Limited clinical activity has been seen in osteosarcoma (OS) patients treated with immune checkpoint inhibitors (ICI). To gain insights into the immunogenic potential of these tumors, we conducted ...whole genome, RNA, and T-cell receptor sequencing, immunohistochemistry and reverse phase protein array profiling (RPPA) on OS specimens from 48 pediatric and adult patients with primary, relapsed, and metastatic OS. Median immune infiltrate level was lower than in other tumor types where ICI are effective, with concomitant low T-cell receptor clonalities. Neoantigen expression in OS was lacking and significantly associated with high levels of nonsense-mediated decay (NMD). Samples with low immune infiltrate had higher number of deleted genes while those with high immune infiltrate expressed higher levels of adaptive resistance pathways. PARP2 expression levels were significantly negatively associated with the immune infiltrate. Together, these data reveal multiple immunosuppressive features of OS and suggest immunotherapeutic opportunities in OS patients.
Owing to a lack of response to the anti-PD1 therapy for most cancer patients, we develop a network approach to infer genes, pathways, and potential therapeutic combinations that are associated with ...tumor response to anti-PD1. Here, our prediction identifies genes and pathways known to be associated with anti-PD1, and is further validated by 6 CRISPR gene sets associated with tumor resistance to cytotoxic T cells and targets of the 36 compounds that have been tested in clinical trials for combination treatments with anti-PD1. Integration of our top prediction and TCGA data identifies hundreds of genes whose expression and genetic alterations that could affect response to anti-PD1 in each TCGA cancer type, and the comparison of these genes across cancer types reveals that the tumor immunoregulation associated with response to anti-PD1 would be tissue-specific. In addition, the integration identifies the gene signature to calculate the MHC I association immunoscore (MIAS) that shows a good correlation with patient response to anti-PD1 for 411 melanoma samples complied from 6 cohorts. Furthermore, mapping drug target data to the top genes in our association prediction identifies inhibitors that could potentially enhance tumor response to anti-PD1, such as inhibitors of the encoded proteins of CDK4, GSK3B, and PTK2.
Osteosarcoma is the most common primary malignant tumour of the bone. Osteosarcoma incidence is bimodal, peaking at 18 and 60 years of age, and is slightly more common in males. The key ...pathophysiological mechanism involves several possible genetic drivers of disease linked to bone formation, causing malignant progression and metastasis. While there have been significant improvements in the outcome of patients with localized disease, with event-free survival outcomes exceeding 60%, in patients with metastatic disease, event-free survival outcomes remain poor at less than 30%. The suspicion of osteosarcoma based on radiographs still requires pathological evaluation of a bone biopsy specimen for definitive diagnosis and CT imaging of the chest should be performed to identify lung nodules. So far, population-based screening and surveillance strategies have not been implemented due to the rarity of osteosarcoma and the lack of reliable markers. Current screening focuses only on groups at high risk such as patients with genetic cancer predisposition syndromes. Management of osteosarcoma requires a multidisciplinary team of paediatric and medical oncologists, orthopaedic and general surgeons, pathologists, radiologists and specialist nurses. Survivors of osteosarcoma require specialized medical follow-up, as curative treatment consisting of chemotherapy and surgery has long-term adverse effects, which also affect the quality of life of patients. The development of osteosarcoma model systems and related research as well as the evaluation of new treatment approaches are ongoing to improve disease outcomes, especially for patients with metastases.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Low-dose UCN-01 mediates G1 arrest in normal proliferating cell lines with an intact G1 to S transition but not tumour cells with a deregulated G1 to S checkpoint. Here we hypothesised that UCN-01 is ...effective in mediating a selective, reversible G1 arrest of normal proliferating cells, resulting in decreased chemotoxicity, improved tolerance and enhanced chemotherapeutic efficacy in vivo in both non-tumour-bearing mice and in breast cancer cell line xenograft models.
Murine small bowel epithelium was used to examine the kinetics and mechanism of low-dose UCN-01-mediated arrest of normal proliferating cells and if it can protect tumour-bearing mice (MDA-MB-468 xenografts) against the toxic effects of chemotherapy (5-fluorouricil (5-FU)) allowing for its full therapeutic activity.
UCN-01 causes significant, reversible arrest of normal gut epithelial cells at 24 h; this arrest persists for up to 7 days. Normal cellular proliferation returns by 2 weeks. Pre-treatment of both non-tumour-bearing and MDA-MB-468 tumour-bearing mice with UCN-01 prior to bolus 5-FU (450 mg/kg) yielded enhanced therapeutic efficacy with significantly decreased tumour volumes and increased survival.
UCN-01 mediates a specific, reversible G1 arrest of normal cells in vivo and provides a cytoprotective strategy that decreases toxicity of cytotoxic chemotherapy without compromising efficacy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Radiation therapy (RT) is a common treatment for adolescents and young adults (AYAs, 15–39 years old) with cancer; however, it may cause toxicities that affect health‐related ...quality‐of‐life (HRQOL). Thus, we assessed HRQOL in AYAs before, during, and after RT.
Methods
We identified 265 AYAs who completed HRQOL PROMIS® surveys before (n = 87), during (n = 84), or after (n = 94) RT. Higher PROMIS® score represents more of the concept. Mean scores were compared to the general US population and minimally important differences (MIDs) were used to evaluate the impact of cancer on HRQOL. Linear regression modeling was used to evaluate the effect of clinical and demographic factors on PROMIS scores.
Results
Median IQR age was 26 20–31 years. Cancer types varied; most had sarcoma (26%) or CNS malignancy (23%). Compared to the general US population, the before RT cohort had worse anxiety (mean score 55.2 vs. 50, MID 3, p < 0.001) and the during RT cohort had worse global physical health (mean score 44.9 vs. 50, MID 5, p < 0.001). In the during RT cohort, patients with regional/distant disease had significantly worse pain (B = 15.94, p < 0.01) and fatigue (B = 14.20, p = 0.01) than patients with localized disease. In the after RT cohort, adolescents (15–18 years) and young adults (26–39 years) had worse global physical health (B = ‐6.87, p < 0.01, and B = ‐7.87, p < 0.01, respectively) and global mental health (B = ‐6.74, p < 0.01, and B = ‐5.67, p = 0.01, respectively) than emerging adults (19–25 years).
Conclusions
AYAs with cancer receiving RT experience impairments in various domains of HRQOL. Advanced cancer stage may contribute to poorer short‐term HRQOL and developmental stage may contribute to differing long‐term HRQOL.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Purpose
Adolescent and young adult (AYA) cancer patients face challenges when navigating cancer treatment and survivorship. Many are at risk for cancer predisposition syndromes; however, factors ...influencing pursuit of genetic counseling and testing have not been reported. We describe AYA cancer patients’ decision-making process, including motivational factors and barriers, as it relates to utilization of genetic services.
Methods
Thirty AYAs diagnosed with cancer previously referred for cancer predisposition genetic counseling completed semi-structured interviews via audio-only Zoom calls. Thematic analysis was used to perform qualitative analysis and identify major themes.
Results
The sample comprised 21 AYAs who had genetic counseling and nine who did not. Motivational factors identified included learning genetic counseling is an available service, concern about the impact of a hereditary syndrome on family members and family planning, learning about the need for cancer screening or prevention, affordability of genetic testing, and easing worry about additional cancer risks. For those who did not pursue genetic counseling, barriers included scheduling or other priorities, worry, and cost. However, the majority expressed they would reconsider genetic counseling in the future.
Conclusion
AYA cancer patients have similar motivational factors to pursue genetic counseling compared to other patients; however, their younger age of diagnosis may alter how these factors affect decision-making. While there are barriers limiting access to genetic services, they did not decrease interest in future genetic counseling for most patients. Genetic counseling and testing should be discussed with patients who previously declined genetic services.
Osteosarcoma is the most common pediatric and adult primary malignant bone cancer. Curative regimens target the folate pathway, downstream of serine metabolism, with high-dose methotrexate. Here, the ...rate-limiting enzyme in the biosynthesis of serine from glucose, 3-phosphoglycerate dehydrogenase (PHGDH), is examined, and an inverse correlation between PHGDH expression and relapse-free and overall survival in osteosarcoma patients is found. PHGDH inhibition in osteosarcoma cell lines attenuated cellular proliferation without causing cell death, prompting a robust metabolic analysis to characterize pro-survival compensation. Using metabolomic and lipidomic profiling, cellular response to PHGDH inhibition is identified as accumulation of unsaturated lipids, branched chain amino acids, and methionine cycle intermediates, leading to activation of pro-survival mammalian target of rapamycin complex 1 (mTORC1) signaling. Increased mTORC1 activation sensitizes cells to mTORC1 pathway inhibition, resulting in significant, synergistic cell death in vitro and in vivo. Identifying a therapeutic combination for PHGDH-high cancers offers preclinical justification for a dual metabolism-based combination therapy for osteosarcoma.
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•Upregulated PHGDH in osteosarcoma correlates with poor survival•Inhibiting PHGDH attenuates osteosarcoma proliferation without causing cell death•TCA cycle blockade and accumulation of metabolites results in mTORC1 activation•PHGDH inhibition combined with non-rapalog mTORC1 inhibition is synergistic
Rathore et al. identify 3-phosphoglycerate dehydrogenase (PHGDH) overexpression as a marker of poor prognosis in osteosarcoma. PHGDH inhibition causes decreased proliferation, inhibited TCA cycle, and accumulation of metabolites that drive the activation of mTORC1. Non-rapalog mTORC1 inhibition combined with PHGDH inhibition demonstrates a possible synergistic dual metabolic therapy for osteosarcoma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To prevent damage to the host or its commensal microbiota, epithelial tissues must match the intensity of the immune response to the severity of a biological threat. Toll-like receptors allow ...epithelial cells to identify microbe associated molecular patterns. However, the mechanisms that mitigate biological noise in single cells to ensure quantitatively appropriate responses remain unclear. Here we address this question using single cell and single molecule approaches in mammary epithelial cells and primary organoids. We find that epithelial tissues respond to bacterial microbe associated molecular patterns by activating a subset of cells in an all-or-nothing (i.e. digital) manner. The maximum fraction of responsive cells is regulated by a bimodal epigenetic switch that licenses the TLR2 promoter for transcription across multiple generations. This mechanism confers a flexible memory of inflammatory events as well as unique spatio-temporal control of epithelial tissue-level immune responses. We propose that epigenetic licensing in individual cells allows for long-term, quantitative fine-tuning of population-level responses.
Purpose
Radiation therapy (RT) is a critical component of treatment for adolescents and young adults (AYAs, age 15–39 years old) diagnosed with cancer. Limited prior studies have focused on AYAs ...receiving RT despite the potentially burdensome effects of RT. We reviewed the literature to assess health-related quality of life (HRQOL) in AYAs with cancer who received RT.
Methods
The MEDLINE, EMBASE, and Web of Science databases were searched in January 2022 to identify studies that analyzed HRQOL measured by patient-reported outcomes in AYAs who received RT. After title (
n
= 286) and abstract (
n
= 58) screening and full-text review (
n
= 19), articles that met eligibility criteria were analyzed.
Results
Six studies were analyzed. Two studies included AYAs actively receiving treatment and all included patients in survivorship; time between diagnosis and HRQOL data collection ranged from 3 to > 20 years. Physical and mental health were commonly assessed (6/6 studies) with social health assessed in three studies. AYA-relevant HRQOL needs were rarely assessed: fertility (1/6 studies), financial hardship (1/6), body image (0/6), spirituality (0/6), and sexual health (0/6). No study compared HRQOL between patients actively receiving RT and those post-treatment. None of the studies collected HRQOL data longitudinally.
Conclusion
HRQOL data in AYAs receiving RT is limited. Future studies examining longitudinal, clinician- vs. patient-reported, and AYA-relevant HRQOL are needed to better understand the unique needs in this population.
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