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Despite high levels of distress, family caregivers of patients with cancer rarely seek psychosocial support and Internet-based interventions (IBIs) are a promising approach to reduce some access barriers. Therefore, we developed a self-guided IBI for family caregivers of patients with cancer (OAse), which, in addition to patients' spouses, also addresses other family members (e.g., adult children, parents). This study aimed to determine the feasibility of OAse (recruitment, dropout, adherence, participant satisfaction). Secondary outcomes were caregivers’ self-efficacy, emotional state, and supportive care needs. N = 41 family caregivers participated in the study (female: 65%), mostly spouses (71%), followed by children (20%), parents (7%), and friends (2%). Recruitment (47%), retention (68%), and adherence rates (76% completed at least 4 of 6 lessons) support the feasibility of OAse. Overall, the results showed a high degree of overall participant satisfaction (96%). There were no significant pre-post differences in secondary outcome criteria, but a trend toward improvement in managing difficult interactions/emotions (p = .06) and depression/anxiety (p = .06). Although the efficacy of the intervention remains to be investigated, our results suggest that OAse can be well implemented in caregivers’ daily lives and has the potential to improve family caregivers’ coping strategies.
Background
Despite advances in treatment of patients with non-small cell lung cancer, carriers of certain genetic alterations are prone to failure. One such factor frequently mutated, is the tumor suppressor PTEN. These tumors are supposed to be more resistant to radiation, chemo- and immunotherapy.
Results
We demonstrate that loss of PTEN led to altered expression of transcriptional programs which directly regulate therapy resistance, resulting in establishment of radiation resistance. While PTEN-deficient tumor cells were not dependent on DNA-PK for IR resistance nor activated ATR during IR, they showed a significant dependence for the DNA damage kinase ATM. Pharmacologic inhibition of ATM, via KU-60019 and AZD1390 at non-toxic doses, restored and even synergized with IR in PTEN-deficient human and murine NSCLC cells as well in a multicellular organotypic ex vivo tumor model.
Conclusion
PTEN tumors are addicted to ATM to detect and repair radiation induced DNA damage. This creates an exploitable bottleneck. At least in cellulo and ex vivo we show that low concentration of ATM inhibitor is able to synergise with IR to treat PTEN-deficient tumors in genetically well-defined IR resistant lung cancer models.
Personalized oncology is a rapidly evolving area and offers cancer patients therapy options that are more specific than ever. However, there is still a lack of understanding regarding transcriptomic similarities or differences of metastases and corresponding primary sites. Applying two unsupervised dimension reduction methods (t-Distributed Stochastic Neighbor Embedding (t-SNE) and Uniform Manifold Approximation and Projection (UMAP)) on three datasets of metastases (n = 682 samples) with three different data transformations (unprocessed, log10 as well as log10 + 1 transformed values), we visualized potential underlying clusters. Additionally, we analyzed two datasets (n = 616 samples) containing metastases and primary tumors of one entity, to point out potential familiarities. Using these methods, no tight link between the site of resection and cluster formation outcome could be demonstrated, or for datasets consisting of solely metastasis or mixed datasets. Instead, dimension reduction methods and data transformation significantly impacted visual clustering results. Our findings strongly suggest data transformation to be considered as another key element in the interpretation of visual clustering approaches along with initialization and different parameters. Furthermore, the results highlight the need for a more thorough examination of parameters used in the analysis of clusters.
The nuclear paraspeckle assembly transcript 1 (NEAT1) locus encodes two long non-coding (lnc)RNA isoforms that are upregulated in many tumours and dynamically expressed in response to stress. NEAT1 transcripts form ribonucleoprotein complexes with numerous RNA-binding proteins (RBPs) to assemble paraspeckles and modulate the localisation and activity of gene regulatory enzymes as well as a subset of messenger (m)RNA transcripts. The investigation of the dynamic composition of NEAT1-associated proteins and mRNAs is critical to understand the function of NEAT1. Interestingly, a growing number of biochemical and genetic tools to assess NEAT1 interactomes has been reported. Here, we discuss the Hybridisation Proximity (HyPro) labeling technique in the context of NEAT1. HyPro labeling is a recently developed method to detect spatially ordered interactions of RNA-containing nuclear compartments in cultured human cells. After introducing NEAT1 and paraspeckles, we describe the advantages of the HyPro technology in the context of other methods to study RNA interactomes, and review the key findings in mapping NEAT1-associated RNA transcripts and protein binding partners. We further discuss the limitations and potential improvements of HyPro labeling, and conclude by delineating its applicability in paraspeckles-related cancer research.
Cancer and heart disease are leading causes of morbidity and mortality worldwide. These diseases have common risk factors, common molecular signaling pathways that are central to their pathogenesis, and even some disease phenotypes that are interdependent. Thus, a detailed understanding of common regulators is critical for the development of new and synergistic therapeutic strategies. The Raf kinase inhibitory protein (RKIP) is a regulator of the cellular kinome that functions to maintain cellular robustness and prevent the progression of diseases including heart disease and cancer. Two of the key signaling pathways controlled by RKIP are the β-adrenergic receptor (βAR) signaling to protein kinase A (PKA), particularly in the heart, and the MAP kinase cascade Raf/MEK/ERK1/2 that regulates multiple diseases. The goal of this review is to discuss how we can leverage RKIP to suppress cancer without incurring deleterious effects on the heart. Specifically, we discuss: (1) How RKIP functions to either suppress or activate βAR (PKA) and ERK1/2 signaling; (2) How we can prevent cancer-promoting kinase signaling while at the same time avoiding cardiotoxicity.
Background
Previous studies have identified IFNγ as an important early barrier to oncolytic viruses including vaccinia. The existing innate and adaptive immune barriers restricting oncolytic virotherapy, however, can be overcome using autologous or allogeneic mesenchymal stem cells as carrier cells with unique immunosuppressive properties.
Methods
To test the ability of mesenchymal stem cells to overcome innate and adaptive immune barriers and to successfully deliver oncolytic vaccinia virus to tumor cells, we performed flow cytometry and virus plaque assay analysis of ex vivo co-cultures of stem cells infected with vaccinia virus in the presence of peripheral blood mononuclear cells from healthy donors. Comparative analysis was performed to establish statistically significant correlations and to evaluate the effect of stem cells on the activity of key immune cell populations.
Results
Here, we demonstrate that adipose-derived stem cells (ADSCs) have the potential to eradicate resistant tumor cells through a combination of potent virus amplification and sensitization of the tumor cells to virus infection. Moreover, the ADSCs demonstrate ability to function as a virus-amplifying Trojan horse in the presence of both autologous and allogeneic human PBMCs, which can be linked to the intrinsic immunosuppressive properties of stem cells and their unique potential to overcome innate and adaptive immune barriers. The clinical application of ready-to-use ex vivo expanded allogeneic stem cell lines, however, appears significantly restricted by patient-specific allogeneic differences associated with the induction of potent anti-stem cell cytotoxic and IFNγ responses. These allogeneic responses originate from both innate (NK)- and adaptive (T)- immune cells and might compromise therapeutic efficacy through direct elimination of the stem cells or the induction of an anti-viral state, which can block the potential of the Trojan horse to amplify and deliver vaccinia virus to the tumor.
Conclusions
Overall, our findings and data indicate the feasibility to establish simple and informative assays that capture critically important patient-specific differences in the immune responses to the virus and stem cells, which allows for proper patient-stem cell matching and enables the effective use of off-the-shelf allogeneic cell-based delivery platforms, thus providing a more practical and commercially viable alternative to the autologous stem cell approach.
Squamous cell carcinomas are therapeutically challenging tumor entities. Low response rates to radiotherapy and chemotherapy are commonly observed in squamous patients and, accordingly, the mortality rate is relatively high compared to other tumor entities. Recently, targeting USP28 has been emerged as a potential alternative to improve the therapeutic response and clinical outcomes of squamous patients. USP28 is a catalytically active deubiquitinase that governs a plethora of biological processes, including cellular proliferation, DNA damage repair, apoptosis and oncogenesis. In squamous cell carcinoma, USP28 is strongly expressed and stabilizes the essential squamous transcription factor ΔNp63, together with important oncogenic factors, such as NOTCH1, c-MYC and c-JUN. It is presumed that USP28 is an oncoprotein; however, recent data suggest that the deubiquitinase also has an antineoplastic effect regulating important tumor suppressor proteins, such as p53 and CHK2. In this review, we discuss: (1) The emerging role of USP28 in cancer. (2) The complexity and mutational landscape of squamous tumors. (3) The genetic alterations and cellular pathways that determine the function of USP28 in squamous cancer. (4) The development and current state of novel USP28 inhibitors.
Adrenocortical carcinoma (ACC) is a malignant tumor originating from the adrenal gland cortex with a heterogeneous but overall dismal prognosis in advanced stages. For more than 50 years, mitotane has remained a cornerstone for the treatment of ACC as adjuvant and palliative therapy. It has a very poor aqueous solubility of 0.1 mg/l and high partition coefficient in octanol/water (log P) value of 6. The commercially available dosage form is 500 mg tablets (Lysodren®). Even at doses up to 6 g/day (12 tablets in divided doses) for several months, > 50% patients do not achieve therapeutic plasma concentration > 14 mg/l due to poor water solubility, large volume of distribution and inter/intra-individual variability in bioavailability. This article aims to give a concise update of the clinical challenges associated with the administration of high-dose mitotane oral therapy which encompass the issues of poor bioavailability, difficult-to-predict pharmacokinetics and associated adverse events. Moreover, we present recent efforts to improve mitotane formulations. Their success has been limited, and we therefore propose an injectable mitotane formulation instead of oral administration, which could bypass many of the main issues associated with high-dose oral mitotane therapy. A parenteral administration of mitotane could not only help to alleviate the adverse effects but also circumvent the variable oral absorption, give better control over therapeutic plasma mitotane concentration and potentially shorten the time to achieve therapeutic drug plasma concentrations considerably.
Mitotane as tablet form is currently the standard treatment for adrenocortical carcinoma. It has been used for 5 decades but suffers from highly variable responses in patients, subsequent adverse effects and overall lower response rate. This can be fundamentally linked to the exceedingly poor water solubility of mitotane itself. In terms of enhancing water solubility, a few research groups have attempted to develop better formulations of mitotane to overcome the issues associated with tablet dosage form. However, the success rate was limited, and these formulations did not make it into the clinics. In this article, we have comprehensively reviewed the properties of these formulations and discuss the reasons for their limited utility. Furthermore, we discuss a recently developed mitotane nanoformulation that led us to propose a novel approach to mitotane therapy, where intravenous delivery supplements the standard oral administration. With this article, we combine the current state of knowledge as a single piece of information about the various problems associated with the use of mitotane tablets, and herein we postulate the development of a new injectable mitotane formulation, which can potentially circumvent the major problems associated to mitotane's poor water solubility.
Background
Cancer patients' mental health and quality of life can be improved through professional support according to their needs. In previous analyses of the UNSAID study, we showed that a relevant proportion of cancer patients did not express their needs during the admission interview of inpatient rehabilitation. We now examine trajectories of mental health, quality of life, and utilization of professional help in cancer patients with unexpressed needs.
Methods
We enrolled 449 patients with breast, prostate, and colon cancer at beginning (T0) and end (T1) of a 3-week inpatient rehabilitation and 3 (T2) and 9 (T3) months after discharge. We explored depression (PHQ-2), anxiety (GAD-2), emotional functioning (EORTC QLQ-C30), fear of progression (FoP-Q-SF), and global quality of life (EORTC QLQ-C30) using structuring equation models. Furthermore, we evaluated self-reports about expressing needs and utilization of professional help at follow-up.
Results
Patients with unexpressed needs (24.3%, n = 107) showed decreased mental health compared to other patients (e.g., depression: d T0 = 0.32, d T1-T3 = 0.39). They showed a significant decline in global quality of life at discharge and follow-up (d = 0.28). Furthermore, they had a higher need for support (Cramer's V T2 = 0.10, T3 = 0.15), talked less about their needs (Cramer’s V T2 = 0.18), and made less use of different health care services at follow-up.
Conclusion
Unexpressed needs in cancer patients may be a risk factor for decreased mental health, quality of life, and non-utilization of professional help in the long term. Further research should clarify causal relationships and focus on this specific group of patients to improve cancer care.
The adoptive transfer of the chimeric antigen receptor (CAR) expressing T-cells has produced unprecedented successful results in the treatment of B-cell malignancies. However, the use of this technology in other malignancies remains less effective. In the setting of solid neoplasms, CAR T-cell metabolic fitness needs to be optimal to reach the tumor and execute their cytolytic function in an environment often hostile. It is now well established that both tumor and T cell metabolisms play critical roles in controlling the immune response by conditioning the tumor microenvironment and the fate and activity of the T cells. In this review, after a brief description of the tumoral and T cell metabolic reprogramming, we summarize the latest advances and new strategies that have been developed to improve the metabolic fitness and efficacy of CAR T-cell products.