DNA damage is fundamental to tumorigenesis, and the inability to repair DNA damage is a hallmark of many human cancers. DNA is repaired via the DNA damage repair (DDR) apparatus, which includes five major pathways. DDR deficiencies in cancers give rise to potential therapeutic targets, as cancers harboring DDR deficiencies become increasingly dependent on alternative DDR pathways for survival. In this review, we summarize the DDR apparatus, and examine the current state of research efforts focused on identifying vulnerabilities in DDR pathways that can be therapeutically exploited in pediatric extracranial solid tumors. We assess the potential for synergistic combinations of different DDR inhibitors as well as combinations of DDR inhibitors with chemotherapy. Lastly, we discuss the immunomodulatory implications of targeting DDR pathways and the potential for using DDR inhibitors to enhance tumor immunogenicity, with the goal of improving the response to immune checkpoint blockade in pediatric solid tumors. We review the ongoing and future research into DDR in pediatric tumors and the subsequent pediatric clinical trials that will be critical to further elucidate the efficacy of the approaches targeting DDR.

New treatments are needed to improve survival in children with rhabdomyosarcoma (RMS). Nicotinamide adenine dinucleotide (NAD+) biosynthesis, regulated by the enzymes nicotinic acid phosphoribosyltransferase (NAPRT) and nicotinamide phosphoribosyltransferase (NAMPT), represents a metabolic vulnerability due to high NAD+ turnover in cancers. Although NAMPT inhibitors (NAMPTi) show preclinical promise, clinical translation has been limited by toxicity and the lack of predictive biomarkers. In this study, we evaluated NAPRT expression in RMS and its potential as an actionable biomarker to guide NAMPTi therapy. NAPRT promoter methylation, transcript levels, and protein expression were assessed in RMS cells, patient-derived xenografts (PDX), and primary tumors (n = 109) from the Children’s Oncology Group. In vitro sensitivity to NAMPTi was tested in isogenic RMS cell lines, examining the role of NAPRT expression in mediating cytotoxicity and the ability of nicotinic acid (NA) to rescue viability. In vivo efficacy was assessed using cell-derived, NAPRT-isogenic, and orthotopic PDX models. NAPRT promoter hypermethylation was found in a subset of RMS models and patient samples. Immunohistochemistry showed loss of NAPRT protein in 30% to 40% of tumors, defined as <1% tumor cell staining. Methylation modestly correlated with protein expression. NAPRT-deficient cells were highly sensitive to NAMPTi, driven by NAD+ depletion and not reversible with NA. In vivo, NAMPTi induced significant tumor regression, which was not abrogated with NA administration in NAPRT-deficient models. NAPRT loss occurs in a subset of RMS and may offer a biomarker-driven strategy to expand the therapeutic window of NAMPTi. Further research is needed to understand NAPRT regulation and optimize biomarker assays in future clinical trials.

Individuals with severe mental illness and substance use disorders face complex barriers to achieving physical health. This study aims to explore the barriers and facilitators of primary care access among an Assertive Community Treatment (ACT) team. Semi-structured qualitative interviews were conducted with 14 clients and 7 clinicians from an ACT team at a community mental health center in Connecticut. Data analysis followed a grounded theory approach, with codes and themes emerging iteratively during the interview process. The study identified multifaceted barriers to accessing primary care, including economic challenges, homelessness, and the prioritization of mental health and substance use symptoms over healthcare. The conceptual framework consists of seven dominant themes: clients’ abilities, attitudes, experiences, knowledge, motivations, resources, and ACT-team level factors. This research provides valuable insights into the various barriers faced by ACT clients in accessing primary care. Improving primary care access for individuals with severe mental illness and substance use disorders is crucial for reducing health disparities in this vulnerable population.

Connectedness is vital for health and well-being. Families with lower socioeconomic status and of racial and ethnic minority groups experience inequities in social connections compared to families with higher income and of White race in the United States. We aimed to understand how families in lower-income neighborhoods experienced social connectedness and isolation during the COVID-19 pandemic and if and how political, economic, and other societal factors influenced social connectedness. We conducted in-depth interviews with nineteen caregivers of young children in Cincinnati, Ohio. Participants had a decreased sense of social connectedness to family and friends but also across all aspects of their lives. The current crisis has exacerbated preexisting societal conditions within the United States. We can learn from these caregivers how best to bolster social connectedness and disrupt social isolation.