a sex-averaged excess relative risk of 0.510, 95% confidence interval: (0.414, 0.612) per gray of weighted absorbed colon dose, as well as strong evidence of a curvilinear dose response among males (P = 0.008). Selection of not-in-city residents as the reference group resulted in a larger excess relative risk of 0.560, 95% confidence interval: (0.467, 0.657) per gray, and reduced evidence of a curvilinear dose response among males (P = 0.042). These differences were particularly apparent at weighted absorbed colon doses < 1 gray. In cohort studies, selection of an appropriate reference group requires understanding of the nature of unmeasured confounding to which the results could be sensitive.

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Diet and risk of diabetic retinopathy: a systematic review

Abstract

Diabetic retinopathy is a microvascular complication of diabetes that threatens all individuals with diabetes, leading to vision loss or blindness if left untreated. It is frequently associated with diabetic macular edema, which can occur at any point during the development of diabetic retinopathy. The key factors known to lead to its development include hyperglycemia, hypertension, and the duration of diabetes. Though the diet is important in the development of diabetes, its role in diabetic retinopathy has not been clearly identified. In this systematic review, we aimed to identify, summarize and interpret the literature on the association between the diet and dietary intakes of specific foods, nutrients, and food groups, and the risk of diabetic retinopathy. We searched PubMed and Web of Science for English-language studies evaluating the association between the dietary intake of individual foods, macro or micronutrients, dietary supplements, and dietary patterns and their association with retinopathy or macular edema. After reviewing potentially relevant abstracts and, when necessary, full texts, we identified 27 relevant studies. Identified studies investigated intakes of fruit, vegetables, fish, milk, carbohydrates, fibre, fat, protein, salt, potassium, vitamins C, D, and E, carotenoids, dietary supplements, green tea and alcohol. Studies suggest that adherence to the Mediterranean diet and high fruit, vegetable and fish intake may protect against the development of diabetic retinopathy, although the evidence is limited. Studies concerning other aspects of the diet are not in agreement. The role of the diet in the development of diabetic retinopathy is an area that warrants more attention.

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Corrigendum

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Issue Information - Ed Board

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Corrigendum

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Trends in prostate cancer incidence between 1996 and 2013 in two Swiss regions by age, grade, and T-stage

Abstract

Purpose

To investigate differences in prostate cancer incidence between two distinct Swiss regions from 1996 to 2013 stratified by age group, grade, and T-stage.

Methods

The dataset included 17,495 men living in Zurich and 3,505 men living in Ticino, diagnosed with prostate cancer between 1996 and 2013. We computed age-standardized incidence rates per 100,000 person-years using the European Standard Population. Trends were assessed using JoinPoint regression analysis Software.

Results

Age-standardized incidence rates were generally higher in Zurich compared to Ticino but the difference decreased over time. Incidence rates increased significantly up to 2002 in Zurich and 2007 in Ticino and then decreased. A statistically significant increase was observed for men aged < 65 years, for grade 3 tumors, and for T-stage 2 and 3 tumors. The largest decrease was seen for grade 1 tumors. Furthermore, the incidence of tumors of unknown grade or T-stage decreased significantly in both regions.

Conclusions

The trends in prostate cancer incidence rates were similar in both regions, although on a higher level in Zurich compared to Ticino. However, the difference decreased over time. The distribution of T-stage and grade did not explain the difference in incidence rates. Different use of opportunistic screening may play a role.

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Trends in prostate cancer incidence between 1996 and 2013 in two Swiss regions by age, grade, and T-stage

Abstract

Purpose

To investigate differences in prostate cancer incidence between two distinct Swiss regions from 1996 to 2013 stratified by age group, grade, and T-stage.

Methods

The dataset included 17,495 men living in Zurich and 3,505 men living in Ticino, diagnosed with prostate cancer between 1996 and 2013. We computed age-standardized incidence rates per 100,000 person-years using the European Standard Population. Trends were assessed using JoinPoint regression analysis Software.

Results

Age-standardized incidence rates were generally higher in Zurich compared to Ticino but the difference decreased over time. Incidence rates increased significantly up to 2002 in Zurich and 2007 in Ticino and then decreased. A statistically significant increase was observed for men aged < 65 years, for grade 3 tumors, and for T-stage 2 and 3 tumors. The largest decrease was seen for grade 1 tumors. Furthermore, the incidence of tumors of unknown grade or T-stage decreased significantly in both regions.

Conclusions

The trends in prostate cancer incidence rates were similar in both regions, although on a higher level in Zurich compared to Ticino. However, the difference decreased over time. The distribution of T-stage and grade did not explain the difference in incidence rates. Different use of opportunistic screening may play a role.

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Trends in incidence, mortality and survival of penile squamous cell carcinoma in Norway 1956-2015

Abstract

We examine trends in incidence, mortality and survival of penile squamous cell carcinoma (SCC) in Norway over 60 years. Data on all cases of penile cancer diagnosed in Norway during 1956-2015 was obtained from the Cancer Registry of Norway. Trends in age-standardised rates of penile SCC incidence, mortality and 5-year relative survival were assessed by the annual percentage change statistic and joinpoint regression. A total of 1596 penile cancer cases were diagnosed during 1956-2015, among which 1474 (92.4%) were SCC. During 2011-2015, the age-standardised incidence and mortality of penile SCC were 0.91 (95% confidence interval (CI): 0.78;1.05) and 0.50 (0.42;0.60) per 100,000, respectively, and the 5-year relative survival was 61.6% (41.9;76.4). The incidence of SCC increased during 1956-2015, with an average annual percentage change (AAPC) of 0.80% (0.46;1.15). The increase was strongest among men diagnosed at a relatively early age (age<=64 years; AAPC: 1.47% (0.90;2.05)). Mortality also increased over the study period (AAPC: 0.47% (0.10;0.85)), whereas 5-year relative survival did not change (AAPC: 0.08% (-0.19; 0.36)). We conclude that the incidence of penile SCC has increased at a moderate and constant rate during 1956-2015, and that the most consistent increase occurred among younger men. Mortality also increased during the study period. However, survival did not change, thus changes in diagnostics and treatment had little impact on survival from penile SCC. Since a substantial proportion of penile SCC is caused by human papillomavirus (HPV), the incidence increase may in part be attributed to increased exposure to HPV in the population. This article is protected by copyright. All rights reserved.

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Sodium glucose cotransporter 2 inhibitor canagliflozin attenuates liver cancer cell growth and angiogenic activity by inhibiting glucose uptake

Abstract

Sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) comprise a new class of antidiabetic agents that inhibit glucose reabsorption in the renal proximal tubules. Although a recent report demonstrated the potential ability of SGLT2-Is to attenuate cancer growth of SGLT2-expressing cancer cells, little is known about the effects of SGLT2-Is on hepatocellular carcinoma (HCC). Here, we investigate the anti-cancer properties of a SGLT2-I, canagliflozin, against human liver cancer cells. SGTL2 mRNA and protein expression were detected in Huh7 and HepG2 cells, although not in HLE as well as primary human hepatocytes and hepatic stellate cells. Canagliflozin exerted antiproliferative effects on SGLT2-expressing Huh7 and HepG2 cells in a dose-dependent manner by inhibiting glycolytic metabolism including glucose uptake, lactate and intracellular ATP production. This agent also induced G2/M arrest and apoptosis with inhibited phosphorylation of ERK, p38 and AKT and cleavage of caspase3.

Xenograft tumor growth assay showed that oral administration of canagliflozin (10 mg/kg/day) significantly reduced subcutaneous tumor burdens in a glycemic status-independent manner, and attenuated intratumor vascularization in Huh7- and HepG2-derived xenograft tumors in BALB/c nude mice. In vitro, canagliflozin suppressed the increased human umbilical vein endothelial cell (HUVEC) proliferation and tubular formation which were observed in Huh7 or HepG2 co-cultures. By contrast, canagliflozin had no effect on tumor growth and intratumor angiogenesis in SGLT2-null HLE-derived xenograft models. These results indicate that SGLT2-I therapy is a potential new strategy for the treatment of HCC. This article is protected by copyright. All rights reserved.

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Acne in late adolescence and risk of prostate cancer

Abstract

Accumulating evidence suggest that Propionibacterium acnes may play a role in prostate carcinogenesis, but data are so far limited and inconclusive. The aim of this population-based cohort study was therefore to test whether presence of acne vulgaris during late adolescence is associated with an increased risk of prostate cancer later in life.

We identified a large cohort of young men born in Sweden between 1952 and 1956, who underwent mandatory assessment for military conscription around the age of 18 (n= 243,187). Test information along with health data including medical diagnoses at time of conscription was available through the Swedish Military Conscription Register and the National Patient Register. The cohort was followed through linkages to the Swedish Cancer Register to identify the occurrence of prostate cancer until December 31^st 2009. We used Cox regression to calculate adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between acne in adolescence and prostate cancer risk.

A total of 1,633 men were diagnosed with prostate cancer during a median follow-up of 36.7 years. A diagnosis of acne was associated with a statistically significant increased risk for prostate cancer (adjusted HR: 1.43 95%; CI: 1.06-1.92), particularly for advanced stage disease (HR: 2.37 95%; CI 1.19-4.73). A diagnosis of acne classified as severe conferred a 6-fold increased risk of prostate cancer (HR: 5.70 95% CI 1.42-22.85). Data from this large prospective population-based cohort add new evidence supporting a role of P acnes infection in prostate cancer. This article is protected by copyright. All rights reserved.

http://ift.tt/2ATejBc

Trends in incidence, mortality and survival of penile squamous cell carcinoma in Norway 1956-2015

Abstract

We examine trends in incidence, mortality and survival of penile squamous cell carcinoma (SCC) in Norway over 60 years. Data on all cases of penile cancer diagnosed in Norway during 1956-2015 was obtained from the Cancer Registry of Norway. Trends in age-standardised rates of penile SCC incidence, mortality and 5-year relative survival were assessed by the annual percentage change statistic and joinpoint regression. A total of 1596 penile cancer cases were diagnosed during 1956-2015, among which 1474 (92.4%) were SCC. During 2011-2015, the age-standardised incidence and mortality of penile SCC were 0.91 (95% confidence interval (CI): 0.78;1.05) and 0.50 (0.42;0.60) per 100,000, respectively, and the 5-year relative survival was 61.6% (41.9;76.4). The incidence of SCC increased during 1956-2015, with an average annual percentage change (AAPC) of 0.80% (0.46;1.15). The increase was strongest among men diagnosed at a relatively early age (age<=64 years; AAPC: 1.47% (0.90;2.05)). Mortality also increased over the study period (AAPC: 0.47% (0.10;0.85)), whereas 5-year relative survival did not change (AAPC: 0.08% (-0.19; 0.36)). We conclude that the incidence of penile SCC has increased at a moderate and constant rate during 1956-2015, and that the most consistent increase occurred among younger men. Mortality also increased during the study period. However, survival did not change, thus changes in diagnostics and treatment had little impact on survival from penile SCC. Since a substantial proportion of penile SCC is caused by human papillomavirus (HPV), the incidence increase may in part be attributed to increased exposure to HPV in the population. This article is protected by copyright. All rights reserved.

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Sodium glucose cotransporter 2 inhibitor canagliflozin attenuates liver cancer cell growth and angiogenic activity by inhibiting glucose uptake

Abstract

Sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) comprise a new class of antidiabetic agents that inhibit glucose reabsorption in the renal proximal tubules. Although a recent report demonstrated the potential ability of SGLT2-Is to attenuate cancer growth of SGLT2-expressing cancer cells, little is known about the effects of SGLT2-Is on hepatocellular carcinoma (HCC). Here, we investigate the anti-cancer properties of a SGLT2-I, canagliflozin, against human liver cancer cells. SGTL2 mRNA and protein expression were detected in Huh7 and HepG2 cells, although not in HLE as well as primary human hepatocytes and hepatic stellate cells. Canagliflozin exerted antiproliferative effects on SGLT2-expressing Huh7 and HepG2 cells in a dose-dependent manner by inhibiting glycolytic metabolism including glucose uptake, lactate and intracellular ATP production. This agent also induced G2/M arrest and apoptosis with inhibited phosphorylation of ERK, p38 and AKT and cleavage of caspase3.

Xenograft tumor growth assay showed that oral administration of canagliflozin (10 mg/kg/day) significantly reduced subcutaneous tumor burdens in a glycemic status-independent manner, and attenuated intratumor vascularization in Huh7- and HepG2-derived xenograft tumors in BALB/c nude mice. In vitro, canagliflozin suppressed the increased human umbilical vein endothelial cell (HUVEC) proliferation and tubular formation which were observed in Huh7 or HepG2 co-cultures. By contrast, canagliflozin had no effect on tumor growth and intratumor angiogenesis in SGLT2-null HLE-derived xenograft models. These results indicate that SGLT2-I therapy is a potential new strategy for the treatment of HCC. This article is protected by copyright. All rights reserved.

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Acne in late adolescence and risk of prostate cancer

Abstract

Accumulating evidence suggest that Propionibacterium acnes may play a role in prostate carcinogenesis, but data are so far limited and inconclusive. The aim of this population-based cohort study was therefore to test whether presence of acne vulgaris during late adolescence is associated with an increased risk of prostate cancer later in life.

We identified a large cohort of young men born in Sweden between 1952 and 1956, who underwent mandatory assessment for military conscription around the age of 18 (n= 243,187). Test information along with health data including medical diagnoses at time of conscription was available through the Swedish Military Conscription Register and the National Patient Register. The cohort was followed through linkages to the Swedish Cancer Register to identify the occurrence of prostate cancer until December 31^st 2009. We used Cox regression to calculate adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between acne in adolescence and prostate cancer risk.

A total of 1,633 men were diagnosed with prostate cancer during a median follow-up of 36.7 years. A diagnosis of acne was associated with a statistically significant increased risk for prostate cancer (adjusted HR: 1.43 95%; CI: 1.06-1.92), particularly for advanced stage disease (HR: 2.37 95%; CI 1.19-4.73). A diagnosis of acne classified as severe conferred a 6-fold increased risk of prostate cancer (HR: 5.70 95% CI 1.42-22.85). Data from this large prospective population-based cohort add new evidence supporting a role of P acnes infection in prostate cancer. This article is protected by copyright. All rights reserved.

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Therapeutic reduction of cell-mediated immunosuppression in mycosis fungoides and Sézary syndrome

Abstract

Tumor progression is associated with progressive immunosuppression mediated in part by T regulatory cell(s) (Treg) and/or myeloid-derived suppressor cell(s) (MDSC). Development of strategies to reduce populations of immune cells with suppressive function in cancer patients may enable the induction or recovery of immunity against tumor cells, which may limit or reverse disease progression. With a goal of developing Treg and MDSC neutralizing strategies to treat mycosis fungoides (MF) and Sézary syndrome (SzS), we determined the association between disease stage and suppressor cell populations in patients with MF/SzS, including those responding to therapy. We found elevations in Treg populations, across Treg subtypes, in patients with SzS, and these Treg markedly suppressed proliferation of autologous CD4⁺CD25⁻ responder T cells. Interestingly, while MDSC numbers were not increased in MF/SzS patients, MDSC from patients with stage IB and above produced significantly more reactive oxygen species than those from stage IA MF patients and control cohorts. Therapy with the CD25-targeting agent denileukin diftitox or IFN-α2b was associated with a reduction in Treg numbers or MDSC function, respectively. These studies identify potential mechanisms of action for these therapies and support the development of coordinated strategies targeting both Treg and MDSC activities in patients with MF/SzS.

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Therapeutic reduction of cell-mediated immunosuppression in mycosis fungoides and Sézary syndrome

Abstract

Tumor progression is associated with progressive immunosuppression mediated in part by T regulatory cell(s) (Treg) and/or myeloid-derived suppressor cell(s) (MDSC). Development of strategies to reduce populations of immune cells with suppressive function in cancer patients may enable the induction or recovery of immunity against tumor cells, which may limit or reverse disease progression. With a goal of developing Treg and MDSC neutralizing strategies to treat mycosis fungoides (MF) and Sézary syndrome (SzS), we determined the association between disease stage and suppressor cell populations in patients with MF/SzS, including those responding to therapy. We found elevations in Treg populations, across Treg subtypes, in patients with SzS, and these Treg markedly suppressed proliferation of autologous CD4⁺CD25⁻ responder T cells. Interestingly, while MDSC numbers were not increased in MF/SzS patients, MDSC from patients with stage IB and above produced significantly more reactive oxygen species than those from stage IA MF patients and control cohorts. Therapy with the CD25-targeting agent denileukin diftitox or IFN-α2b was associated with a reduction in Treg numbers or MDSC function, respectively. These studies identify potential mechanisms of action for these therapies and support the development of coordinated strategies targeting both Treg and MDSC activities in patients with MF/SzS.

http://ift.tt/2jHWv16

Unusual presentation of prune belly syndrome: a case report

Prune belly syndrome is a rare congenital malformation of unknown etiology, with the following triad of findings: abdominal muscle wall weakness, undescended testes, and urinary tract abnormalities. In most ca...

http://ift.tt/2ASa1ub

Therapeutic reduction of cell-mediated immunosuppression in mycosis fungoides and Sézary syndrome

Abstract

Tumor progression is associated with progressive immunosuppression mediated in part by T regulatory cell(s) (Treg) and/or myeloid-derived suppressor cell(s) (MDSC). Development of strategies to reduce populations of immune cells with suppressive function in cancer patients may enable the induction or recovery of immunity against tumor cells, which may limit or reverse disease progression. With a goal of developing Treg and MDSC neutralizing strategies to treat mycosis fungoides (MF) and Sézary syndrome (SzS), we determined the association between disease stage and suppressor cell populations in patients with MF/SzS, including those responding to therapy. We found elevations in Treg populations, across Treg subtypes, in patients with SzS, and these Treg markedly suppressed proliferation of autologous CD4⁺CD25⁻ responder T cells. Interestingly, while MDSC numbers were not increased in MF/SzS patients, MDSC from patients with stage IB and above produced significantly more reactive oxygen species than those from stage IA MF patients and control cohorts. Therapy with the CD25-targeting agent denileukin diftitox or IFN-α2b was associated with a reduction in Treg numbers or MDSC function, respectively. These studies identify potential mechanisms of action for these therapies and support the development of coordinated strategies targeting both Treg and MDSC activities in patients with MF/SzS.

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Issue Information

Cover of this issue. Vash2 contributes to gastric tumor growth. See also Suzuki et al. (pp. 2342-2351 of this issue).

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Reviewers

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In This Issue

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Issue Information

Cover of this issue. Vash2 contributes to gastric tumor growth. See also Suzuki et al. (pp. 2342-2351 of this issue).

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Reviewers

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In This Issue

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The Anti-inflammatory Effect of Personalized Omega-3 Fatty Acid Dosing for Reducing Prostaglandin E2 in the Colonic Mucosa Is Attenuated in Obesity

This clinical trial developed a personalized dosing model for reducing prostaglandin E₂ (PGE₂) in colonic mucosa using -3 fatty acid supplementation. The model utilized serum eicosapentaenoic acid (EPA, -3):arachidonic acid (AA, -6) ratios as biomarkers of colonic mucosal PGE₂ concentration. Normal human volunteers were given low and high -3 fatty acid test doses for 2 weeks. This established a slope and intercept of the line for dose versus serum EPA:AA ratio in each individual. The slope and intercept was utilized to calculate a personalized target dose that was given for 12 weeks. This target dose was calculated on the basis of a model, initially derived from lean rodents, showing a log-linear relationship between serum EPA:AA ratios and colonic mucosal PGE₂ reduction. Bayesian methods allowed addition of human data to the rodent model as the trial progressed. The dosing model aimed to achieve a serum EPA:AA ratio that is associated with a 50% reduction in colonic PGE₂. Mean colonic mucosal PGE₂ concentrations were 6.55 ng/mg protein (SD, 5.78) before any supplementation and 3.59 ng/mg protein (SD, 3.29) after 12 weeks of target dosing. In secondary analyses, the decreases in PGE₂ were significantly attenuated in overweight and obese participants. This occurred despite a higher target dose for the obese versus normal weight participants, as generated by the pharmacodynamic predictive model. Large decreases also were observed in 12-hydroxyicosatetraenoic acids, and PGE₃ increased substantially. Future biomarker-driven dosing models for cancer prevention therefore should consider energy balance as well as overall eicosanoid homeostasis in normal tissue. Cancer Prev Res; 10(12); 729–37. ©2017 AACR.

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The Next Frontier: Head and Neck Cancer Immunoprevention

Restoring T cell–mediated antitumor immunity by targeting immune checkpoint inhibitors in head and neck squamous cell carcinoma (HNSCC) results in immunomodulation and durable remissions. However, the overall response rate to these immunotherapies in HNSCC is only approximately 20%. This raises the possibility that immunologic intervention earlier in the HNSCC continuum, such as in oral premalignant lesions (OPL) could elicit an increased therapeutic response. New experimental studies suggest that immune therapies can be used for HNSCC prevention rather than therapy. Given the current excitement for precision medicine, these findings support the future development of multimodality approaches for preventive immune oncology. Cancer Prev Res; 10(12); 681–3. ©2017 AACR.

See related article by Jin Wang, et al., p. 684

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PD-1 Blockade Prevents the Development and Progression of Carcinogen-Induced Oral Premalignant Lesions

Oral squamous cell carcinoma (OSCC) is preceded by progressive oral premalignant lesions (OPL). Therefore, therapeutic strategies that prevent malignant progression of OPLs are expected to reduce the incidence of OSCC development. Immune checkpoint inhibitors that target the interaction of programmed death receptor 1 (PD-1) on T cells with the PD-1 ligand PD-L1 on cancer cells have been shown to extend the survival of patients with advanced OSCC. Here, we used the 4-nitroquinoline-1-oxide (4-NQO) mouse model of oral carcinogenesis to test the hypothesis that PD-1 blockade may control the progression of OPLs. Mice were exposed to 4-NQO in their drinking water and then randomly assigned to two treatment groups that received either a blocking antibody for PD-1 or a control IgG. We found that anti–PD-1 treatment significantly reduced the number of oral lesions that developed in these mice and prevented malignant progression. Low-grade dysplastic lesions responded to PD-1 blockade with a significant increase in the recruitment of CD8⁺ and CD4⁺ T cells and the accumulation of CTLA-4⁺ T cells in their microenvironment. Notably, PD-1 inhibition was accompanied by induction of IFN, STAT1 activation and the production of the T-cell effector granzyme B in infiltrating cells, and by the induction of apoptosis in the epithelial cells of the oral lesions, suggesting that T-cell activation mediates the immunopreventive effects of anti–PD-1. These results support the potential clinical benefit of PD-1 immune checkpoint blockade to prevent OSCC development and progression and suggest that CTLA-4 inhibitors may enhance the preventive effects of anti–PD-1. Cancer Prev Res; 10(12); 684–93. ©2017 AACR.

See related editorial by Gutkind et al., p. 681

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Risk Prediction of Cervical Cancer and Precancers by Type-Specific Human Papillomavirus: Evidence from a Population-Based Cohort Study in China

Risk stratification of human papillomavirus (HPV)-positive women is needed to avoid excessive colposcopy and overtreatment in cervical cancer screening. We aimed to evaluate the predictive value of type-specific HPV in detecting cervical cancer and precancers in a Chinese population–based cohort and provide evidence of HPV genotyping to triage HPV-positive women. We typed all Hybrid Capture 2–positive cytologic samples of 1,742 women in Shanxi Province Cervical Cancer Screening Study cohort. Cumulative risks of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) among HPV-positive women and cumulative detection rates of CIN2+ among general women by type-specific HPV were estimated during the course of 10-year follow-up. HPV 16 and HPV 52 were most prevalent types among the screening population. Ten-year cumulative risk of CIN2+ was 47.5% [95% confidence interval (CI), 31.6–62.3] for HPV 16–positive women and 46.3% (95% CI, 15.3–75.4) for HPV 31–positive women. Ten-year cumulative risks of CIN2+ among HPV 58, 39, 33, 18, and 52 positive women ranged from 34.3% to 12.0% in a decreasing order. CIN2+ risks were found to be positively associated with infection times of the same genotypes of HPV 16, 31, 33, and 58 (all P_trend < 0.001). Cumulative detection rates of CIN2+ within 10 years were predominantly contributed by HPV 16, 31, and 58. Our results support the risk-based management of HPV-positive women using HPV genotyping and also indicate the significance of including HPV 31 and 58 apart from commonly acknowledged HPV 16 and HPV 18 in achieving better risk stratification. Cancer Prev Res; 10(12); 745–51. ©2017 AACR.

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Differential Gene Regulation and Tumor-Inhibitory Activities of Alpha-, Delta-, and Gamma-Tocopherols in Estrogen-Mediated Mammary Carcinogenesis

Despite experimental evidence elucidating the antitumor activities of tocopherols, clinical trials with α-tocopherol (α-T) have failed to demonstrate its beneficial effects in cancer prevention. This study compared the chemopreventive efficacy of individual tocopherols (α-, -, and -T) and a -T–rich tocopherol mixture (-TmT) in the August-Copenhagen Irish (ACI) rat model of estrogen-mediated mammary cancer. Female ACI rats receiving 17β-estradiol (E2) implants were administered with 0.2% α-T, -T, -T, or -TmT for 30 weeks. Although α-T had no significant effects on mammary tumor growth in ACI rats, -T, -T, and -TmT reduced mammary tumor volume by 51% (P < 0.05), 60% (P < 0.01), and 59% (P < 0.01), respectively. Immunohistochemical analysis revealed that -T, -T, and -TmT reduced levels of the cell proliferation marker, proliferating cell nuclear antigen, in the rat mammary tumors. To gain further insight into the biological functions of different forms of tocopherols, RNA-seq analysis of the tumors was performed. Treatment with -T induced robust gene expression changes in the mammary tumors of ACI rats. Ingenuity Pathway Analysis identified "Cancer" as a top disease pathway and "Tumor growth" and "Metastasis" as the top signaling pathways modulated by -T. Although the results need further functional validation, this study presents an unbiased attempt to understand the differences between biological activities of individual forms of tocopherols at the whole transcriptome level. In conclusion, -T and -T have superior cancer preventive properties compared to α-T in the prevention of estrogen-mediated mammary carcinogenesis. Cancer Prev Res; 10(12); 694–703. ©2017 AACR.

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Voluntary Wheel Running Reduces the Acute Inflammatory Response to Liver Carcinogen in a Sex-specific Manner

Inflammation contributes to the development of cancer, yet acute inflammatory responses are also needed to eradicate tumorigenic cells and activate adaptive immune responses to combat cancer. Physical exercise has direct immunomodulatory effects, and in line with this, exercise has been demonstrated to inhibit tumor growth, including diethylnitrosamine-(DEN)-induced hepatocarcinoma. Having observed a sex-dependent development of DEN-induced hepatocarcinoma, we aimed to evaluate the effect of exercise and sex on the acute inflammatory response to DEN. Thus, we randomized male and female mice to cages with or without running wheels for 6 weeks, whereafter DEN was administered and the inflammatory response was evaluated for up to 96 hours. DEN administration caused marked acute inflammatory responses in female mice with weight loss, reduced food intake, release of liver enzymes, and increased systemic levels of IL6. Moreover, DEN caused increased hepatic expression of cytokines, immune cell markers, and components of the toll-like receptor signaling pathway. In male mice, DEN administration provoked similar physiologic effects with weight loss and reduced food intake, but less systemic and hepatic acute inflammation, which was associated with a higher baseline expression of the detoxifying enzyme glutathione S-transferase and lower expression of ERα in male mice. Voluntary wheel running attenuated systemic and hepatic inflammation, in particular in the female mice, and shifted the peak time of the inflammatory response. In conclusion, DEN elicited an acute inflammatory response in particular in female mice, and this response was attenuated by prior exercise. Cancer Prev Res; 10(12); 719–28. ©2017 AACR.

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Association between Cigar or Pipe Smoking and Cancer Risk in Men: A Pooled Analysis of Five Cohort Studies

Introduction: Use of non-cigarette tobacco products such as cigars and pipe has been increasing, even though these products entail exposure to similar carcinogens to those in cigarettes. More research is needed to explore the risk of these products to guide cancer prevention efforts.

Methods: To measure the association between cigars and/or pipe smoking, and cancer incidence in men, we performed meta-analyses of data from five prospective cohorts. Cox regression was used to evaluate the association between different aspects of cigars and pipe smoking and risk of each smoking-related cancer (head and neck, esophagus, lung, stomach, liver, pancreas, kidney, and bladder) for each study. Adjusted HRs were combined using random-effects models.

Results: Cigars and/or pipe smokers were at increased risk for head and neck [HR, 1.51; 95% confidence interval (CI), 1.22–1.87], lung (HR, 2.04; 95% CI, 1.68–2.47), and liver cancers (HR, 1.56; 95% CI, 1.08–2.26). Ever-smokers of cigars and/or pipe had an increased risk of developing a smoking-related cancer when compared with never smokers of any tobacco product (overall HR, 1.07; 95% CI, 1.03–1.12). The risk for smoking-related cancers was also increased in mixed smokers who smoked cigars or pipe as well as cigarettes, even when they were smoking predominantly pipe or cigars.

Discussion: This pooled analysis highlights the increased risk for smoking-related cancers, particularly for lung and head and neck cancers in exclusive and predominant smokers (former and current) of cigars and pipe. Tobacco prevention efforts should include these products in addition to cigarettes. Cancer Prev Res; 10(12); 704–9. ©2017 AACR.

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IKZF1 Gene in Childhood B-cell Precursor Acute Lymphoblastic Leukemia: Interplay between Genetic Susceptibility and Somatic Abnormalities

SNPs in IKZF1 are associated with inherited susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Besides, somatic copy number abnormalities (CNA) in genes related to lymphopoiesis (e.g., IKZF1, CDKN2A/B, BTG1) impact patient's outcome. Therefore, this study aimed to investigate an association between germline susceptibility and CNAs in BCP-ALL. The IKZF1 SNPs (rs11978267 and rs4132601) were genotyped in 276 cases and 467 controls. Bone marrow samples were used to determine the presence of somatic abnormalities. The IKZF1 transcript levels were quantified and associated with the SNPs and CNAs. Categorical variables were compared by ² test. ORs were estimated with unconditional logistic regression with 95% confidence interval (CI). The variant allele of IKZF1 rs4132601 conferred increased risk of BCP-ALL (OR, 2.09; 95% CI, 1.16–3.74). Individuals with either rs11978267 or rs4132601 had an increased risk for harboring IKZF1 deletion (OR, 2.80; 95% CI, 1.25–6.23 and OR, 2.88; 95% CI, 1.24–6.69, respectively). Increased risks were observed for individuals harboring both IKZF1 and BTG1 deletions (OR, 4.90; 95% CI, 1.65–14.55, rs11978267 and OR, 5.80; 95% CI, 1.94–17.41, rs4132601). Germline genetic variation increases the risk for childhood ALL in general, but also acts as a susceptibility factor bound for risk of specific somatic alterations. These findings provide new insight into the development of childhood ALL regarding causal variants and the biological basis of the risk association, offering the opportunity for future tailored research. Cancer Prev Res; 10(12); 738–44. ©2017 AACR.

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A Randomized Controlled Trial of Green Tea Extract Supplementation and Mammographic Density in Postmenopausal Women at Increased Risk of Breast Cancer

Epidemiologic and animal studies suggest a protective role of green tea against breast cancer. However, the underlying mechanism is not understood. We conducted a randomized, double-blinded, placebo-controlled phase II clinical trial to investigate whether supplementation with green tea extract (GTE) modifies mammographic density (MD), as a potential mechanism, involving 1,075 healthy postmenopausal women. Women assigned to the treatment arm consumed daily 4 decaffeinated GTE capsules containing 1,315 mg total catechins, including 843 mg epigallocatechin-3-gallate (EGCG) for 12 months. A computer-assisted method (Madena) was used to assess MD in digital mammograms at baseline and month 12 time points in 932 completers (462 in GTE and 470 in placebo). GTE supplementation for 12 months did not significantly change percent MD (PMD) or absolute MD in all women. In younger women (50–55 years), GTE supplementation significantly reduced PMD by 4.40% as compared with the placebo with a 1.02% PMD increase from pre- to postintervention (P = 0.05), but had no effect in older women (P_interaction = 0.07). GTE supplementation did not induce MD change in other subgroups of women stratified by catechol-O-methyltransferase genotype or level of body mass index. In conclusion, 1-year supplementation with a high dose of EGCG did not have a significant effect on MD measures in all women, but reduced PMD in younger women, an age-dependent effect similar to those of tamoxifen. Further investigation of the potential chemopreventive effect of green tea intake on breast cancer risk in younger women is warranted. Cancer Prev Res; 10(12); 710–8. ©2017 AACR.

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Acknowledgment to Reviewers

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The Anti-inflammatory Effect of Personalized Omega-3 Fatty Acid Dosing for Reducing Prostaglandin E2 in the Colonic Mucosa Is Attenuated in Obesity

This clinical trial developed a personalized dosing model for reducing prostaglandin E₂ (PGE₂) in colonic mucosa using -3 fatty acid supplementation. The model utilized serum eicosapentaenoic acid (EPA, -3):arachidonic acid (AA, -6) ratios as biomarkers of colonic mucosal PGE₂ concentration. Normal human volunteers were given low and high -3 fatty acid test doses for 2 weeks. This established a slope and intercept of the line for dose versus serum EPA:AA ratio in each individual. The slope and intercept was utilized to calculate a personalized target dose that was given for 12 weeks. This target dose was calculated on the basis of a model, initially derived from lean rodents, showing a log-linear relationship between serum EPA:AA ratios and colonic mucosal PGE₂ reduction. Bayesian methods allowed addition of human data to the rodent model as the trial progressed. The dosing model aimed to achieve a serum EPA:AA ratio that is associated with a 50% reduction in colonic PGE₂. Mean colonic mucosal PGE₂ concentrations were 6.55 ng/mg protein (SD, 5.78) before any supplementation and 3.59 ng/mg protein (SD, 3.29) after 12 weeks of target dosing. In secondary analyses, the decreases in PGE₂ were significantly attenuated in overweight and obese participants. This occurred despite a higher target dose for the obese versus normal weight participants, as generated by the pharmacodynamic predictive model. Large decreases also were observed in 12-hydroxyicosatetraenoic acids, and PGE₃ increased substantially. Future biomarker-driven dosing models for cancer prevention therefore should consider energy balance as well as overall eicosanoid homeostasis in normal tissue. Cancer Prev Res; 10(12); 729–37. ©2017 AACR.

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The Next Frontier: Head and Neck Cancer Immunoprevention

Restoring T cell–mediated antitumor immunity by targeting immune checkpoint inhibitors in head and neck squamous cell carcinoma (HNSCC) results in immunomodulation and durable remissions. However, the overall response rate to these immunotherapies in HNSCC is only approximately 20%. This raises the possibility that immunologic intervention earlier in the HNSCC continuum, such as in oral premalignant lesions (OPL) could elicit an increased therapeutic response. New experimental studies suggest that immune therapies can be used for HNSCC prevention rather than therapy. Given the current excitement for precision medicine, these findings support the future development of multimodality approaches for preventive immune oncology. Cancer Prev Res; 10(12); 681–3. ©2017 AACR.

See related article by Jin Wang, et al., p. 684

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PD-1 Blockade Prevents the Development and Progression of Carcinogen-Induced Oral Premalignant Lesions

Oral squamous cell carcinoma (OSCC) is preceded by progressive oral premalignant lesions (OPL). Therefore, therapeutic strategies that prevent malignant progression of OPLs are expected to reduce the incidence of OSCC development. Immune checkpoint inhibitors that target the interaction of programmed death receptor 1 (PD-1) on T cells with the PD-1 ligand PD-L1 on cancer cells have been shown to extend the survival of patients with advanced OSCC. Here, we used the 4-nitroquinoline-1-oxide (4-NQO) mouse model of oral carcinogenesis to test the hypothesis that PD-1 blockade may control the progression of OPLs. Mice were exposed to 4-NQO in their drinking water and then randomly assigned to two treatment groups that received either a blocking antibody for PD-1 or a control IgG. We found that anti–PD-1 treatment significantly reduced the number of oral lesions that developed in these mice and prevented malignant progression. Low-grade dysplastic lesions responded to PD-1 blockade with a significant increase in the recruitment of CD8⁺ and CD4⁺ T cells and the accumulation of CTLA-4⁺ T cells in their microenvironment. Notably, PD-1 inhibition was accompanied by induction of IFN, STAT1 activation and the production of the T-cell effector granzyme B in infiltrating cells, and by the induction of apoptosis in the epithelial cells of the oral lesions, suggesting that T-cell activation mediates the immunopreventive effects of anti–PD-1. These results support the potential clinical benefit of PD-1 immune checkpoint blockade to prevent OSCC development and progression and suggest that CTLA-4 inhibitors may enhance the preventive effects of anti–PD-1. Cancer Prev Res; 10(12); 684–93. ©2017 AACR.

See related editorial by Gutkind et al., p. 681

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Risk Prediction of Cervical Cancer and Precancers by Type-Specific Human Papillomavirus: Evidence from a Population-Based Cohort Study in China

Risk stratification of human papillomavirus (HPV)-positive women is needed to avoid excessive colposcopy and overtreatment in cervical cancer screening. We aimed to evaluate the predictive value of type-specific HPV in detecting cervical cancer and precancers in a Chinese population–based cohort and provide evidence of HPV genotyping to triage HPV-positive women. We typed all Hybrid Capture 2–positive cytologic samples of 1,742 women in Shanxi Province Cervical Cancer Screening Study cohort. Cumulative risks of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) among HPV-positive women and cumulative detection rates of CIN2+ among general women by type-specific HPV were estimated during the course of 10-year follow-up. HPV 16 and HPV 52 were most prevalent types among the screening population. Ten-year cumulative risk of CIN2+ was 47.5% [95% confidence interval (CI), 31.6–62.3] for HPV 16–positive women and 46.3% (95% CI, 15.3–75.4) for HPV 31–positive women. Ten-year cumulative risks of CIN2+ among HPV 58, 39, 33, 18, and 52 positive women ranged from 34.3% to 12.0% in a decreasing order. CIN2+ risks were found to be positively associated with infection times of the same genotypes of HPV 16, 31, 33, and 58 (all P_trend < 0.001). Cumulative detection rates of CIN2+ within 10 years were predominantly contributed by HPV 16, 31, and 58. Our results support the risk-based management of HPV-positive women using HPV genotyping and also indicate the significance of including HPV 31 and 58 apart from commonly acknowledged HPV 16 and HPV 18 in achieving better risk stratification. Cancer Prev Res; 10(12); 745–51. ©2017 AACR.

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Differential Gene Regulation and Tumor-Inhibitory Activities of Alpha-, Delta-, and Gamma-Tocopherols in Estrogen-Mediated Mammary Carcinogenesis

Despite experimental evidence elucidating the antitumor activities of tocopherols, clinical trials with α-tocopherol (α-T) have failed to demonstrate its beneficial effects in cancer prevention. This study compared the chemopreventive efficacy of individual tocopherols (α-, -, and -T) and a -T–rich tocopherol mixture (-TmT) in the August-Copenhagen Irish (ACI) rat model of estrogen-mediated mammary cancer. Female ACI rats receiving 17β-estradiol (E2) implants were administered with 0.2% α-T, -T, -T, or -TmT for 30 weeks. Although α-T had no significant effects on mammary tumor growth in ACI rats, -T, -T, and -TmT reduced mammary tumor volume by 51% (P < 0.05), 60% (P < 0.01), and 59% (P < 0.01), respectively. Immunohistochemical analysis revealed that -T, -T, and -TmT reduced levels of the cell proliferation marker, proliferating cell nuclear antigen, in the rat mammary tumors. To gain further insight into the biological functions of different forms of tocopherols, RNA-seq analysis of the tumors was performed. Treatment with -T induced robust gene expression changes in the mammary tumors of ACI rats. Ingenuity Pathway Analysis identified "Cancer" as a top disease pathway and "Tumor growth" and "Metastasis" as the top signaling pathways modulated by -T. Although the results need further functional validation, this study presents an unbiased attempt to understand the differences between biological activities of individual forms of tocopherols at the whole transcriptome level. In conclusion, -T and -T have superior cancer preventive properties compared to α-T in the prevention of estrogen-mediated mammary carcinogenesis. Cancer Prev Res; 10(12); 694–703. ©2017 AACR.

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Voluntary Wheel Running Reduces the Acute Inflammatory Response to Liver Carcinogen in a Sex-specific Manner

Inflammation contributes to the development of cancer, yet acute inflammatory responses are also needed to eradicate tumorigenic cells and activate adaptive immune responses to combat cancer. Physical exercise has direct immunomodulatory effects, and in line with this, exercise has been demonstrated to inhibit tumor growth, including diethylnitrosamine-(DEN)-induced hepatocarcinoma. Having observed a sex-dependent development of DEN-induced hepatocarcinoma, we aimed to evaluate the effect of exercise and sex on the acute inflammatory response to DEN. Thus, we randomized male and female mice to cages with or without running wheels for 6 weeks, whereafter DEN was administered and the inflammatory response was evaluated for up to 96 hours. DEN administration caused marked acute inflammatory responses in female mice with weight loss, reduced food intake, release of liver enzymes, and increased systemic levels of IL6. Moreover, DEN caused increased hepatic expression of cytokines, immune cell markers, and components of the toll-like receptor signaling pathway. In male mice, DEN administration provoked similar physiologic effects with weight loss and reduced food intake, but less systemic and hepatic acute inflammation, which was associated with a higher baseline expression of the detoxifying enzyme glutathione S-transferase and lower expression of ERα in male mice. Voluntary wheel running attenuated systemic and hepatic inflammation, in particular in the female mice, and shifted the peak time of the inflammatory response. In conclusion, DEN elicited an acute inflammatory response in particular in female mice, and this response was attenuated by prior exercise. Cancer Prev Res; 10(12); 719–28. ©2017 AACR.

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Association between Cigar or Pipe Smoking and Cancer Risk in Men: A Pooled Analysis of Five Cohort Studies

Introduction: Use of non-cigarette tobacco products such as cigars and pipe has been increasing, even though these products entail exposure to similar carcinogens to those in cigarettes. More research is needed to explore the risk of these products to guide cancer prevention efforts.

Methods: To measure the association between cigars and/or pipe smoking, and cancer incidence in men, we performed meta-analyses of data from five prospective cohorts. Cox regression was used to evaluate the association between different aspects of cigars and pipe smoking and risk of each smoking-related cancer (head and neck, esophagus, lung, stomach, liver, pancreas, kidney, and bladder) for each study. Adjusted HRs were combined using random-effects models.

Results: Cigars and/or pipe smokers were at increased risk for head and neck [HR, 1.51; 95% confidence interval (CI), 1.22–1.87], lung (HR, 2.04; 95% CI, 1.68–2.47), and liver cancers (HR, 1.56; 95% CI, 1.08–2.26). Ever-smokers of cigars and/or pipe had an increased risk of developing a smoking-related cancer when compared with never smokers of any tobacco product (overall HR, 1.07; 95% CI, 1.03–1.12). The risk for smoking-related cancers was also increased in mixed smokers who smoked cigars or pipe as well as cigarettes, even when they were smoking predominantly pipe or cigars.

Discussion: This pooled analysis highlights the increased risk for smoking-related cancers, particularly for lung and head and neck cancers in exclusive and predominant smokers (former and current) of cigars and pipe. Tobacco prevention efforts should include these products in addition to cigarettes. Cancer Prev Res; 10(12); 704–9. ©2017 AACR.

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IKZF1 Gene in Childhood B-cell Precursor Acute Lymphoblastic Leukemia: Interplay between Genetic Susceptibility and Somatic Abnormalities

SNPs in IKZF1 are associated with inherited susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Besides, somatic copy number abnormalities (CNA) in genes related to lymphopoiesis (e.g., IKZF1, CDKN2A/B, BTG1) impact patient's outcome. Therefore, this study aimed to investigate an association between germline susceptibility and CNAs in BCP-ALL. The IKZF1 SNPs (rs11978267 and rs4132601) were genotyped in 276 cases and 467 controls. Bone marrow samples were used to determine the presence of somatic abnormalities. The IKZF1 transcript levels were quantified and associated with the SNPs and CNAs. Categorical variables were compared by ² test. ORs were estimated with unconditional logistic regression with 95% confidence interval (CI). The variant allele of IKZF1 rs4132601 conferred increased risk of BCP-ALL (OR, 2.09; 95% CI, 1.16–3.74). Individuals with either rs11978267 or rs4132601 had an increased risk for harboring IKZF1 deletion (OR, 2.80; 95% CI, 1.25–6.23 and OR, 2.88; 95% CI, 1.24–6.69, respectively). Increased risks were observed for individuals harboring both IKZF1 and BTG1 deletions (OR, 4.90; 95% CI, 1.65–14.55, rs11978267 and OR, 5.80; 95% CI, 1.94–17.41, rs4132601). Germline genetic variation increases the risk for childhood ALL in general, but also acts as a susceptibility factor bound for risk of specific somatic alterations. These findings provide new insight into the development of childhood ALL regarding causal variants and the biological basis of the risk association, offering the opportunity for future tailored research. Cancer Prev Res; 10(12); 738–44. ©2017 AACR.

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A Randomized Controlled Trial of Green Tea Extract Supplementation and Mammographic Density in Postmenopausal Women at Increased Risk of Breast Cancer

Epidemiologic and animal studies suggest a protective role of green tea against breast cancer. However, the underlying mechanism is not understood. We conducted a randomized, double-blinded, placebo-controlled phase II clinical trial to investigate whether supplementation with green tea extract (GTE) modifies mammographic density (MD), as a potential mechanism, involving 1,075 healthy postmenopausal women. Women assigned to the treatment arm consumed daily 4 decaffeinated GTE capsules containing 1,315 mg total catechins, including 843 mg epigallocatechin-3-gallate (EGCG) for 12 months. A computer-assisted method (Madena) was used to assess MD in digital mammograms at baseline and month 12 time points in 932 completers (462 in GTE and 470 in placebo). GTE supplementation for 12 months did not significantly change percent MD (PMD) or absolute MD in all women. In younger women (50–55 years), GTE supplementation significantly reduced PMD by 4.40% as compared with the placebo with a 1.02% PMD increase from pre- to postintervention (P = 0.05), but had no effect in older women (P_interaction = 0.07). GTE supplementation did not induce MD change in other subgroups of women stratified by catechol-O-methyltransferase genotype or level of body mass index. In conclusion, 1-year supplementation with a high dose of EGCG did not have a significant effect on MD measures in all women, but reduced PMD in younger women, an age-dependent effect similar to those of tamoxifen. Further investigation of the potential chemopreventive effect of green tea intake on breast cancer risk in younger women is warranted. Cancer Prev Res; 10(12); 710–8. ©2017 AACR.

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Acknowledgment to Reviewers

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Simultaneous Targeting of Two Distinct Epitopes on MET Effectively Inhibits MET- and HGF-Driven Tumor Growth by Multiple Mechanisms

Increased MET activity is linked with poor prognosis and outcome in several human cancers currently lacking targeted therapies. Here, we report on the characterization of Sym015, an antibody mixture composed of two humanized IgG₁ antibodies against nonoverlapping epitopes of MET. Sym015 was selected by high-throughput screening searching for antibody mixtures with superior growth-inhibitory activity against MET-dependent cell lines. Synergistic inhibitory activity of the antibodies comprising Sym015 was observed in several cancer cell lines harboring amplified MET locus and was confirmed in vivo. Sym015 was found to exert its activity via multiple mechanisms. It disrupted interaction of MET with the HGF ligand and prompted activity-independent internalization and degradation of the receptor. In addition, Sym015 induced high levels of CDC and ADCC in vitro. The importance of these effector functions was confirmed in vivo using an Fc-effector function–attenuated version of Sym015. The enhanced effect of the two antibodies in Sym015 on both MET degradation and CDC and ADCC is predicted to render Sym015 superior to single antibodies targeting MET. Our results demonstrate strong potential for use of Sym015 as a therapeutic antibody mixture for treatment of MET-driven tumors. Sym015 is currently being tested in a phase I dose escalation clinical trial (NCT02648724). Mol Cancer Ther; 16(12); 2780–91. ©2017 AACR.

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CCR5-Dependent Homing of T Regulatory Cells to the Tumor Microenvironment Contributes to Skin Squamous Cell Carcinoma Development

Squamous cell carcinoma (SCC) is one of the most common human cancers worldwide. Recent studies show that regulatory T cells (Treg) have a critical role in the modulation of an antitumor immune response, and consequently the SCC development. Because the accumulation of Tregs at the tumor site is, in part, due to selective recruitment through CCR5- and CCR5-associated chemokines, we investigated the role of CCR5 in the SCC development. Our findings showed that CCR5-deficient mice (CCR5KO) were efficient in controlling papilloma's incidence when compared with wild-type mice. Analysis of tumor lesions in wild-type (WT) and CCR5KO mice revealed that lack of CCR5 lead to significant reduction in frequency of Tregs and increased of CD4 T cells into the tumors. Moreover, the adoptive transfer of naturally occurring Tregs CD4⁺CD25⁺CCR5⁺, CD4⁺CD25^–CCR5⁺ or CD8⁺CCR5⁺ conventional T cells to CCR5KO mice resulted in an increased papilloma incidence. Interestingly, adoptive transfer of WT CD4⁺CD25⁺CCR5⁺ cells to CCR5KO mice induced more undifferentiated SCC lesions, characterized by higher infiltration of macrophages and dendritic cells. In this study, we also demonstrated that Treg migration to the tumor microenvironment is mediated by CCR5, and these cells are promoting tumor growth via inhibition of antitumor cells such as cytotoxic CD8⁺ T cells. Our findings reinforce the therapeutic potential of CCR5 inhibition for cancer treatment, and indicate an attractive approach for SCC treatment. Mol Cancer Ther; 16(12); 2871–80. ©2017 AACR.

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Precision Medicine: Progress, Pitfalls, and Promises

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Theranostic Radiolabeled Anti-CD20 sdAb for Targeted Radionuclide Therapy of Non-Hodgkin Lymphoma

Anti-CD20 radioimmunotherapy is an effective approach for therapy of relapsed or refractory CD20^pos lymphomas, but faces limitations due to poor tumor penetration and undesirable pharmacokinetics of full antibodies. Camelid single-domain Ab fragments (sdAb) might circumvent some of the limitations of radiolabeled full antibodies. In this study, a set of hCD20-targeting sdAbs was generated, and their capacity to bind hCD20 was evaluated in vitro and in vivo. A lead sdAb, sdAb 9079, was selected on the basis of its specific tumor targeting and significant lower kidney accumulation compared with other sdAbs. SdAb 9079 was then radiolabeled with ⁶⁸Ga and ¹⁷⁷Lu for PET imaging and targeted therapy. The therapeutic potential of ¹⁷⁷Lu-DTPA-sdAb was compared with that of ¹⁷⁷Lu-DTPA-rituximab and unlabeled rituximab in mice bearing hCD20^pos tumors. Radiolabeled with ⁶⁸Ga, sdAb 9079 showed specific tumor uptake, with very low accumulation in nontarget organs, except kidneys. The tumor uptake of ¹⁷⁷Lu-DTPA-sdAb 9079 after 1.5 h was 3.4 ± 1.3% ID/g, with T/B and T/M ratios of 13.3 ± 4.6 and 32.9 ± 15.6. Peak tumor accumulation of ¹⁷⁷Lu-DTPA-rituximab was about 9 times higher, but concomitantly with high accumulation in nontarget organs and very low T/B and T/M ratios (0.8 ± 0.1 and 7.1 ± 2.4). Treatment of mice with ¹⁷⁷Lu-DTPA-sdAb 9079 significantly prolonged median survival compared with control groups and was as effective as treatment with rituximab or its ¹⁷⁷Lu-labeled variant. Taken together, sdAb 9079 displays promising features as a theranostic drug to treat CD20^pos lymphomas. Mol Cancer Ther; 16(12); 2828–39. ©2017 AACR.

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Path toward Precision Oncology: Review of Targeted Therapy Studies and Tools to Aid in Defining "Actionability" of a Molecular Lesion and Patient Management Support

Precision medicine trials and targeted therapies have shifted to the forefront of oncology. Although targeted therapies have shown initial promise, implementation across the broad landscape of oncology has many challenges. These limitations include an incomplete understanding of the functional significance of variant alleles as well as the need for clinical research and practice models that are more patient-centered and account for the complexity of individual patient tumors. Furthermore, successful implementation of targeted therapies will also be predicated on efforts to standardize the framework for patient management support. Here, we review current implementations of targeted therapies in precision oncology and discuss how "actionability" is defined for molecular targets in cancer therapeutics. We also comment on the growing need for bioinformatics tools and data platforms to complement advances in precision oncology. Finally, we discuss current frameworks for integrating precision oncology into patient management and propose an integrated model that combines features of molecular tumor boards and decision support systems. Mol Cancer Ther; 16(12); 2645–55. ©2017 AACR.

See related article by Pilié et al., p. 2641

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TRP53 Mutants Drive Neuroendocrine Lung Cancer Through Loss-of-Function Mechanisms with Gain-of-Function Effects on Chemotherapy Response

Lung cancer is the leading cause of cancer-related deaths with small-cell lung cancer (SCLC) as the most aggressive subtype. Preferential occurrence of TP53 missense mutations rather than loss implicates a selective advantage for TP53-mutant expression in SCLC pathogenesis. We show that lung epithelial expression of R270H and R172H (R273H and R175H in humans), common TRP53 mutants in lung cancer, combined with RB1 loss selectively results in two subtypes of neuroendocrine carcinoma, SCLC and large cell neuroendocrine carcinoma (LCNEC). Tumor initiation and progression occur in a remarkably consistent time frame with short latency and uniform progression to lethal metastatic disease by 7 months. R270H or R172H expression and TRP53 loss result in similar phenotypes demonstrating that TRP53 mutants promote lung carcinogenesis through loss-of-function and not gain-of-function mechanisms. Tumor responses to targeted and cytotoxic therapeutics were discordant in mice and corresponding tumor cell cultures demonstrating need to assess therapeutic response at the organismal level. Rapamycin did not have therapeutic efficacy in the mouse model despite inhibiting mTOR signaling and markedly suppressing tumor cell growth in culture. In contrast, cisplatin/etoposide treatment using a patient regimen prolonged survival with development of chemoresistance recapitulating human responses. R270H, but not R172H, expression conferred gain-of-function activity in attenuating chemotherapeutic efficacy. These data demonstrate a causative role for TRP53 mutants in development of chemoresistant lung cancer, and provide tractable preclinical models to test novel therapeutics for refractory disease. Mol Cancer Ther; 16(12); 2913–26. ©2017 AACR.

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Death by HDAC Inhibition in Synovial Sarcoma Cells

Conventional cytotoxic therapies for synovial sarcoma provide limited benefit, and no drugs specifically targeting the causative SS18-SSX fusion oncoprotein are currently available. Histone deacetylase (HDAC) inhibition has been shown in previous studies to disrupt the synovial sarcoma oncoprotein complex, resulting in apoptosis. To understand the molecular effects of HDAC inhibition, RNA-seq transcriptome analysis was undertaken in six human synovial sarcoma cell lines. HDAC inhibition induced pathways of cell-cycle arrest, neuronal differentiation, and response to oxygen-containing species, effects also observed in other cancers treated with this class of drugs. More specific to synovial sarcoma, polycomb group targets were reactivated, including tumor suppressor CDKN2A, and proapoptotic transcriptional patterns were induced. Functional analyses revealed that ROS-mediated FOXO activation and proapoptotic factors BIK, BIM, and BMF were important to apoptosis induction following HDAC inhibition in synovial sarcoma. HDAC inhibitor pathway activation results in apoptosis and decreased tumor burden following a 7-day quisinostat treatment in the Pten^fl/fl;hSS2 mouse model of synovial sarcoma. This study provides mechanistic support for a particular susceptibility of synovial sarcoma to HDAC inhibition as a means of clinical treatment. Mol Cancer Ther; 16(12); 2656–67. ©2017 AACR.

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IL4 Receptor-Targeted Proapoptotic Peptide Blocks Tumor Growth and Metastasis by Enhancing Antitumor Immunity

Cellular cross-talk between tumors and M2-polarized tumor-associated macrophages (TAM) favors tumor progression. Upregulation of IL4 receptor (IL4R) is observed in diverse tumors and TAMs. We tested whether an IL4R-targeted proapoptotic peptide could inhibit tumor progression. The IL4R-binding peptide (IL4RPep-1) preferentially bound to IL4R-expressing tumor cells and M2-polarized macrophages both in vitro and in 4T1 breast tumors in vivo. To selectively kill IL4R-expressing cells, we designed an IL4R-targeted proapoptotic peptide, IL4RPep-1-K, by adding the proapoptotic peptide (KLAKLAK)₂ to the end of IL4RPep-1. IL4RPep-1-K exerted selective cytotoxicity against diverse IL4R-expressing tumor cells and M2-polarized macrophages. Systemic administration of IL4RPep-1-K inhibited tumor growth and metastasis in 4T1 breast tumor-bearing mice. Interestingly, IL4RPep-1-K treatment increased the number of activated cytotoxic CD8⁺ T cells while reducing the numbers of immunosuppressive regulatory T cells and M2-polarized TAMs. No significant systemic side effects were observed. These results suggest that IL4R-targeted proapoptotic peptide has potential for treating diverse IL4R-expressing cancers. Mol Cancer Ther; 16(12); 2803–16. ©2017 AACR.

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The Irreversible Covalent Fibroblast Growth Factor Receptor Inhibitor PRN1371 Exhibits Sustained Inhibition of FGFR after Drug Clearance

An increasing number of cancers are known to harbor mutations, translocations, or amplifications in the fibroblast growth factor receptor (FGFR) family of kinases. The FGFR inhibitors evaluated in clinical trials to date have shown promise at treating these cancers. Here, we describe PRN1371, an irreversible covalent inhibitor of FGFR1-4 targeting a cysteine within the kinase active site. PRN1371 demonstrated strong FGFR potency and excellent kinome-wide selectivity in a number of biochemical and cellular assays, including in various cancer cell lines exhibiting FGFR alterations. Furthermore, PRN1371 maintained FGFR inhibition in vivo, not only when circulating drug levels were high but also after the drug had been cleared from circulation, indicating the possibility of sustained FGFR inhibition in the clinic without the need for continuous drug exposure. Durable tumor regression was also obtained in multiple tumor xenografts and patient-derived tumor xenograft models and was sustained even using an intermittent dosing strategy that provided drug holidays. PRN1371 is currently under clinical investigation for treatment of patients with solid tumors. Mol Cancer Ther; 16(12); 2668–76. ©2017 AACR.

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Basal-A Triple-Negative Breast Cancer Cells Selectively Rely on RNA Splicing for Survival

Prognosis of triple-negative breast cancer (TNBC) remains poor. To identify shared and selective vulnerabilities of basal-like TNBC, the most common TNBC subtype, a directed siRNA lethality screen was performed in 7 human breast cancer cell lines, focusing on 154 previously identified dependency genes of 1 TNBC line. Thirty common dependency genes were identified, including multiple proteasome and RNA splicing genes, especially those associated with the U4/U6.U5 tri-snRNP complex (e.g., PRPF8, PRPF38A). PRPF8 or PRPF38A knockdown or the splicing modulator E7107 led to widespread intronic retention and altered splicing of transcripts involved in multiple basal-like TNBC dependencies, including protein homeostasis, mitosis, and apoptosis. E7107 treatment suppressed the growth of basal-A TNBC cell line and patient-derived basal-like TNBC xenografts at a well-tolerated dose. The antitumor response was enhanced by adding the proteasome inhibitor bortezomib. Thus, inhibiting both splicing and the proteasome might be an effective approach for treating basal-like TNBC. Mol Cancer Ther; 16(12); 2849–61. ©2017 AACR.

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Discovery of a Highly Selective NAMPT Inhibitor That Demonstrates Robust Efficacy and Improved Retinal Toxicity with Nicotinic Acid Coadministration

NAMPT, an enzyme essential for NAD⁺ biosynthesis, has been extensively studied as an anticancer target for developing potential novel therapeutics. Several NAMPT inhibitors have been discovered, some of which have been subjected to clinical investigations. Yet, the on-target hematological and retinal toxicities have hampered their clinical development. In this study, we report the discovery of a unique NAMPT inhibitor, LSN3154567. This molecule is highly selective and has a potent and broad spectrum of anticancer activity. Its inhibitory activity can be rescued with nicotinic acid (NA) against the cell lines proficient, but not those deficient in NAPRT1, essential for converting NA to NAD⁺. LSN3154567 also exhibits robust efficacy in multiple tumor models deficient in NAPRT1. Importantly, this molecule when coadministered with NA does not cause observable retinal and hematological toxicities in the rodents, yet still retains robust efficacy. Thus, LSN3154567 has the potential to be further developed clinically into a novel cancer therapeutic. Mol Cancer Ther; 16(12); 2677–88. ©2017 AACR.

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Pathway-Enriched Gene Signature Associated with 53BP1 Response to PARP Inhibition in Triple-Negative Breast Cancer

Effective treatment of patients with triple-negative (ER-negative, PR-negative, HER2-negative) breast cancer remains a challenge. Although PARP inhibitors are being evaluated in clinical trials, biomarkers are needed to identify patients who will most benefit from anti-PARP therapy. We determined the responses of three PARP inhibitors (veliparib, olaparib, and talazoparib) in a panel of eight triple-negative breast cancer cell lines. Therapeutic responses and cellular phenotypes were elucidated using high-content imaging and quantitative immunofluorescence to assess markers of DNA damage (53BP1) and apoptosis (cleaved PARP). We determined the pharmacodynamic changes as percentage of cells positive for 53BP1, mean number of 53BP1 foci per cell, and percentage of cells positive for cleaved PARP. Inspired by traditional dose–response measures of cell viability, an EC₅₀ value was calculated for each cellular phenotype and each PARP inhibitor. The EC₅₀ values for both 53BP1 metrics strongly correlated with IC₅₀ values for each PARP inhibitor. Pathway enrichment analysis identified a set of DNA repair and cell cycle–associated genes that were associated with 53BP1 response following PARP inhibition. The overall accuracy of our 63 gene set in predicting response to olaparib in seven breast cancer patient-derived xenograft tumors was 86%. In triple-negative breast cancer patients who had not received anti-PARP therapy, the predicted response rate of our gene signature was 45%. These results indicate that 53BP1 is a biomarker of response to anti-PARP therapy in the laboratory, and our DNA damage response gene signature may be used to identify patients who are most likely to respond to PARP inhibition. Mol Cancer Ther; 16(12); 2892–901. ©2017 AACR.

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The Combination of Metformin and Valproic Acid Induces Synergistic Apoptosis in the Presence of p53 and Androgen Signaling in Prostate Cancer

We investigated the potential of combining the hypoglycemic drug metformin (MET) and the antiepileptic drug valproic acid (VPA), which act via different biochemical pathways, to provide enhanced antitumor responses in prostate cancer. Prostate cancer cell lines (LNCaP and PC-3), normal prostate epithelial cells (PrEC), and patient-derived prostate tumor explants were treated with MET and/or VPA. Proliferation and apoptosis were assessed. The role of p53 in response to MET + VPA was assessed in cell lines using RNAi in LNCaP (p53⁺) and ectopic expression of p53 in PC-3 (p53^–). The role of the androgen receptor (AR) was investigated using the AR antagonist enzalutamide. The combination of MET and VPA synergistically inhibited proliferation in LNCaP and PC-3, with no significant effect in PrEC. LNCaP, but not PC-3, demonstrated synergistic intrinsic apoptosis in response to MET + VPA. Knockdown of p53 in LNCaP (p53⁺, AR⁺) reduced the synergistic apoptotic response as did inhibition of AR. Ectopic expression of p53 in PC-3 (p53^–, AR^–) increased apoptosis in response to MET + VPA. In patient-derived prostate tumor explants, MET + VPA also induced a significant decrease in proliferation and an increase in apoptosis in tumor cells. In conclusion, we demonstrate that MET + VPA can synergistically kill more prostate cancer cells than either drug alone. The response is dependent on the presence of p53 and AR signaling, which have critical roles in prostate carcinogenesis. Further in vivo/ex vivo preclinical studies are required to determine the relative efficacy of MET + VPA as a potential treatment for prostate cancer. Mol Cancer Ther; 16(12); 2689–700. ©2017 AACR.

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Highlights of This Issue

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HPMA-Copolymer Nanocarrier Targets Tumor-Associated Macrophages in Primary and Metastatic Breast Cancer

Polymeric nanocarriers such as N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers deliver drugs to solid tumors and avoid the systemic toxicity of conventional chemotherapy. Because HPMA copolymers can target sites of inflammation and accumulate within innate immune cells, we hypothesized that HPMA copolymers could target tumor-associated macrophages (TAM) in both primary and metastatic tumor microenvironments. We verified this hypothesis, first in preliminary experiments with isolated bone marrow macrophage cultures in vitro and subsequently in a spontaneously metastatic murine breast cancer model generated from a well-established, cytogenetically characterized 4T1 breast cancer cell line. Using our standardized experimental conditions, we detected primary orthotopic tumor growth at 7 days and metastatic tumors at 28 days after orthotopic transplantation of 4T1 cells into the mammary fat pad. We investigated the uptake of HPMA copolymer conjugated with Alexa Fluor 647 and folic acid (P-Alexa647-FA) and HPMA copolymer conjugated with IRDye 800CW (P-IRDye), following their retroorbital injection into the primary and metastatic tumor-bearing mice. A significant uptake of P-IRDye was observed at all primary and metastatic tumor sites in these mice, and the P-Alexa647-FA signal was found specifically within CD11b⁺ TAMs costained with pan-macrophage marker CD68. These findings demonstrate, for the first time, a novel capacity of a P-Alexa647-FA conjugate to colocalize to CD11b⁺CD68⁺ TAMs in both primary and metastatic breast tumors. This underscores the potential of this HPMA nanocarrier to deliver functional therapeutics that specifically target tumor-promoting macrophage activation and/or polarization during tumor development. Mol Cancer Ther; 16(12); 2701–10. ©2017 AACR.

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Superior Properties of Fc-comprising scTRAIL Fusion Proteins

The TNF-related apoptosis-inducing ligand (TRAIL) has been considered as a promising molecule for cancer treatment. However, clinical studies with soluble TRAIL failed to show therapeutic activity, which resulted in subsequent development of more potent TRAIL-based therapeutics. In this study, we applied defined oligomerization and tumor targeting as strategies to further improve the activity of a single-chain version of TRAIL (scTRAIL). We compared three different formats of EGF receptor (EGFR)-targeting dimeric scTRAIL fusion proteins [Diabody (Db)-scTRAIL, scFv-IgE heavy chain domain 2 (EHD2)-scTRAIL, scFv-Fc-scTRAIL] as well as two nontargeted dimeric scTRAIL molecules (EHD2-scTRAIL, Fc-scTRAIL) to reveal the influence of targeting and protein format on antitumor activity. All EGFR-targeted dimeric scTRAIL molecules showed similar binding properties and comparable cell death induction in vitro, exceeding the activity of the respective nontargeted dimeric format and monomeric scTRAIL. Superior properties were observed for the Fc fusion proteins with respect to production and in vivo half-life. In vivo studies using a Colo205 xenograft model revealed potent antitumor activity of all EGFR-targeting formats and Fc-scTRAIL and furthermore highlighted the higher efficacy of fusion proteins comprising an Fc part. Despite enhanced in vitro cell death induction of targeted scTRAIL molecules, however, comparable antitumor activities were found for the EGFR-targeting scFv-Fc-scTRAIL and the nontargeting Fc-scTRAIL in vivo. Mol Cancer Ther; 16(12); 2792–802. ©2017 AACR.

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Lycorine Promotes Autophagy and Apoptosis via TCRP1/Akt/mTOR Axis Inactivation in Human Hepatocellular Carcinoma

Lycorine is a multifunctional bioactive compound, and it possesses potential anticancer activities. However, little is known about the underlying mechanism. In this research, we have found that lycorine significantly induces the apoptotic and autophagic capacities of hepatocellular carcinoma (HCC) cells in vitro and in vivo. Treatment with specific autophagy inhibitor (3-methyladenine/Bafilomycin A1) or knockdown of LC-3B/Atg5 by siRNA drastically enhances the apoptotic cell death effect by facilitating the switch from autophagy to apoptosis. Molecular validation mechanistically demonstrates that lycorine-induced apoptosis and autophagy in HCC cells is associated with decreased protein levels of tongue cancer resistance–associated protein 1 (TCRP1), and we further find that inhibition of TCRP1 decreases phosphorylation level of Akt and represses Akt/mTOR signaling. Finally, lycorine-induced apoptosis and autophagy suppress the growth of xenograft hepatocellular tumors without remarkable toxicity. Our results elucidate a novel molecular mechanism whereby lycorine promotes apoptosis and autophagy through the TCRP1/Akt/mTOR pathway in HCC. Our results reveal that lycorine might be a potential therapeutic agent for the treatment of HCC. Mol Cancer Ther; 16(12); 2711–23. ©2017 AACR.

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The DNA Repair Inhibitor Dbait Is Specific for Malignant Hematologic Cells in Blood

Hematologic malignancies are rare cancers that develop refractory disease upon patient relapse, resulting in decreased life expectancy and quality of life. DNA repair inhibitors are a promising strategy to treat cancer but are limited by their hematologic toxicity in combination with conventional chemotherapies. Dbait are large molecules targeting the signaling of DNA damage and inhibiting all the double-strand DNA break pathways. Dbait have been shown to sensitize resistant solid tumors to radiotherapy and platinum salts. Here, we analyze the efficacy and lack of toxicity of AsiDNA, a cholesterol form of Dbait, in hematologic malignancies. We show that AsiDNA enters cells via LDL receptors and activates its molecular target, the DNA dependent protein kinase (DNA-PKcs) in 10 lymphoma and leukemia cell lines (Jurkat-E6.1, MT-4, MOLT-4, 174xCEM.T2, Sup-T1, HuT-78, Raji, IM-9, THP-1, and U-937) and in normal primary human PBMCs, resting or activated T cells, and CD34⁺ progenitors. The treatment with AsiDNA induced necrotic and mitotic cell death in most cancer cell lines and had no effect on blood or bone marrow cells, including immune activation, proliferation, or differentiation. Sensitivity to AsiDNA was independent of p53 status. Survival to combined treatment with conventional therapies (etoposide, cyclophosphamides, vincristine, or radiotherapy) was analyzed by isobolograms and combination index. AsiDNA synergized with all treatments, except vincristine, without increasing their toxicity to normal blood cells. AsiDNA is a novel, potent, and wide-range drug with the potential to specifically increase DNA-damaging treatment toxicity in tumor without adding toxicity in normal hematologic cells or inducing immune dysregulation. Mol Cancer Ther; 16(12); 2817–27. ©2017 AACR.

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ABC294640, A Novel Sphingosine Kinase 2 Inhibitor, Induces Oncogenic Virus-Infected Cell Autophagic Death and Represses Tumor Growth

Kaposi sarcoma–associated herpes virus (KSHV) is the etiologic agent of several malignancies, including Kaposi sarcoma and primary effusion lymphoma (PEL), which preferentially arise in HIV⁺ patients and lack effective treatment. Sphingosine kinase 2 (SphK2) is a key factor within sphingolipid metabolism, responsible for the conversion of proapoptotic ceramides to antiapoptotic sphingosine-1-phosphate (S1P). We have previously demonstrated that targeting SphK2 using a novel selective inhibitor, ABC294640, leads to the accumulation of intracellular ceramides and induces apoptosis in KSHV-infected primary endothelial cells and PEL tumor cells but not in uninfected cells. In this study, we found that ABC294640 induces autophagic death instead of apoptosis in a KSHV long-term–infected immortalized endothelial cell-line, TIVE-LTC, but not in uninfected TIVE cells, through the upregulation of LC3B protein. Transcriptomic analysis indicates that many genes related to cellular stress responses, cell cycle/proliferation, and cellular metabolic process are altered in TIVE-LTC exposed to ABC294640. One of the candidates, Egr-1, was found to directly regulate LC3B expression and was required for the ABC294640-induced autophagic death. By using a Kaposi sarcoma–like nude mice model with TIVE-LTC, we found that ABC294640 treatment significantly suppressed KSHV-induced tumor growth in vivo, which indicates that targeting sphingolipid metabolism, especially SphK2, may represent a promising therapeutic strategy against KSHV-related malignancies. Mol Cancer Ther; 16(12); 2724–34. ©2017 AACR.

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MicroRNA-720 Regulates E-cadherin-{alpha}E-catenin Complex and Promotes Renal Cell Carcinoma

miRNAs are implicated in regulating cancer progression and metastasis. Here, we show that miR-720 is positively associated with renal cell carcinoma (RCC). Elevated levels of miR-720 were observed in a panel of RCC cell lines and clinical tissues compared with nonmalignant cell line and normal samples. Loss of miR-720 function inhibited proliferation, migration, and invasion and induced apoptosis in RCC cell lines in vitro and repressed tumor growth in xenograft mouse models. Conversely, gain of miR-720 function in nonmalignant HK-2 cells induced procancerous characteristics. Silencing of miR-720 caused a marked induction in the levels of endogenous αE-catenin and E-cadherin protein levels in anti720 transfected cells compared with control, whereas miR-720 overexpression in RCC cell lines reduced activity of a luciferase reporter gene fused to the wild-type αE-catenin or E-cadherin 3'UTR compared with nonspecific 3'UTR control, indicating that αE-catenin–E-cadherin complex is a direct and functional target of miR-720 in RCC. We also observed attenuation of β-catenin, CD44, and Akt expression in RCC cells transfected with miR-720 inhibitor compared with control. Furthermore, miR-720 exhibited clinical significance in RCC. Expression of miR-720 significantly distinguished malignant from normal samples. Elevated miR-720 levels positively correlated with higher Fuhrman grade, pathologic stage, and poor overall survival of RCC patients. These findings uncover a new regulatory network in RCC involving metastasis-promoting miR-720 that directly targets expression of key metastasis-suppressing proteins E-cadherin and αE-catenin complex. These results suggest that therapeutic regulation of miR-720 may provide an opportunity to regulate EMT and metastasis in RCC. Mol Cancer Ther; 16(12); 2840–8. ©2017 AACR.

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Simultaneous Targeting of Two Distinct Epitopes on MET Effectively Inhibits MET- and HGF-Driven Tumor Growth by Multiple Mechanisms

Increased MET activity is linked with poor prognosis and outcome in several human cancers currently lacking targeted therapies. Here, we report on the characterization of Sym015, an antibody mixture composed of two humanized IgG₁ antibodies against nonoverlapping epitopes of MET. Sym015 was selected by high-throughput screening searching for antibody mixtures with superior growth-inhibitory activity against MET-dependent cell lines. Synergistic inhibitory activity of the antibodies comprising Sym015 was observed in several cancer cell lines harboring amplified MET locus and was confirmed in vivo. Sym015 was found to exert its activity via multiple mechanisms. It disrupted interaction of MET with the HGF ligand and prompted activity-independent internalization and degradation of the receptor. In addition, Sym015 induced high levels of CDC and ADCC in vitro. The importance of these effector functions was confirmed in vivo using an Fc-effector function–attenuated version of Sym015. The enhanced effect of the two antibodies in Sym015 on both MET degradation and CDC and ADCC is predicted to render Sym015 superior to single antibodies targeting MET. Our results demonstrate strong potential for use of Sym015 as a therapeutic antibody mixture for treatment of MET-driven tumors. Sym015 is currently being tested in a phase I dose escalation clinical trial (NCT02648724). Mol Cancer Ther; 16(12); 2780–91. ©2017 AACR.

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CCR5-Dependent Homing of T Regulatory Cells to the Tumor Microenvironment Contributes to Skin Squamous Cell Carcinoma Development

Squamous cell carcinoma (SCC) is one of the most common human cancers worldwide. Recent studies show that regulatory T cells (Treg) have a critical role in the modulation of an antitumor immune response, and consequently the SCC development. Because the accumulation of Tregs at the tumor site is, in part, due to selective recruitment through CCR5- and CCR5-associated chemokines, we investigated the role of CCR5 in the SCC development. Our findings showed that CCR5-deficient mice (CCR5KO) were efficient in controlling papilloma's incidence when compared with wild-type mice. Analysis of tumor lesions in wild-type (WT) and CCR5KO mice revealed that lack of CCR5 lead to significant reduction in frequency of Tregs and increased of CD4 T cells into the tumors. Moreover, the adoptive transfer of naturally occurring Tregs CD4⁺CD25⁺CCR5⁺, CD4⁺CD25^–CCR5⁺ or CD8⁺CCR5⁺ conventional T cells to CCR5KO mice resulted in an increased papilloma incidence. Interestingly, adoptive transfer of WT CD4⁺CD25⁺CCR5⁺ cells to CCR5KO mice induced more undifferentiated SCC lesions, characterized by higher infiltration of macrophages and dendritic cells. In this study, we also demonstrated that Treg migration to the tumor microenvironment is mediated by CCR5, and these cells are promoting tumor growth via inhibition of antitumor cells such as cytotoxic CD8⁺ T cells. Our findings reinforce the therapeutic potential of CCR5 inhibition for cancer treatment, and indicate an attractive approach for SCC treatment. Mol Cancer Ther; 16(12); 2871–80. ©2017 AACR.

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Precision Medicine: Progress, Pitfalls, and Promises

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Theranostic Radiolabeled Anti-CD20 sdAb for Targeted Radionuclide Therapy of Non-Hodgkin Lymphoma

Anti-CD20 radioimmunotherapy is an effective approach for therapy of relapsed or refractory CD20^pos lymphomas, but faces limitations due to poor tumor penetration and undesirable pharmacokinetics of full antibodies. Camelid single-domain Ab fragments (sdAb) might circumvent some of the limitations of radiolabeled full antibodies. In this study, a set of hCD20-targeting sdAbs was generated, and their capacity to bind hCD20 was evaluated in vitro and in vivo. A lead sdAb, sdAb 9079, was selected on the basis of its specific tumor targeting and significant lower kidney accumulation compared with other sdAbs. SdAb 9079 was then radiolabeled with ⁶⁸Ga and ¹⁷⁷Lu for PET imaging and targeted therapy. The therapeutic potential of ¹⁷⁷Lu-DTPA-sdAb was compared with that of ¹⁷⁷Lu-DTPA-rituximab and unlabeled rituximab in mice bearing hCD20^pos tumors. Radiolabeled with ⁶⁸Ga, sdAb 9079 showed specific tumor uptake, with very low accumulation in nontarget organs, except kidneys. The tumor uptake of ¹⁷⁷Lu-DTPA-sdAb 9079 after 1.5 h was 3.4 ± 1.3% ID/g, with T/B and T/M ratios of 13.3 ± 4.6 and 32.9 ± 15.6. Peak tumor accumulation of ¹⁷⁷Lu-DTPA-rituximab was about 9 times higher, but concomitantly with high accumulation in nontarget organs and very low T/B and T/M ratios (0.8 ± 0.1 and 7.1 ± 2.4). Treatment of mice with ¹⁷⁷Lu-DTPA-sdAb 9079 significantly prolonged median survival compared with control groups and was as effective as treatment with rituximab or its ¹⁷⁷Lu-labeled variant. Taken together, sdAb 9079 displays promising features as a theranostic drug to treat CD20^pos lymphomas. Mol Cancer Ther; 16(12); 2828–39. ©2017 AACR.

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Path toward Precision Oncology: Review of Targeted Therapy Studies and Tools to Aid in Defining "Actionability" of a Molecular Lesion and Patient Management Support

Precision medicine trials and targeted therapies have shifted to the forefront of oncology. Although targeted therapies have shown initial promise, implementation across the broad landscape of oncology has many challenges. These limitations include an incomplete understanding of the functional significance of variant alleles as well as the need for clinical research and practice models that are more patient-centered and account for the complexity of individual patient tumors. Furthermore, successful implementation of targeted therapies will also be predicated on efforts to standardize the framework for patient management support. Here, we review current implementations of targeted therapies in precision oncology and discuss how "actionability" is defined for molecular targets in cancer therapeutics. We also comment on the growing need for bioinformatics tools and data platforms to complement advances in precision oncology. Finally, we discuss current frameworks for integrating precision oncology into patient management and propose an integrated model that combines features of molecular tumor boards and decision support systems. Mol Cancer Ther; 16(12); 2645–55. ©2017 AACR.

See related article by Pilié et al., p. 2641

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TRP53 Mutants Drive Neuroendocrine Lung Cancer Through Loss-of-Function Mechanisms with Gain-of-Function Effects on Chemotherapy Response

Lung cancer is the leading cause of cancer-related deaths with small-cell lung cancer (SCLC) as the most aggressive subtype. Preferential occurrence of TP53 missense mutations rather than loss implicates a selective advantage for TP53-mutant expression in SCLC pathogenesis. We show that lung epithelial expression of R270H and R172H (R273H and R175H in humans), common TRP53 mutants in lung cancer, combined with RB1 loss selectively results in two subtypes of neuroendocrine carcinoma, SCLC and large cell neuroendocrine carcinoma (LCNEC). Tumor initiation and progression occur in a remarkably consistent time frame with short latency and uniform progression to lethal metastatic disease by 7 months. R270H or R172H expression and TRP53 loss result in similar phenotypes demonstrating that TRP53 mutants promote lung carcinogenesis through loss-of-function and not gain-of-function mechanisms. Tumor responses to targeted and cytotoxic therapeutics were discordant in mice and corresponding tumor cell cultures demonstrating need to assess therapeutic response at the organismal level. Rapamycin did not have therapeutic efficacy in the mouse model despite inhibiting mTOR signaling and markedly suppressing tumor cell growth in culture. In contrast, cisplatin/etoposide treatment using a patient regimen prolonged survival with development of chemoresistance recapitulating human responses. R270H, but not R172H, expression conferred gain-of-function activity in attenuating chemotherapeutic efficacy. These data demonstrate a causative role for TRP53 mutants in development of chemoresistant lung cancer, and provide tractable preclinical models to test novel therapeutics for refractory disease. Mol Cancer Ther; 16(12); 2913–26. ©2017 AACR.

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Death by HDAC Inhibition in Synovial Sarcoma Cells

Conventional cytotoxic therapies for synovial sarcoma provide limited benefit, and no drugs specifically targeting the causative SS18-SSX fusion oncoprotein are currently available. Histone deacetylase (HDAC) inhibition has been shown in previous studies to disrupt the synovial sarcoma oncoprotein complex, resulting in apoptosis. To understand the molecular effects of HDAC inhibition, RNA-seq transcriptome analysis was undertaken in six human synovial sarcoma cell lines. HDAC inhibition induced pathways of cell-cycle arrest, neuronal differentiation, and response to oxygen-containing species, effects also observed in other cancers treated with this class of drugs. More specific to synovial sarcoma, polycomb group targets were reactivated, including tumor suppressor CDKN2A, and proapoptotic transcriptional patterns were induced. Functional analyses revealed that ROS-mediated FOXO activation and proapoptotic factors BIK, BIM, and BMF were important to apoptosis induction following HDAC inhibition in synovial sarcoma. HDAC inhibitor pathway activation results in apoptosis and decreased tumor burden following a 7-day quisinostat treatment in the Pten^fl/fl;hSS2 mouse model of synovial sarcoma. This study provides mechanistic support for a particular susceptibility of synovial sarcoma to HDAC inhibition as a means of clinical treatment. Mol Cancer Ther; 16(12); 2656–67. ©2017 AACR.

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IL4 Receptor-Targeted Proapoptotic Peptide Blocks Tumor Growth and Metastasis by Enhancing Antitumor Immunity

Cellular cross-talk between tumors and M2-polarized tumor-associated macrophages (TAM) favors tumor progression. Upregulation of IL4 receptor (IL4R) is observed in diverse tumors and TAMs. We tested whether an IL4R-targeted proapoptotic peptide could inhibit tumor progression. The IL4R-binding peptide (IL4RPep-1) preferentially bound to IL4R-expressing tumor cells and M2-polarized macrophages both in vitro and in 4T1 breast tumors in vivo. To selectively kill IL4R-expressing cells, we designed an IL4R-targeted proapoptotic peptide, IL4RPep-1-K, by adding the proapoptotic peptide (KLAKLAK)₂ to the end of IL4RPep-1. IL4RPep-1-K exerted selective cytotoxicity against diverse IL4R-expressing tumor cells and M2-polarized macrophages. Systemic administration of IL4RPep-1-K inhibited tumor growth and metastasis in 4T1 breast tumor-bearing mice. Interestingly, IL4RPep-1-K treatment increased the number of activated cytotoxic CD8⁺ T cells while reducing the numbers of immunosuppressive regulatory T cells and M2-polarized TAMs. No significant systemic side effects were observed. These results suggest that IL4R-targeted proapoptotic peptide has potential for treating diverse IL4R-expressing cancers. Mol Cancer Ther; 16(12); 2803–16. ©2017 AACR.

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The Irreversible Covalent Fibroblast Growth Factor Receptor Inhibitor PRN1371 Exhibits Sustained Inhibition of FGFR after Drug Clearance

An increasing number of cancers are known to harbor mutations, translocations, or amplifications in the fibroblast growth factor receptor (FGFR) family of kinases. The FGFR inhibitors evaluated in clinical trials to date have shown promise at treating these cancers. Here, we describe PRN1371, an irreversible covalent inhibitor of FGFR1-4 targeting a cysteine within the kinase active site. PRN1371 demonstrated strong FGFR potency and excellent kinome-wide selectivity in a number of biochemical and cellular assays, including in various cancer cell lines exhibiting FGFR alterations. Furthermore, PRN1371 maintained FGFR inhibition in vivo, not only when circulating drug levels were high but also after the drug had been cleared from circulation, indicating the possibility of sustained FGFR inhibition in the clinic without the need for continuous drug exposure. Durable tumor regression was also obtained in multiple tumor xenografts and patient-derived tumor xenograft models and was sustained even using an intermittent dosing strategy that provided drug holidays. PRN1371 is currently under clinical investigation for treatment of patients with solid tumors. Mol Cancer Ther; 16(12); 2668–76. ©2017 AACR.

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