• Autophagy Inhibition to Augment mTOR Inhibition: a Phase I/II Trial of Everolimus and Hydroxychloroquine in Patients with Previously Treated Renal Cell Carcinoma

      Haas, Naomi B; Appleman, Leonard J; Stein, Mark; Redlinger, Maryann; Wilks, Melissa; Xu, Xiaowei; Onorati, Angelique; Kalavacharla, Anusha; Kim, Taehyong; Zhen, Chao Jie; et al. (AMER ASSOC CANCER RESEARCH, 2019-04-01)
      Purpose: Everolimus inhibits the mTOR, activating cytoprotective autophagy. Hydroxychloroquine inhibits autophagy. On the basis of preclinical data demonstrating synergistic cytotoxicity when mTOR inhibitors are combined with an autophagy inhibitor, we launched a clinical trial of combined everolimus and hydroxychloroquine, to determine its safety and activity in patients with clear-cell renal cell carcinoma (ccRCC). Patients and Methods: Three centers conducted a phase I/II trial of everolimus 10 mg daily and hydroxychloroquine in patients with advanced ccRCC. The objectives were to determine the MTD of hydroxychloroquine with daily everolimus, and to estimate the rate of 6-month progression-free survival (PFS) in patients with ccRCC receiving everolimus/hydroxychloroquine after 1-3 prior treatment regimens. Correlative studies to identify patient subpopulations that achieved the most benefit included population pharmacokinetics, measurement of autophagosomes by electron microscopy, and next-generation tumor sequencing. Results: No dose-limiting toxicity was observed in the phase I trial. The recommended phase II dose of hydroxychloroquine 600 mg twice daily with everolimus was identified. Disease control [stable disease thorn partial response (PR)] occurred in 22 of 33 (67%) evaluable patients. PR was observed in 2 of 33 patients (6%). PFS >= 6 months was achieved in 15 of 33 (45%) of patients who achieved disease control. Conclusions: Combined hydroxychloroquine 600 mg twice daily with 10 mg daily everolimus was tolerable. The primary endpoint of >40% 6-month PFS rate was met. Hydroxychloroquine is a tolerable autophagy inhibitor in future RCC or other trials.
    • Disruption of Aneuploidy and Senescence Induced by Aurora Inhibition Promotes Intrinsic Apoptosis in Double Hit or Double Expressor Diffuse Large B-cell Lymphomas

      Islam, Shariful; Qi, Wenqing; Morales, Carla; Cooke, Laurence; Spier, Catherine; Weterings, Eric; Mahadevan, Daruka; Univ Arizona, Canc Biol Grad Interdisciplinary Program, Canc Ctr; Univ Arizona, Canc Ctr, Dept Med; Univ Arizona, Dept Pathol; et al. (AMER ASSOC CANCER RESEARCH, 2017-10-01)
      Double hit (DH) or double expressor (DE) diffuse large B-cell lymphomas (DLBCL) are aggressive non-Hodgkin's lymphomas (NHL) with translocations and/or overexpressions of MYC and BCL-2, which are difficult to treat. Aurora kinase (AK) inhibition with alisertib in DH/DE-DLBCL induces cell death in ∼30%, while ∼70% are aneuploid and senescent cells (AASC), a mitotic escape mechanism contributing to drug resistance. These AASCs elaborated a high metabolic rate by increased AKT/mTOR and ERK/MAPK activity via BTK signaling through the chronic active B-cell receptor (BCR) pathway. Combinations of alisertib + ibrutinib or alisertib + ibrutinib + rituximab significantly reduced AASCs with enhanced intrinsic cell death. Inhibition of AK + BTK reduced phosphorylation of AKT/mTOR and ERK-1/2, upregulated phospho-H2A-X and Chk-2 (DNA damage), reduced Bcl-6, and decreased Bcl-2 and Bcl-xL and induced apoptosis by PARP cleavage. In a DE-DLBCL SCID mouse xenograft model, ibrutinib alone was inactive, while alisertib + ibrutinib was additive with a tumor growth inhibition (TGI) rate of ∼25%. However, TGI for ibrutinib + rituximab was ∼50% to 60%. In contrast, triple therapy showed a TGI rate of >90%. Kaplan-Meier survival analysis showed that 67% of mice were alive at day 89 with triple therapy versus 20% with ibrutinib + rituximab. All treatments were well tolerated with no changes in body weights. A novel triple therapy consisting of alisertib + ibrutinib + rituximab inhibits AASCs induced by AK inhibition in DH/DE-DLBCL leading to a significant antiproliferative signal, enhanced intrinsic apoptosis and may be of therapeutic potential in these lymphomas. Mol Cancer Ther; 16(10); 2083-93. ©2017 AACR.
    • Ethnic Disparities in Gastric Cancer Presentation and Screening Practice in the United States: Analysis of 1997-2010 Surveillance, Epidemiology, and End Results-Medicare Data

      Florea, Ana; Brown, Heidi E; Harris, Robin B; Oren, Eyal; Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Dept Epidemiol & Biostat (AMER ASSOC CANCER RESEARCH, 2019-04-01)
      Background: Chronic infection with Helicobacter pylori (H. pylori) is the strongest risk factor for distal gastric cancer. Although gastric cancer incidence has decreased, variation by race and ethnicity is observed. This study describes gastric cancer presentation and screening services among Medicare patients by race/ethnicity, place of birth, and history of gastric cancer-related conditions. Methods: Using demographic, location, and disease staging information, extracted from the Surveillance, Epidemiology and End Results-Medicare gastric cancer database (1997-2010), we compared frequencies of gastric cancer-related conditions (e.g., peptic ulcer, gastric ulcer, gastritis) and screening (H. pylori testing and endoscopy) from inpatient and outpatient services claims by selected race/ethnicity and place of birth. Results: Data included 47,994 incident gastric cancer cases with Medicare claims. The majority (48.0%) of Asian/Pacific Islanders (API) were foreign-born, compared with non-Hispanic whites (NHW), Hispanics, and blacks (with 64.4%, 33.9%, and 72.9% U.S.-born, respectively). For NHWs, the most frequently diagnosed gastric cancer site was the cardia (35.6%) compared with < 15%(P < 0.001) for APIs, Hispanics, and blacks. Although more than 57% of all cases had a history of gastric cancer-related conditions, H. pylori testing was reported in only 11.6% of those cases. H. pylori testing was highest for APIs (22.8%) and lowest for blacks (6.5%). Conclusions: Noncardia gastric cancer, associated with H. pylori infection, was diagnosed more frequently among APIs, blacks, and Hispanics than NHWs. Testing for H. pylori was low among all gastric cancer cases despite evidence of risk factors for which screening is recommended. Studies are needed to increase appropriate testing for H. pylori among higher risk populations. Impact: This study sheds light on poor screening practices despite presence of gastric cancer-related conditions.
    • Loss of PTEN Accelerates NKX3.1 Degradation to Promote Prostate Cancer Progression

      Bowen, Cai; Ostrowski, Michael C; Leone, Gustavo; Gelmann, Edward P; Univ Arizona (AMER ASSOC CANCER RESEARCH, 2019-08-15)
      NKX3.1 is the most commonly deleted gene in prostate cancer and a gatekeeper suppressor. NKX3.1 is a growth suppressor, mediator of apoptosis, inducer of antioxidants, and enhancer of DNA repair. PTEN is a ubiquitous tumor suppressor that is often decreased in prostate cancer during tumor progression. Steady-state turnover of NKX3.1 is mediated by DYRK1B phosphorylation at NKX3.1 serine 185 that leads to polyubiquitination and proteasomal degradation. In this study, we show PTEN is an NKX3.1 phosphatase that protects NKX3.1 from degradation. PTEN specifically opposed phosphorylation at NKX3.1(S185) and prolonged NKX3.1 half-life. PTEN and NKX3.1 interacted primarily in the nucleus as loss of PTEN nuclear localization abrogated its ability to bind to and protect NKX3.1 from degradation. The effect of PTEN on NKX3.1 was mediated via rapid enzyme-substrate interaction. An effect of PTEN on Nkx3.1 gene transcription was seen in vitro, but not in vivo. In gene-targeted mice, Nkx3.1 expression significantly diminished shortly after loss of Pten expression in the prostate. Nkx3.1 loss primarily increased prostate epithelial cell proliferation in vivo. In these mice, Nkx3.1 mRNA was not affected by Pten expression. Thus, the prostate cancer suppressors PTEN and NKX3.1 interact and loss of PTEN is responsible, at least in part, for progressive loss of NKX3.1 that occurs during tumor progression. SIGNIFICANCE: PTEN functions as a phosphatase of NKX3.1, a gatekeeper suppressor of prostate cancer.
    • Mechanisms Behind Resistance to PI3K Inhibitor Treatment Induced by the PIM Kinase.

      Song, Jin H; Singh, Neha; Luevano, Libia A; Padi, Sathish K R; Okumura, Koichi; Olive, Virginie; Black, Stephen M; Warfel, Noel A; Goodrich, David W; Kraft, Andrew S; et al. (AMER ASSOC CANCER RESEARCH, 2018-12-01)
      Cancer resistance to PI3K inhibitor therapy can be in part mediated by increases in the PIM1 kinase. However, the exact mechanism by which PIM kinase promotes tumor cell resistance is unknown. Our study unveils the pivotal control of redox signaling by PIM kinases as a driver of this resistance mechanism. PIM1 kinase functions to decrease cellular ROS levels by enhancing nuclear factor erythroid 2-related factor 2 (NRF2)/antioxidant response element activity. PIM prevents cell death induced by PI3K-AKT-inhibitory drugs through a noncanonical mechanism of NRF2 ubiquitination and degradation and translational control of NRF2 protein levels through modulation of eIF4B and mTORC1 activity. Importantly, PIM also controls NAD(P)H production by increasing glucose flux through the pentose phosphate shunt decreasing ROS production, and thereby diminishing the cytotoxicity of PI3K-AKT inhibitors. Treatment with PIM kinase inhibitors reverses this resistance phenotype, making tumors increasingly susceptible to small-molecule therapeutics, which block the PI3K-AKT pathway.
    • Metabolic Phenotype and Risk of Colorectal Cancer in Normal-Weight Postmenopausal Women

      Liang, Xiaoyun; Margolis, Karen L.; Hendryx, Michael; Rohan, Thomas E.; Groessl, Erik J.; Thomson, Cynthia A.; Kroenke, Candyce H.; Simon, Michael S.; Lane, Dorothy; Stefanick, Marcia; et al. (AMER ASSOC CANCER RESEARCH, 2017-02-05)
      Background: The prevalence of metabolically unhealthy phenotype in normal-weight adults is 30%, and few studies have explored the association between metabolic phenotype and colorectal cancer incidence in normal-weight individuals. Our aim was to compare the risk of colorectal cancer in normal-weight postmenopausal women who were characterized by either the metabolically healthy phenotype or the metabolically unhealthy phenotype. Methods: A large prospective cohort, the Women's Health Initiative, was used. The analytic sample included 5,068 postmenopausal women with BMI 18.5 to <25 kg/m(2). Metabolic phenotype was defined using the Adult Treatment Panel-III definition, excluding waist circumference; therefore, women with one or none of the four components (elevated triglycerides, low high-density lipoprotein cholesterol, elevated blood pressure, and elevated fasting glucose) were classified as metabolically healthy. Multivariable Cox proportional hazards regression was used to estimate adjusted HRs for the association between metabolic phenotype and risk of colorectal cancer. Results: Among normal-weight women, those who were metabolically unhealthy had higher risks of colorectal cancer (HR, 1.49; 95% CI, 1.02-2.18) compared with those who were metabolically healthy. Conclusions: A metabolically unhealthy phenotype was associated with higher risk of colorectal cancer among normal-weight women. Impact: Normal-weight women should still be evaluated for metabolic health and appropriate steps taken to reduce their risk of colorectal cancer. (C)2017 AACR.
    • Novel Regulation of Integrin Trafficking by Rab11-FIP5 in Aggressive Prostate Cancer

      Das, Lipsa; Gard, Jaime M.C.; Prekeris, Rytis; Nagle, Raymond B.; Morrissey, Colm; Knudsen, Beatrice S.; Miranti, Cindy K.; Cress, Anne E.; Univ Arizona, Canc Biol Grad Interdisciplinary Program; Univ Arizona, Canc Ctr; et al. (AMER ASSOC CANCER RESEARCH, 2018-08)
      The laminin-binding integrins, alpha 3 beta 1 and alpha 6 beta 1, are needed for tumor metastasis and their surface expression is regulated by endocytic recycling. beta 1 integrins share the Rab11 recycling machinery, but the trafficking of alpha 3 beta 1 and alpha 6 beta 1 are distinct by an unknown mechanism. Using a mouse PDX tumor model containing human metastatic prostate cancer, Rab11 family interacting protein 5 (Rab11-FIP5) was identified as a lead candidate for a6b1 trafficking. Rab11-FIP5 and its membrane-binding domain were required for alpha 6 beta 1 recycling, without affecting the other laminin-binding integrin (i.e., alpha 6 beta 1) or unrelated membrane receptors like CD44, transferrin receptor, or E-cad-herin. Depletion of Rab11-FIP5 resulted in the intracellular accumulation of alpha 6 beta 1 in the Rab11 recycling compartment, loss of cell migration on laminin, and an unexpected loss of alpha 6 beta 1 recycling in cell-cell locations. Taken together, these data demonstrate that alpha 6 beta 1 is distinct from alpha 3 beta 1 via Rab11-FIP5 recycling and recycles in an unexpected cell-cell location.
    • Patterns and Disparities in Human Papillomavirus (HPV) Vaccine Uptake for Young Female Adolescents among U.S. States: NIS-Teen (2008-2016)

      Yoo, Wonsuk; Koskan, Alexis; Scotch, Matthew; Pottinger, Heidi; Huh, Warner K; Helitzer, Deborah; Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Dept Hlth Promot Sci (AMER ASSOC CANCER RESEARCH, 2020-04-28)
      Background: Several studies have reported differential vaccine uptake outcomes that are associated with sociodemographic and socioeconomic characteristics, as well as provider type. However, none has examined a trend over a multiple-year span. In this study, we utilize a longitudinal data-based approach to examine state-level human papillomavirus (HPV) vaccine trends and their influences over time. Methods: We analyzed National Immunization Survey - Teen data (2008-2016) to estimate HPV vaccine initiation rate in young female adolescent ages 13-17 years old among U.S. States. We identified growth patterns using the latent class growth method and explored state-level characteristics, including socioeconomic and sociodemographic attributes, and health legislation and policy-related programs among patterns. Results: We identified three growth patterns, which showed gradually increasing vaccination trends but different baseline HPV uptake rates (high, moderate, low). States within Pattern 1 (highest HPV vaccination rates) included the lowest percentage of families with incomes below federal poverty level, the highest percentage of bachelor's degree or higher, and the lowest number of uninsured, while states within Pattern 3 (lowest HPV vaccination rates) included families with socioeconomic attributes along the opposite end of the spectrum. Conclusions: Latent class growth models are an effective tool to be able to capture health disparities in heterogeneity among states in relation to HPV vaccine uptake trajectories. Impact: These findings might lead to designing and implementing effective interventions and changes in policies and health care coverage to promote HPV vaccination uptake for states represented under the lowest trajectory pattern.
    • PD-1 Inhibition Achieves a Complete Metabolic Response in a Patient with Malignant Peripheral Nerve Sheath Tumor

      Davis, Lisa E; Nicholls, Lauren A; Babiker, Hani M; Liau, Joy; Mahadevan, Daruka; Univ Arizona, Coll Pharm, Dept Pharm Practice & Sci; Univ Arizona, Ctr Canc; Univ Arizona, Coll Med, Dept Med; Univ Arizona, Coll Med, Dept Med Imaging (AMER ASSOC CANCER RESEARCH, 2019-09-01)
      High-grade malignant peripheral nerve sheath tumors (MPNST) have a poor prognosis with limited responsiveness to systemic therapy. We document a case of a complete metabolic response to pembrolizumab monotherapy in metastatic disease. Tumor molecular profiling identified programmed-death ligand-1 (PD-L1) positivity. This characteristic provided a rationale for immune-checkpoint therapy. Treatment with pembrolizumab resulted in a complete metabolic response after four cycles of therapy. Patients with PD-L1-positive, metastatic MPNST may be candidates for immune-checkpoint therapy, which may produce a durable completere mission. Future study of anti-PD-1/PD-L1 therapy is warranted.
    • Using Continuous Glucose Monitoring to Motivate Physical Activity in Overweight and Obese Adults: A Pilot Study

      Liao, Yue; Basen-Engquist, Karen M; Urbauer, Diana L; Bevers, Therese B; Hawk, Ernest; Schembre, Susan M; Univ Arizona, Dept Family & Community Med (AMER ASSOC CANCER RESEARCH, 2020-04)
      Background: Regular physical activity (PA) is associated with a lower risk of several types of cancers. However, two-thirds of overweight/obese adults are not sufficiently active; this, in combination with the unfavorable effect of excess body weight, puts them at a greater risk for cancer. One reason that these individuals do not engage in enough PA may be their lack of motivation to change their current behavior due to the perception of putting in effort for possible future gain without obvious short-term benefits. There is a need for innovative ways to help individuals recognize the immediate health benefits of PA and thus increase their motivation. Methods: This pilot intervention tested a PA education module that included a one-on-one counseling session highlighting the acute effects of PA on glucose patterns, followed by a 10-day self-monitoring period with a continuous glucose monitor (CGM) and a Fitbit tracker. Participants rated the acceptability of the education module on a 5-point Likert scale and completed surveys assessing stages of change for motivational readiness. Results: Nineteen overweight/obese adults (84% female) completed the study. Participants gave high ratings to the counseling session for improving their PA-related knowledge (mean 4.22), increasing motivation (mean 4.29), and providing personally relevant information (mean 4.35). The summary acceptability scores for the self-monitoring period were 4.46 for CGM and 4.51 -for Fitbit. Participants reported a significant decrease in the precontemplation stage and an increase in the action stage (P < 0.05). Conclusions: CGM is a feasible tool for PA interventions. Impact: Information from CGM could be used as biologicalbased feedback to motivate PA.