Childhood Protective Factors and Future Adult Health Outcomes in an Urban Environment.

Purpose: To evaluate protective factors that help individuals overcome adverse health outcomes associated with childhood trauma in an urban environment. Methods: This retrospective cohort study included adults born between 1970 and 1995 who grew up in the former Cabrini-Green Homes, a low-income, Chicago public housing development. Participants completed surveys asking about general health, smoking, and mental health status. Surveys included questions related to neighborhood and family support, community safety, and childhood youth program participation. Simple regression models were performed to compare childhood exposure of adverse and protective factors to adult health outcomes. Multivariable logistic regression models were constructed to adjust for age, sex, and educational attainment. Results: 334 former residents completed the survey, and only those that reported an adversity score ≥ 2 were included in the analysis (n = 248). For those individuals who reported that their families cared for them as children, they described feeling hopeful about the future (OR 2.77, 95% CI, 1.28-6.00, aOR 2.63, 95% CI, 1.21-5.75) and reported decreased smoking rates as adults (OR 0.30, 95% CI, 0.14-0.66, aOR 0.35, 95% CI, 0.16-0.78). Better self-reported adult health status was associated with residents who believed the neighborhood looked out for one another (OR 2.31, 95% CI, 1.21-4.42, aOR 2.01, 95% CI, 1.02-3.95). Conclusion: These findings suggest that a caring family and neighborhood connectedness are protective in mitigating childhood adversity. Devoting resources to strengthen families and communities is a promising strategy to promote healthier adult behaviors.

Long-term effects of a community-based positive youth development program for Black youth: health, education, and financial well-being in adulthood.

BACKGROUND: Childhood poverty is known to be associated with poor health. For youth living in extreme poverty, community-based programs focused on youth development are one strategy to improve health and well-being outcomes. However, very few evaluations of the long-term effectiveness of youth development programs have been conducted. The aim of this study was to assess the long-term effectiveness of a positive youth development program (PYD), serving a segregated housing project with a history of community violence, to improve the health, education, and financial well-being of its alumni. METHODS: A quasi-experimental causal comparative study design was used to study the effectiveness of the Cabrini-Green Youth Program (CGYP). CGYP alumni (mean: 16.8 +/- 7.4 years after program participation) were surveyed. For comparison, participants from the same housing project who were eligible to participate in the CGYP but did not, were identified. RESULTS: In total, 246/417 (59%) eligible alumni were located. 221 alumni were available to be interviewed; 191/221 (86%) completed the interview survey along with 143 in the comparison group. Both groups self-identified as being Black, African American, and of Other race. Alumni were younger (34.6 vs. 38.1 years, p < .001), less likely to be female (62% vs. 74%, p =.03), and more likely to have been abused as a child (26% vs. 11%, p = .001). The majority in both groups reported to be in good to excellent health (83% of alumni vs. 74% of comparison group). After adjusting for comparison group differences, alumni were more likely to have completed college, 24% vs. 12% (adjusted odds ratio (aOR) 2.47, 95% CI, 1.25-4.86), and to end up with some money at the end of the month, 35% vs. 19% (aOR 2.16, 95% CI, 1.17, 3.97). CONCLUSIONS: Participation in a PYD program starting at a young age may be associated with reduced poverty in adulthood, possibly aided by higher educational attainment and resultant increased income. PYD may be an effective strategy to supplement evidenced-based poverty reducing policies. This study of a voluntary, community-based PYD program is unique in its up to 33-year follow-up and an outcome assessment that measures more than knowledge change.

MERTK Mediates Intrinsic and Adaptive Resistance to AXL-targeting Agents.

The TAM (TYRO3, AXL, MERTK) family receptor tyrosine kinases (RTK) play an important role in promoting growth, survival, and metastatic spread of several tumor types. AXL and MERTK are overexpressed in head and neck squamous cell carcinoma (HNSCC), triple-negative breast cancer (TNBC), and non-small cell lung cancer (NSCLC), malignancies that are highly metastatic and lethal. AXL is the most well-characterized TAM receptor and mediates resistance to both conventional and targeted cancer therapies. AXL is highly expressed in aggressive tumor types, and patients with cancer are currently being enrolled in clinical trials testing AXL inhibitors. In this study, we analyzed the effects of AXL inhibition using a small-molecule AXL inhibitor, a monoclonal antibody (mAb), and siRNA in HNSCC, TNBC, and NSCLC preclinical models. Anti-AXL-targeting strategies had limited efficacy across these different models that, our data suggest, could be attributed to upregulation of MERTK. MERTK expression was increased in cell lines and patient-derived xenografts treated with AXL inhibitors and inhibition of MERTK sensitized HNSCC, TNBC, and NSCLC preclinical models to AXL inhibition. Dual targeting of AXL and MERTK led to a more potent blockade of downstream signaling, synergistic inhibition of tumor cell expansion in culture, and reduced tumor growth in vivo Furthermore, ectopic overexpression of MERTK in AXL inhibitor-sensitive models resulted in resistance to AXL-targeting strategies. These observations suggest that therapeutic strategies cotargeting both AXL and MERTK could be highly beneficial in a variety of tumor types where both receptors are expressed, leading to improved survival for patients with lethal malignancies. Mol Cancer Ther; 17(11); 2297-308. ©2018 AACR.

Overcoming Resistance to Cetuximab with Honokiol, A Small-Molecule Polyphenol.

Overexpression and activation of the EGFR have been linked to poor prognosis in several human cancers. Cetuximab is a mAb against EGFR that is used for the treatment in head and neck squamous cell carcinoma (HNSCC) and metastatic colorectal cancer. Unfortunately, most tumors have intrinsic or will acquire resistance to cetuximab during the course of therapy. Honokiol is a natural compound found in the bark and leaves of the Chinese Magnolia tree and is established to have several anticancer properties without appreciable toxicity. In this study, we hypothesized that combining cetuximab and honokiol treatments could overcome acquired resistance to cetuximab. We previously developed a model of acquired resistance to cetuximab in non-small cell lung cancer H226 cell line. Treatment of cetuximab-resistant clones with honokiol and cetuximab resulted in a robust antiproliferative response. Immunoblot analysis revealed the HER family and their signaling pathways were downregulated after combination treatment, most notably the proliferation (MAPK) and survival (AKT) pathways. In addition, we found a decrease in phosphorylation of DRP1 and reactive oxygen species after combination treatment in cetuximab-resistant clones, which may signify a change in mitochondrial function. Furthermore, we utilized cetuximab-resistant HNSCC patient-derived xenografts (PDX) to test the benefit of combinatorial treatment in vivo There was significant growth delay in PDX tumors after combination treatment with a subsequent downregulation of active MAPK, AKT, and DRP1 signaling as seen in vitro Collectively, these data suggest that honokiol is a promising natural compound in overcoming acquired resistance to cetuximab. Mol Cancer Ther; 17(1); 204-14. ©2017 AACR.

Targeting the HER Family with Pan-HER Effectively Overcomes Resistance to Cetuximab.

Cetuximab, an antibody against the EGFR, has shown efficacy in treating head and neck squamous cell carcinoma (HNSCC), metastatic colorectal cancer, and non-small cell lung cancer (NSCLC). Despite the clinical success of cetuximab, many patients do not respond to cetuximab. Furthermore, virtually all patients who do initially respond become refractory, highlighting both intrinsic and acquired resistance to cetuximab as significant clinical problems. To understand mechanistically how cancerous cells acquire resistance, we previously developed models of acquired resistance using the H226 NSCLC and UM-SCC1 HNSCC cell lines. Cetuximab-resistant clones showed a robust upregulation and dependency on the HER family receptors EGFR, HER2, and HER3. Here, we examined pan-HER, a mixture of six antibodies targeting these receptors on cetuximab-resistant clones. In cells exhibiting acquired or intrinsic resistance to cetuximab, pan-HER treatment decreased all three receptors' protein levels and downstream activation of AKT and MAPK. This correlated with decreased cell proliferation in cetuximab-resistant clones. To determine whether pan-HER had a therapeutic benefit in vivo, we established de novo cetuximab-resistant mouse xenografts and treated resistant tumors with pan-HER. This regimen resulted in a superior growth delay of cetuximab-resistant xenografts compared with mice continued on cetuximab. Furthermore, intrinsically cetuximab-resistant HNSCC patient-derived xenograft tumors treated with pan-HER exhibited significant growth delay compared with vehicle/cetuximab controls. These results suggest that targeting multiple HER family receptors simultaneously with pan-HER is a promising treatment strategy for tumors displaying intrinsic or acquired resistance to cetuximab. Mol Cancer Ther; 15(9); 2175-86. ©2016 AACR.

Adaptive responses to antibody based therapy.

Receptor tyrosine kinases (RTKs) represent a large class of protein kinases that span the cellular membrane. There are 58 human RTKs identified which are grouped into 20 distinct families based upon their ligand binding, sequence homology and structure. They are controlled by ligand binding which activates intrinsic tyrosine-kinase activity. This activity leads to the phosphorylation of distinct tyrosines on the cytoplasmic tail, leading to the activation of cell signaling cascades. These signaling cascades ultimately regulate cellular proliferation, apoptosis, migration, survival and homeostasis of the cell. The vast majority of RTKs have been directly tied to the etiology and progression of cancer. Thus, using antibodies to target RTKs as a cancer therapeutic strategy has been intensely pursued. Although antibodies against the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) have shown promise in the clinical arena, the development of both intrinsic and acquired resistance to antibody-based therapies is now well appreciated. In this review we provide an overview of the RTK family, the biology of EGFR and HER2, as well as an in-depth review of the adaptive responses undertaken by cells in response to antibody based therapies directed against these receptors. A greater understanding of these mechanisms and their relevance in human models will lead to molecular insights in overcoming and circumventing resistance to antibody based therapy.