Modulation of autophagy: a Phase II study of vorinostat plus hydroxychloroquine versus regorafenib in chemotherapy-refractory metastatic colorectal cancer (mCRC).

BACKGROUND: In metastatic colorectal cancer (mCRC), regorafenib (RGF), a multi-kinase inhibitor with angiogenic inhibition has modest effects on survival. We reported that autophagy modulation using hydroxychloroquine (HCQ), enhances the anticancer activity of the histone deacetylase inhibitor, vorinostat (VOR), in mCRC, is well tolerated, and has comparable activity to RGF. Thus, we conducted a prospective study of VOR/HCQ versus RGF in mCRC. METHODS: This is a randomised, controlled trial of VOR 400 mg and HCQ 600 mg orally daily versus RGF 160 mg orally daily (3 weeks on/1 week off), every 4 weeks, in patients with mCRC. PRIMARY ENDPOINT: median progression-free survival (mPFS). Secondary endpoints: median overall survival (mOS); adverse events; pharmacodynamic analyses. RESULTS: From 2/2015-10/2017, 42 patients were randomised to VOR/HCQ and RGF. Median age was 58.4 years. mPFS on VOR/HCQ was 1.9 months versus 4.35 months with RGF (P = 0.032). There was no difference in mOS (P = 0.9). Treatment was tolerated in both arms. In both arms, there was improved anti-tumour immunity. CONCLUSIONS: VOR/HCQ had an inferior PFS when compared to RGF, although there was an increase in anti-tumour immunity in mCRC. VOR/HCQ has a favourable safety profile, and immune or tumour biomarkers may be used to identify clinical benefit of autophagy modulation in mCRC. CLINICAL TRIAL REGISTRATION: NCT02316340.

Examining 24-Hour Activity and Sleep Behaviors and Related Determinants in Latino Adolescents and Young Adults With Obesity.

Background. Few studies have examined 24-hour activity and sleep behaviors and their contribution to type 2 diabetes (T2D) in Latino adolescents and young adults with obesity. Aim. This study included quantitative data on T2D risk and 24-hour activity and sleep behaviors and qualitative data on individual, social, and environmental behavioral determinants. Method. A 7 day, 24-hour, wrist-worn accelerometer protocol assessed moderate-to-vigorous physical activity (PA), sedentary behaviors (SB), sleep, and sleep regularity, in adolescents (N = 38; 12-16 years) and young adults (N = 22; 18-22 years). T2D-related outcomes included adiposity (BMI, BF%, waist circumference), fasting, and 2-hour glucose. A subsample of participants (N = 16 adolescents, N = 15 young adults) completed interviews to identify behavioral determinants. Results. High levels of PA were observed among adolescents (M = 103.8 ± 67.5 minutes/day) and young adults (M = 96.8 ± 78.8 minutes/day) as well as high levels of SB across both age groups (≥10 hours/day). Sleep regularity was negatively associated with adiposity (all ps < .05) in both age groups as well as fasting and 2-hour glucose in young adults (all ps < .05). Social support was associated with PA in both age groups as well as SB in younger youth. Auditory noises, lights, and safety inhibited sleep in both age groups. Conclusion. PA is critical for disease reduction, yet reducing SB and improving sleep are also important targets for reducing T2D risk in Hispanic adolescents and young adults. Future health promotion and disease prevention strategies should leverage qualitative findings regarding behavioral determinants.

Perceptions of Family-Level Social Factors That Influence Health Behaviors in Latinx Adolescents and Young Adults at High Risk for Type 2 Diabetes.

Given that health behaviors occur within the context of familial social relationships, a deeper understanding of social factors that influence health behaviors in Latinx families is needed to develop more effective diabetes prevention programming. This qualitative study identified perceived family-level social factors that influence health behaviors in Latinx adolescents (12-16 years; N = 16) and young adults (18-24 years; N = 15) with obesity and explored differences in perceptions across sex and age. Participants completed an in-depth interview that was recorded, transcribed, and coded using thematic content analysis. Emergent themes central to health behaviors included: perceived parental roles and responsibilities, perceived family social support for health behaviors, and familial social relationships. Mom's role as primary caregiver and dad's role as a hard worker were seen as barriers to engaging in health behaviors among adolescent females and young adults, males and females. Adolescents perceived receiving more support compared to young adults and males perceived receiving more support compared to females. Health behaviors in both age groups were shaped through early familial social interactions around physical activity. These insights suggest that traditional gender roles, social support, and social interaction around health behaviors are critical components for family-based diabetes prevention programs in high-risk Latinx youth and young adults.

CD122-Selective IL2 Complexes Reduce Immunosuppression, Promote Treg Fragility, and Sensitize Tumor Response to PD-L1 Blockade.

The IL2 receptor (IL2R) is an attractive cancer immunotherapy target that controls immunosuppressive T regulatory cells (Treg) and antitumor T cells. Here we used IL2Rß-selective IL2/anti-IL2 complexes (IL2c) to stimulate effector T cells preferentially in the orthotopic mouse ID8agg ovarian cancer model. Despite strong tumor rejection, IL2c unexpectedly lowered the tumor microenvironmental CD8+/Treg ratio. IL2c reduced tumor microenvironmental Treg suppression and induced a fragile Treg phenotype, helping explain improved efficacy despite numerically increased Tregs without affecting Treg in draining lymph nodes. IL2c also reduced Treg-mediated, high-affinity IL2R signaling needed for optimal Treg functions, a likely mechanism for reduced Treg suppression. Effector T-cell IL2R signaling was simultaneously improved, suggesting that IL2c inhibits Treg functions without hindering effector T cells, a limitation of most Treg depletion agents. Anti-PD-L1 antibody did not treat ID8agg, but adding IL2c generated complete tumor regressions and protective immune memory not achieved by either monotherapy. Similar anti-PD-L1 augmentation of IL2c and degradation of Treg functions were seen in subcutaneous B16 melanoma. Thus, IL2c is a multifunctional immunotherapy agent that stimulates immunity, reduces immunosuppression in a site-specific manner, and combines with other immunotherapies to treat distinct tumors in distinct anatomic compartments. SIGNIFICANCE: These findings present CD122-targeted IL2 complexes as an advancement in cancer immunotherapy, as they reduce Treg immunosuppression, improve anticancer immunity, and boost PD-L1 immune checkpoint blockade efficacy in distinct tumors and anatomic locations.

¡Viva Maryvale!: A Multilevel, Multisector Model to Community-Based Diabetes Prevention.

INTRODUCTION: Latino communities are disproportionately affected by type 2 diabetes and experience disparities in access to diabetes prevention programs. The purpose of this study was to test the preliminary efficacy of a culturally grounded, diabetes prevention program for high-risk Latino families delivered through an integrated research-practice partnership. STUDY DESIGN: The integrated research-practice partnership was established in a predominantly Latino community and consisted of a Federally Qualified Health Center, a YMCA, an accredited diabetes education program, and an academic research center. Data were collected and analyzed from 2015 to 2018. SETTING/PARTICIPANTS: Latino families consisting of a parent with an obese child between age 8 and 12 years. INTERVENTION: The 12-week lifestyle intervention included nutrition education and behavioral skills training (60 minutes, once/week) and physical activity classes (60 minutes, three times/week) delivered at a YMCA. MAIN OUTCOME MEASURES: Outcomes included measures of adiposity (BMI, waist circumference, and body fat); HbA1c; and weight-specific quality of life. RESULTS: Over the course of the 2-year project period, 58 families (parents n=59, children n=68) were enrolled with 36% of parents and 29% of children meeting the criteria for prediabetes at baseline. Feasibility and acceptability were high, with 83% of enrolled families completing the program, 91% of the intervention sessions attended, and 100% of families stating they would recommend the program. The intervention led to significant decreases in percentage body fat among parents (46.4% [SD=10.8] to 43.5% [SD=10.5], p=0.001) as well as children (43.1% [SD=8.0] to 41.8% [SD=7.2], p=0.03). Additionally, HbA1c was significantly reduced in parents (5.6% [SD=0.4] to 5.5% [SD=0.3], p=0.03), and remained stable in children (5.5% [SD=0.3] vs 5.5% [SD=0.3], p>0.05). Significant improvements in quality of life were reported in parents (64.6 [SD=15.8] to 71.0 [SD=13.7], p=0.001) and children (69.7 [SD=15.8] to 72.6 [SD=13.7], p=0.05). CONCLUSIONS: These findings support the preliminary efficacy of an integrated research-practice partnership to meet the diabetes prevention needs of high-risk Latino families within a vulnerable community.