Publications by authors named "Anna Capasso"

126 Publications

Testing Cancer Immunotherapy in a Human Immune System Mouse Model: Correlating Treatment Responses to Human Chimerism, Therapeutic Variables and Immune Cell Phenotypes.

Front Immunol 2021 29;12:607282. Epub 2021 Mar 29.

Division of Medical Oncology, School of Medicine, University of Colorado, Aurora, CO, United States.

Over the past decade, immunotherapies have revolutionized the treatment of cancer. Although the success of immunotherapy is remarkable, it is still limited to a subset of patients. More than 1500 clinical trials are currently ongoing with a goal of improving the efficacy of immunotherapy through co-administration of other agents. Preclinical, small-animal models are strongly desired to increase the pace of scientific discovery, while reducing the cost of combination drug testing in humans. Human immune system (HIS) mice are highly immune-deficient mouse recipients rtpeconstituted with human hematopoietic stem cells. These HIS-mice are capable of growing human tumor cell lines and patient-derived tumor xenografts. This model allows rapid testing of multiple, immune-related therapeutics for tumors originating from unique clinical samples. Using a cord blood-derived HIS-BALB/c-Rag2Il2rγSIRPα (BRGS) mouse model, we summarize our experiments testing immune checkpoint blockade combinations in these mice bearing a variety of human tumors, including breast, colorectal, pancreatic, lung, adrenocortical, melanoma and hematological malignancies. We present in-depth characterization of the kinetics and subsets of the HIS in lymph and non-lymph organs and relate these to protocol development and immune-related treatment responses. Furthermore, we compare the phenotype of the HIS in lymph tissues and tumors. We show that the immunotype and amount of tumor infiltrating leukocytes are widely-variable and that this phenotype is tumor-dependent in the HIS-BRGS model. We further present flow cytometric analyses of immune cell subsets, activation state, cytokine production and inhibitory receptor expression in peripheral lymph organs and tumors. We show that responding tumors bear human infiltrating T cells with a more inflammatory signature compared to non-responding tumors, similar to reports of "responding" patients in human immunotherapy clinical trials. Collectively these data support the use of HIS mice as a preclinical model to test combination immunotherapies for human cancers, if careful attention is taken to both protocol details and data analysis.
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http://dx.doi.org/10.3389/fimmu.2021.607282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040953PMC
March 2021

Outcomes That Matter Most to Young Adults Diagnosed with Cancer: A Qualitative Study.

J Adolesc Young Adult Oncol 2020 Nov 25. Epub 2020 Nov 25.

Department of Internal Medicine, The University of Texas at Austin Dell Medical School, Austin, Texas, USA.

The purpose of this study is to provide insight for improvement in care for young adults diagnosed with cancer (YADC), by identifying underemphasized outcomes that strongly matter to YADC and the gaps in care that may limit achieving these outcomes for this unique and vulnerable population. Twenty-seven YADC, ages 25-39, participated in unstructured discussions focusing on topics relating to diagnosis, daily experiences living with cancer outside of the clinical setting, goals, concerns, and clinical care experience. Most participants engaged in group discussions using Experience Group methodology. Discussions were designed to collect information on three dimensions of health: capability, comfort, and calm (CCC). Data were coded using thematic analysis with NVivo software. Several themes were identified within the CCC framework: in terms of confronting mortality at a young age, losing youthful identity and control over major life course decisions, especially fertility, and debilitating side effects, in terms of the lack of understanding from peers and family and the fear of cancer recurrence, and was discussed as the difficulty of making complex medical decisions, financial toxicity, and loss of clinical support in survivorship. This research highlighted four care additions that are important for YADC: (1) concise and understandable education about their condition and treatment; (2) same-age support groups; (3) fertility support; and (4) better care transitions for life after cancer. These findings emphasize the importance of creating a collaborative, multidisciplinary care team and a holistic approach with care innovations that support clinicians to meet the unique needs of YADC.
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http://dx.doi.org/10.1089/jayao.2020.0150DOI Listing
November 2020

Haematological disorders following kidney transplantation.

Nephrol Dial Transplant 2020 Nov 5. Epub 2020 Nov 5.

1st Department of Nephrology and Transplantology, Medical University of Bialystok, Bialystok, Poland.

Transplantation offers cure for some haematological cancers, end-stage organ failure, but at the cost of long-term complications. Renal transplantation is the best-known kidney replacement therapy and it can prolong end-stage renal disease patient lives for decades. However, patients after renal transplantation are at a higher risk of developing different complications connected not only with surgical procedure but also with immunosuppressive treatment, chronic kidney disease progression and rejection processes. Various blood disorders can develop in post-transplant patients ranging from relatively benign anaemia through cytopenias to therapy-related myelodysplasia and acute myeloid leukaemia (AML) and post-transplant lymphoproliferative disorders followed by a rare and fatal condition of thrombotic microangiopathy and haemophagocytic syndrome. So far literature mainly focused on the post-transplant lymphoproliferative disease. In this review, a variety of haematological problems after transplantation ranging from rare disorders such as myelodysplasia and AML to relatively common conditions such as anaemia and iron deficiency are presented with up-to-date diagnosis and management.
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http://dx.doi.org/10.1093/ndt/gfaa219DOI Listing
November 2020

RX-5902, a novel β-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast Cancer.

BMC Cancer 2020 Nov 4;20(1):1063. Epub 2020 Nov 4.

Division of Medical Oncology, School of Medicine, University of Colorado Anschutz Medical Campus, 12801 E 17th Ave, MS8117, Aurora, CO, 80045, USA.

Background: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited systemic treatment options. RX-5902 is a novel anti-cancer agent that inhibits phosphorylated-p68 and thus attenuates nuclear β-catenin signaling. The purpose of this study was to evaluate the ability of β-catenin signaling blockade to enhance the efficacy of anti-CTLA-4 and anti-PD-1 immune checkpoint blockade in immunocompetent, preclinical models of TNBC.

Methods: Treatment with RX-5902, anti-PD-1, anti-CTLA-4 or the combination was investigated in BALB/c mice injected with the 4 T1 TNBC cell line. Humanized BALB/c-Rag2Il2rγSIRPα (hu-CB-BRGS) mice transplanted with a human immune system were implanted with MDA-MB-231 cells. Mice were randomized into treatment groups according to human hematopoietic chimerism and treated with RX-5902, anti-PD-1 or the combination. At sacrifice, bone marrow, lymph nodes, spleen and tumors were harvested for flow cytometry analysis of human immune cells.

Results: The addition of RX-5902 to CTLA-4 or PD-1 inhibitors resulted in decreased tumor growth in the 4 T1 and human immune system and MDA-MB-231 xenograft models. Immunologic analyses demonstrated a significant increase in the number of activated T cells in tumor infiltrating lymphocytes (TILs) with RX-5902 treatment compared to vehicle (p < 0.05). In the RX-5902/nivolumab combination group, there was a significant increase in the percentage of CD4+ T cells in TILs and increased systemic granzyme B production (p < 0.01).

Conclusions: Conclusions: RX-5902 enhanced the efficacy of nivolumab in a humanized, preclinical model of TNBC. Several changes in immunologic profiles were noted in mice treated with RX-5902 and the combination, including an increase in activated TILs and a decrease in human myeloid populations, that are often associated with immunosuppression in a tumor microenvironment. RX-5902 also was shown to potentiate the effects of checkpoint inhibitors of CTLA4 and the PD-1 inhibitor in the 4 T-1 murine TNBC model. These findings indicate that RX-5902 may have important immunomodulatory, as well as anti-tumor activity, in TNBC when combined with a checkpoint inhibitor.
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http://dx.doi.org/10.1186/s12885-020-07500-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641792PMC
November 2020

Current methods in translational cancer research.

Cancer Metastasis Rev 2021 Mar 14;40(1):7-30. Epub 2020 Sep 14.

Department of Oncology, Dell Medical School, University of Texas at Austin, Austin, TX, USA.

Recent developments in pre-clinical screening tools, that more reliably predict the clinical effects and adverse events of candidate therapeutic agents, has ushered in a new era of drug development and screening. However, given the rapid pace with which these models have emerged, the individual merits of these translational research tools warrant careful evaluation in order to furnish clinical researchers with appropriate information to conduct pre-clinical screening in an accelerated and rational manner. This review assesses the predictive utility of both well-established and emerging pre-clinical methods in terms of their suitability as a screening platform for treatment response, ability to represent pharmacodynamic and pharmacokinetic drug properties, and lastly debates the translational limitations and benefits of these models. To this end, we will describe the current literature on cell culture, organoids, in vivo mouse models, and in silico computational approaches. Particular focus will be devoted to discussing gaps and unmet needs in the literature as well as current advancements and innovations achieved in the field, such as co-clinical trials and future avenues for refinement.
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http://dx.doi.org/10.1007/s10555-020-09931-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897192PMC
March 2021

Integrated Genomic Characterization of the Human Immunome in Cancer.

Cancer Res 2020 11 27;80(21):4854-4867. Epub 2020 Aug 27.

Department of Oncology, The University of Texas at Austin, Dell Medical School, Livestrong Cancer Institutes, Austin, Texas.

Alterations in immune-related pathways are common hallmarks of cancer. A comprehensive understanding of how cancer mutations rewire immune signaling networks and functional output across cancer types is instrumental to realize the full potential of immunotherapy. Here, we systematically interrogated somatic mutations involved in immune signaling that alter immune responses in patients with cancer. To do so, we developed a Network-based Integrative model to Prioritize Potential immune respondER genes (NIPPER). Identified mutations were enriched in essential protein domains and genes identified by NIPPER were associated with responsiveness to multiple immunotherapy modalities. These genes were used to devise an interactome network propagation framework integrated with drug-associated gene signatures to identify potential immunomodulatory drug candidates. Together, our systems-level analysis results help interpret the heterogeneous immune responses among patients and serve as a resource for future functional studies and targeted therapeutics. SIGNIFICANCE: This study demonstrates that integration of multi-omics data can help identify critical molecular determinants for effective targeted therapeutics.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642109PMC
November 2020

Recent Advances in Treatment of Childhood Obesity.

Curr Drug Metab 2020 ;21(14):1072-1078

Department of Pharmacy, University of Salerno, Salerno, Italy.

Childhood obesity has assumed epidemic proportions and is currently one of the most widespread public health problems. Many are the factors involved in the pathogenesis of excess weight with interactions between genetic, environmental and biological factors and therefore, also the therapeutic approach must be multidisciplinary and multidimensional. In this review of the literature, we report the contiguity of childhood obesity with eating disorders and the importance of involving the family context in order to induce stable lifestyle changes, both in relation to dietary and nutritional habits, but also in increasing physical activity. Finally, among the therapeutic options, although for selected cases, pharmacotherapy and bariatric surgery can be used as treatment strategies.
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http://dx.doi.org/10.2174/1389200221666200817112311DOI Listing
January 2020

Lanreotide Induces Cytokine Modulation in Intestinal Neuroendocrine Tumors and Overcomes Resistance to Everolimus.

Front Oncol 2020 7;10:1047. Epub 2020 Jul 7.

Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

Somatostatin analogs mantain their major role in the treatment of patients with advanced neuroendocrine tumors (NETs) and have multiple modulatory effects on the immune system. Here, we evaluated the effects of lanreotide treatment on expression of Th1, Th2 cytokine patterns in serum of patients with NETs and in bronchial and pancreatic NET cell lines. Our results showed that lanreotide treatment promoted a Th1 cytotoxic immune-phenotype in patients with NETs originated by intestinal sites. Similar results were obtained also where lanreotide induced expression of Th1 cytokines only in pancreatic and not in bronchial-derived NET cell lines. It seems, therefore, that cytokinomics can represent a useful tool for the identification of tumor biomarkers for the early diagnosis and evaluation of the response to therapy in NET patients. To avoid the drug-resistance induced by everolimus (mTOR inhibitor), we made the pancreatic NET cell line resistant to this drug. After treatment with lanreotide we found that the drug reduced its viability compared to that of sensitive cells. These data may have direct implications in design of future translation combination trial on NET patients.
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http://dx.doi.org/10.3389/fonc.2020.01047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379869PMC
July 2020

The link between kidney disease and cancer: complications and treatment.

Lancet 2020 07;396(10246):277-287

Department of Oncology, Livestrong Cancer Institutes, Dell Medical School, University of Texas at Austin, TX, USA.

Acute and chronic kidney disease encompasses a complex set of diseases that can both lead to, and result from, cancer. In particular, kidney disease can arise from the use of chemotherapeutic agents. Many of the current and newly developed cancer chemotherapeutic agents are nephrotoxic and can promote kidney dysfunction, which frequently manifests during the terminal stages of cancer. Given the link between kidney disease and cancer development and treatment, the aim of this Review is to highlight the importance of multidisciplinary collaboration between oncologists and nephrologists to predict and prevent chemotherapeutic-induced nephrotoxicity. As new therapies are introduced to treat cancer, new renal toxicities require proper diagnosis and management. We anticipate that multidisciplinary collaborations will lead to the development and implementation of guidelines for clinicians to improve the therapeutic management of patients with both cancer and renal impairment.
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http://dx.doi.org/10.1016/S0140-6736(20)30540-7DOI Listing
July 2020

Skin Architecture, Kidney Transplantation, and Their Relationship to Basal and Squamous Cell Carcinomas.

Anticancer Res 2020 Jul;40(7):4017-4022

Department of Translational Medical Sciences, University of Campania "L. Vanvitelli", Naples, Italy

Background/aim: Squamous cell carcinoma (SCC) is highly prevalent in kidney transplant patients (KT). It is characterized by the presence of an inflammatory infiltrate. In this study, we examined the presence of similar infiltrates in intact skin, which could be regarded as a precancerous step.

Patients And Methods: We retrospectively analyzed skin biopsies of 19 non-transplanted patients with a diagnosis of SCC or basal cell carcinoma (BCC) and 17 KT with either SCC or BCC.

Results: KT showed increased inflammatory infiltrate in the subepithelial region, compared to non-transplanted patients. The density of basal cell nuclei was also different among the four groups with an interaction effect between tumor type and transplantation. The extent of inflammatory infiltrates did not correlate with the eGFR and proteinuria.

Conclusion: KT with a non-melanoma skin cancer show increased intact skin inflammatory infiltrate and alterations in the density of the basal cell layer compared to non-transplanted patients.
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http://dx.doi.org/10.21873/anticanres.14396DOI Listing
July 2020

Depression and Obesity: Analysis of Common Biomarkers.

Diseases 2020 Jun 14;8(2). Epub 2020 Jun 14.

Department of Pharmacy, University of Salerno, Fisciano, 84084 Salerno, Italy.

Depression and obesity are very common pathologies. Both cause significant problems of both morbidity and mortality and have decisive impacts not only on the health and well-being of patients, but also on socioeconomic and health expenditure aspects. Many epidemiological studies, clinical studies and meta-analyses support the association between mood disorders and obesity in relationships to different conditions such as the severity of depression, the severity of obesity, gender, socioeconomic status, genetic susceptibility, environmental influences and adverse experiences of childhood. Currently, both depression and obesity are considered pathologies with a high-inflammatory impact; it is believed that several overlapping factors, such as the activation of the cortico-adrenal axis, the exaggerated and prolonged response of the innate immune system and proinflammatory cytokines to stress factors and pathogens-as well as alterations of the intestinal microbiota which promote intestinal permeability-can favor the expression of an increasingly proinflammatory phenotype that can be considered a key and common phenomenon between these two widespread pathologies. The purpose of this literature review is to evaluate the common and interacting mechanisms between depression and obesity.
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http://dx.doi.org/10.3390/diseases8020023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348907PMC
June 2020

Kidney Transplant Modifies the Architecture and Microenvironment of Basal Cell Carcinomas.

Kidney Blood Press Res 2020 20;45(3):368-377. Epub 2020 May 20.

Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania L. Vanvitelli, Naples, Italy.

Background/aims: Basal cell carcinoma (BCC) is a frequent type of nonmelanoma skin cancer, which shows a greater prevalence in kidney-transplanted (KT) patients than in the general population. The study of this tumor in KT patients may allow us to understand the influence of the tumor inflammatory microenvironment on cancer behavior, and to design new image analysis methods to determine prognosis and apply personalized medicine. The major hypothesis of the present work is that antirejection drugs, by modifying the B-cell/T-cell balance, induce measurable differences in tumoral cell microarchitecture and in the inflammatory microenvironment in KT patients compared to nontransplanted controls.

Methods: In this retrospective study in an Italian cohort including 15 KT patients and 15 control subjects from the general population who developed BCC, we analyzed tissue microarchitecture and inflammatory infiltrates of BCC using state-of-the-art nonlinear image analysis techniques such as fractal dimension and sample entropy of internuclear distances.

Results: KT patients showed a nonsignificant trend to a greater number of nuclei in the basal cell layer compared to non-KT controls and subtle changes in the intact skin compared to controls. Similarly, the number of mitoses per unit length was almost doubled in the patients with KT compared to controls. However, when the number of mitotic cells was normalized by the total number of cells in the basal layer (mitotic index), these differences were not significant, although a clear trend was still present. Finally, KT patients showed a nonsignificant trend to an increased -density of inflammatory cells close to the tumoral cell layer. When considering the intact skin, this difference was significant, with a 70% increase in the density of inflammatory cells.

Conclusion: Data comparing the microarchitecture of BCC in normal subjects and KT patients are scanty, and the present study is the first to use nonlinear image analysis techniques to this aim. The observed differences underscore the relevance of T-cell suppression in cancer behavior. These data suggest that BCC develops in treated patients with specific biological characteristics which should be further analyzed in terms of therapeutic response.
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http://dx.doi.org/10.1159/000507581DOI Listing
January 2021

Preclinical and Dose-Finding Phase I Trial Results of Combined Treatment with a TORC1/2 Inhibitor (TAK-228) and Aurora A Kinase Inhibitor (Alisertib) in Solid Tumors.

Clin Cancer Res 2020 Sep 15;26(17):4633-4642. Epub 2020 May 15.

University of Colorado Cancer Center, Aurora, Colorado.

Purpose: The purpose of this study was to evaluate the rational combination of TORC1/2 inhibitor TAK-228 and Aurora A kinase inhibitor alisertib in preclinical models of triple-negative breast cancer (TNBC) and to conduct a phase I dose escalation trial in patients with advanced solid tumors.

Experimental Design: TNBC cell lines and patient-derived xenograft (PDX) models were treated with alisertib, TAK-228, or the combination and evaluated for changes in proliferation, cell cycle, mTOR pathway modulation, and terminal cellular fate, including apoptosis and senescence. A phase I clinical trial was conducted in patients with advanced solid tumors treated with escalating doses of alisertib and TAK-228 using a 3+3 design to determine the maximum tolerated dose (MTD).

Results: The combination of TAK-228 and alisertib resulted in decreased proliferation and cell-cycle arrest in TNBC cell lines. Treatment of TNBC PDX models resulted in significant tumor growth inhibition and increased apoptosis with the combination. In the phase I dose escalation study, 18 patients with refractory solid tumors were enrolled. The MTD was alisertib 30 mg b.i.d. days 1 to 7 of a 21-day cycle and TAK-228 2 mg daily, continuous dosing. The most common treatment-related adverse events were neutropenia, fatigue, nausea, rash, mucositis, and alopecia.

Conclusions: The addition of TAK-228 to alisertib potentiates the antitumor activity of alisertib , resulting in increased cell death and apoptosis. The combination is tolerable in patients with advanced solid tumors and should be evaluated further in expansion cohorts with additional pharmacodynamic assessment.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864382PMC
September 2020

Obesity: The New Global Epidemic Pharmacological Treatment, Opportunities and Limits for Personalized Therapy.

Endocr Metab Immune Disord Drug Targets 2020 ;20(8):1232-1243

Department of Pharmacy, University of Salerno, 84084, Fisciano, Salerno, Italy.

Background: The increase in global obesity rates over the past three decades has been remarkable, a true epidemic, both in developed and in developing countries. The projections, based on current trends, suggest an increase in the prevalence of obesity at 60% in adult men, 40% in adult women and 25% in children in 2050. Given the limitations of lifestyle and surgery interventions bariatric, drug therapy approaches for the treatment of obesity, therefore become important options.

Aim: The purpose of this review is a review of the literature, based on research on MEDLINE until 2019, on the possible pharmacological options in the treatment of obesity.

Results: Currently, the FDA has approved several molecules for the treatment of obesity, both in monotherapy and in combination. Pharmacological monotherapies focus mainly on a single protein target and include orlistat, lorcaserin and liraglutide while the combination molecules propose a multitarget approach and include phentermine/topiramate and naltrexone/bupropion. All the approved drugs showed, in the different studies, a weight reduction of at least 5%, compared to placebo, in 52 weeks of observation. Phentermine-topiramate and liraglutide have been associated with the highest probability of at least 5% weight loss. Liraglutide and naltrexone-bupropion had the lowest rates of therapy discontinuation due to adverse events.

Conclusion: The drugs, associated with the standard diet and/or exercise protocols, represent a good therapeutic opportunity to allow not only weight loss but also to reduce the risk of developing diseases caused by obesity, particularly cardiovascular diseases, and to maintain the set objectives over time. However, future research on the pharmacological treatment of obesity should encourage greater personalization of therapy, given the differences in safety, efficacy and response to therapy, in the different subpopulations of patients with obesity.
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http://dx.doi.org/10.2174/1871530320666200515112853DOI Listing
January 2020

NMR-based metabolomic profile of hypercholesterolemic human sera: Relationship with in vitro gene expression?

PLoS One 2020 16;15(4):e0231506. Epub 2020 Apr 16.

Department of Pharmacy, University of Salerno, Fisciano, Italy.

Hypercholesterolaemia is considered an important cause of atherosclerotic cardiovascular disease. In a previous investigation, we demonstrated that cultured hepatoma cells treated with hypercholesterolaemic sera compared with cells treated with normocholesterolaemic sera show overexpression of mRNAs related to mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase (HMGCS2). In the present work, using an NMR metabolomic analysis, we demonstrate that the hypercholesterolaemic blood sera previously used to treat cultured hepatoma cells are characterized by a metabolomic profile that is significantly different from the normocholesterolaemic sera. Acetate, acetone, 2-hydroxybutyrate, cysteine, valine, and glutamine are the metabolites distinguishing the two groups. Abnormalities in the concentrations of these metabolites reflect alterations in energy-related pathways, such as pantothenate and CoA biosynthesis, pyruvate, glycolysis/gluconeogenesis, the citrate cycle, and ketone bodies. Regarding ketone bodies, the pathway is regulated by HMGCS2; therefore, serum samples previously found to be able to increase HMGCS2 mRNA levels in cultured cells also contain higher amounts of the metabolites of its encoded enzyme protein product.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231506PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162471PMC
July 2020

How to assess kidney function in oncology patients.

Kidney Int 2020 05 3;97(5):894-903. Epub 2020 Mar 3.

Department of Oncology, Livestrong Cancer Institutes, Dell Medical School, The University of Texas, Austin, Texas, USA.

Assessment of kidney function in oncology patients is a fundamental factor in profiling the survival risk, determining the appropriate dose of chemotherapeutic drugs, and defining a patient eligibility for clinical trials with novel agents. Both overestimation and underestimation of kidney function may affect the treatment efficacy and outcomes. Overestimation may lead to overdosing or inappropriate agent selection and the corresponding toxicity, whereas underestimation may be responsible for underdosing or inappropriate agent exclusion and subsequent treatment failure. This is of utmost importance in patients with cancer. Evaluation of kidney function is not only limited to the estimation of glomerular filtration rate or creatinine clearance. An accurate assessment of kidney function is advisable to reduce variability in decision making and ultimately the therapeutic outcomes of toxicity and clinical benefit. Therefore, additional studies are needed to investigate the validity of currently used formulas estimating kidney function in this population as well as their applicability to traditional chemotherapy, novel targeted therapies, and immunotherapies. Because of rapid discovery and development of new cancer agents, a reliable and comprehensive manner to screen for potential nephrotoxicity is critically important. As kidney function not only is limited to glomerular filtration rate changes but also involves tubular and even vascular dysfunction, urinalysis and kidney imaging studies should also be considered before therapeutic decisions are taken. However, several questions remain regarding these new technologies such as kidney-on-a-chip systems for the assessment of kidney function and injury, particularly in oncology, and it has yet to be implemented in clinical practice.
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http://dx.doi.org/10.1016/j.kint.2019.12.023DOI Listing
May 2020

High glucose concentration produces a short-term increase in pERK1/2 and p85 proteins, having a direct angiogenetic effect by an action similar to VEGF.

Acta Diabetol 2020 Aug 4;57(8):947-958. Epub 2020 Mar 4.

Department of Medicine and Health Science "V. Tiberio", University of Molise, Campobasso, Italy.

Aims: Excessive glucose serum concentration, endothelial dysfunction and microangiopathy are key features of diabetes mellitus, being both diagnostic parameters and pathogenetic mechanisms. Vascular endothelial growth factor (VEGF) is importantly implicated in the physiology and pathology of blood vessels, including diabetic vascular damage.

Methods: These factors certainly affect endothelial cells, and to evaluate mechanisms involved, we took advantage of telomerase-immortalized human microvascular endothelial (TIME) cells. TIME cells were exposed to different glucose concentrations and to VEGF treatments. Culture conditions also included the use of basement membrane extract, as an in vitro differentiation model. Cell morphology was then evaluated in the different conditions, and cellular proteins were extracted to analyze specific protein products by Western blot.

Results: High glucose concentrations and VEGF did substantially affect neither morphology nor growth of cultured TIME cells, while both considerably increased differentiation into "capillary-like" structures when cells were cultured on basement membrane extract.

Conclusions: Under these conditions, high glucose concentration and VEGF also produced a short-term increase in pERK1/2 and p85 proteins, while total and phosphorylated AKT were not affected. These data suggest a direct angiogenetic effect of glucose, affecting intracellular transduction mechanisms with an action similar to that of VEGF. This effect on endothelial cell proliferation and differentiation could be part of pathogenetic mechanisms producing diabetic microvascular alterations.
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http://dx.doi.org/10.1007/s00592-020-01501-zDOI Listing
August 2020

The renal adverse effects of cancer immunotherapy.

J Nephrol 2020 Jun 7;33(3):467-481. Epub 2020 Jan 7.

Department of Oncology, Dell Medical School, The University of Texas at Austin, Health Learning Building, 1501 Red River Street, MC: Z0100, Austin, TX, 78712, USA.

Over the past decade, the development and clinical use of immunotherapy agents has increased exponentially. As clinical experience builds with these agents so too does our understanding of the associated adverse effects. In particular, the effects of immunotherapy on the kidneys, individual nephrons, and kidney function remain less well described than the adverse effects on barrier organ systems such as the gastrointestinal tract and skin. However, phase IV post-marketing surveillance and clinical case studies together with basic research has begun to reveal mechanisms by which immunotherapy mediates renal adverse effects. This work may lead to improvements in treatment guidelines and therapy. These advances are particularly important as post-cancer survival increases leaving patients to cope with the consequences of not only the cancer, but the short- and long-term adverse effects of treatment. Here we discuss the major renal adverse effects encountered with individual immunotherapeutic agents, putative mechanisms, their current management, and how cancer survivorship programs can help patients who have been treated with immunotherapy.
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http://dx.doi.org/10.1007/s40620-019-00691-2DOI Listing
June 2020

Reply to Appropriate considerations of "rural" in National Cancer Data Base analyses.

Cancer 2020 04 10;126(7):1586-1587. Epub 2019 Dec 10.

Departments of Oncology and Internal Medicine and LIVESTRONG Cancer Institutes, University of Texas at Austin, Austin, Texas.

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http://dx.doi.org/10.1002/cncr.32650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069778PMC
April 2020

Eating Disorders in Athletes: From Risk Management to Therapy.

Endocr Metab Immune Disord Drug Targets 2020 ;20(1):2-14

Department of Pharmacy, University of Salerno, Giovanni Paolo II Street, Fisciano (84084) Salerno, Italy.

Background: Balanced sporting activity should be considered a resource in the treatment of eating disorders (ED), in particular of the BED and in obesity and, if conducted and guided by expert preparers and rehabilitators, in some forms of anorexia and in bulimia.

Objective: To assess the role of excessive physical activity, predominantly interfering with daily activities by ultimately resulting in greater energy consumption leading to weight loss, and study the diagnostic criteria of bulimia and anorexia nervosa.

Methods: A number of literature studies also report the presence of ED among athletes. A 2004 study reported that the prevalence of eating disorders in sports would be 13.5% compared to 4.5% of the control subjects.

Results: In general, nutrition is used as a tool for improving performance not only of athletes but also of technicians and coaches. But in the presence of factors of vulnerability towards ED, the tendency to manipulate the weight can result in an eating disorder or the so-called athletic anorexia or the RED-S.

Conclusion: It is important to emphasize that not only do professional athletes suffer from it, but also good-looking amateurs and laypersons.
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http://dx.doi.org/10.2174/1871530319666190418121446DOI Listing
November 2020

Gender Dysphoria, Eating Disorders and Body Image: An Overview.

Endocr Metab Immune Disord Drug Targets 2020 ;20(4):518-524

Department of Pharmacy, University of Salerno, (84084) Fisciano (Salerno), Italy.

Background: Gender dysphoria is a clinical condition in which a state of inner suffering, stress and anxiety is detected when biological sex and a person's gender identity do not coincide. People who identify themselves as transgender people are more vulnerable and may have higher rates of dissatisfaction with their bodies which are often associated with a disorderly diet in an attempt to change the bodily characteristics of the genus of birth and, conversely, to accentuate the characteristics of the desired sexual identity.

Aim: The purpose of this work is to examine the association between dissatisfaction with one's own body and eating and weight disorders in people with gender dysphoria.

Results: Gender dysphoria and eating disorders are characterized by a serious discomfort to the body and the body suffers in both conditions. The results of our study suggest that rates of pathological eating behaviors and symptoms related to a disordered diet are high in patients with gender dysphoria and that standard screening for these symptoms must be considered in both populations at the time of evaluation and during the course of the treatment.

Conclusion: In light of this evidence, clinicians should always investigate issues related to sexuality and gender identity in patients with eating disorders, to develop more effective prevention measures and better strategies for therapeutic intervention.
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http://dx.doi.org/10.2174/1871530319666191015193120DOI Listing
March 2021

Development of an Adrenocortical Cancer Humanized Mouse Model to Characterize Anti-PD1 Effects on Tumor Microenvironment.

J Clin Endocrinol Metab 2020 01;105(1)

Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado School of Medicine at Colorado Anschutz Medical Campus, Aurora, Colorado 80045.

Context: Although the development of immune checkpoint inhibitors has transformed treatment strategies of several human malignancies, research models to study immunotherapy in adrenocortical carcinoma (ACC) are lacking.

Objective: To explore the effect of anti-PD1 immunotherapy on the alteration of the immune milieu in ACC in a newly generated preclinical model and correlate with the response of the matched patient.

Design, Setting, And Intervention: To characterize the CU-ACC2-M2B patient-derived xenograft in a humanized mouse model, evaluate the effect of a PD-1 inhibitor therapy, and compare it with the CU-ACC2 patient with metastatic disease.

Results: Characterization of the CU-ACC2-humanized cord blood-BALB/c-Rag2nullIl2rγnullSirpaNOD model confirmed ACC origin and match with the original human tumor. Treatment of the mice with pembrolizumab demonstrated significant tumor growth inhibition (60%) compared with controls, which correlated with increased tumor infiltrating lymphocyte activity, with an increase of human CD8+ T cells (P < 0.05), HLA-DR+ T cells (P < 0.05) as well as Granzyme B+ CD8+ T cells (<0.001). In parallel, treatment of the CU-ACC2 patient, who had progressive disease, demonstrated a partial response with 79% to 100% reduction in the size of target lesions, and no new sites of metastasis. Pretreatment analysis of the patient's metastatic liver lesion demonstrated abundant intratumoral CD8+ T cells by immunohistochemistry.

Conclusions: Our study reports the first humanized ACC patient-derived xenograft mouse model, which may be useful to define mechanisms and biomarkers of response and resistance to immune-based therapies, to ultimately provide more personalized care for patients with ACC.
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http://dx.doi.org/10.1210/clinem/dgz014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947837PMC
January 2020

First-in-Class Phosphorylated-p68 Inhibitor RX-5902 Inhibits β-Catenin Signaling and Demonstrates Antitumor Activity in Triple-Negative Breast Cancer.

Mol Cancer Ther 2019 11 5;18(11):1916-1925. Epub 2019 Sep 5.

University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

RX-5902 is a first-in-class anticancer agent targeting phosphorylated-p68 and attenuating nuclear shuttling of β-catenin. The purpose of this study was to evaluate the efficacy of RX-5902 in preclinical models of triple-negative breast cancer (TNBC) and to explore effects on β-catenin expression. A panel of 18 TNBC cell lines was exposed to RX-5902, and changes in proliferation, apoptosis, cellular ploidy, and effector protein expression were assessed. Gene expression profiling was used in sensitive and resistant cell lines with pathway analysis to explore pathways associated with sensitivity to RX-5902. The activity of RX-5902 was confirmed in cell line and patient-derived tumor xenograft (PDX) models. RX-5902 demonstrated potent antiproliferative activity against TNBC cell lines with an average IC of 56 nmol/L in sensitive cell lines. RX-5902 treatment resulted in the induction of apoptosis, G-M cell-cycle arrest, and aneuploidy in a subset of cell lines. RX-5902 was active against TNBC PDX models, and treatment resulted in a decrease in nuclear β-catenin. RX-5902 exhibited dose-proportional pharmacokinetics and plasma and tumor tissue in nude mice. Pathway analysis demonstrated an increase in the epithelial-to-mesenchymal transformation (EMT), TGFβ, and Wnt/β-catenin pathways associated with sensitivity to RX-5902. RX-5902 is active against and preclinical models of TNBC. Target engagement was confirmed with decreases in nuclear β-catenin and MCL-1 observed, confirming the proposed mechanism of action. This study supports the continued investigation of RX-5902 in TNBC and combinations with immunotherapy.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-1334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825586PMC
November 2019

Summary of the International Conference on Onco-Nephrology: an emerging field in medicine.

Kidney Int 2019 09 31;96(3):555-567. Epub 2019 May 31.

Department of Translational Medical Sciences, University Luigi Vanvitelli, Naples, Italy; BioGeM Institute, Ariano Irpino, Italy. Electronic address:

Onco-nephrology is an emerging field in medicine. Patients with cancer may suffer from kidney diseases because of the cancer itself and cancer-related therapy. It is critical for nephrologists to be knowledgeable of cancer biology and therapy in order to be fully integrated in the multidisciplinary team and optimally manage patients with cancer and kidney diseases. In a recent international meeting, the key issues in this challenging clinical interface were addressed, including many unresolved basic science questions, such as the high tumor incidence in kidney transplant recipients. To this end, 70 highly qualified faculty members were gathered from all over the world to discuss these issues in 8 plenary sessions, including 5 keynote lectures. In addition, 48 young nephrologists and oncologists were invited to present their original observations that were highlighted in 2 large poster sessions.
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http://dx.doi.org/10.1016/j.kint.2019.04.043DOI Listing
September 2019

Recent trends in the age at diagnosis of colorectal cancer in the US National Cancer Data Base, 2004-2015.

Cancer 2019 11 22;125(21):3828-3835. Epub 2019 Jul 22.

Livestrong Cancer Institutes, University of Texas at Austin, Austin, Texas.

Background: The incidence of colorectal cancer (CRC) in adults younger than 50 years has increased in the United States over the past decades according to Surveillance, Epidemiology, and End Results data. National guidelines conflict over beginning screening at the age of 45 or 50 years.

Methods: This was a retrospective study of National Cancer Data Base data from 2004 to 2015. The Cochran-Armitage test for trend was used to assess changes in the proportion of cases diagnosed at an age younger than 50 years.

Results: This study identified 130,165 patients diagnosed at an age younger than 50 years and 1,055,598 patients diagnosed at the age of 50 years or older. The proportion of the total number of patients diagnosed with CRC at an age younger than 50 years rose (12.2% in 2015 vs 10.0% in 2004; P < .0001). Younger adults presented with more advanced disease (stage III/IV; 51.6% vs 40.0% of those 50 years old or older). Among men, diagnosis at ages younger than 50 years rose only in non-Hispanic whites (P < .0001), whereas among women, Hispanic and non-Hispanic whites had increases in younger diagnoses over time (P < .05). All income quartiles had a proportional increase in younger adults over time (P < .001), with the highest income quartile having the highest proportion of younger cases. The proportion of younger onset CRC cases rose in urban areas (P < .001) but did not rise in rural areas.

Conclusions: The proportion of persons diagnosed with CRC at an age younger than 50 years in the United States has continued to increase over the past decade, and younger adults present with more advanced disease. These data should be considered in the ongoing discussion of screening guidelines.
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http://dx.doi.org/10.1002/cncr.32347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788938PMC
November 2019

A quest for protecting kidneys from cisplatin toxicity.

Nephrol Dial Transplant 2019 10;34(10):1623-1625

Department of Translational Medical Sciences, University Luigi Vanvitelli, Naples, Italy.

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http://dx.doi.org/10.1093/ndt/gfz029DOI Listing
October 2019

BRAF fusions identified in melanomas have variable treatment responses and phenotypes.

Oncogene 2019 02 25;38(8):1296-1308. Epub 2018 Sep 25.

Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, CO, USA.

Oncogenic BRAF fusions have emerged as an alternate mechanism for BRAF activation in melanomas and other cancers. A number of BRAF fusions with different 5' gene partners and BRAF exon breakpoints have been described, but the effects of different partners and breakpoints on cancer phenotypes and treatment responses has not been well characterized. Targeted RNA sequencing was used to screen 60 melanoma patient-derived xenograft (PDX) models for BRAF fusions. We identified three unique BRAF fusions, including a novel SEPT3-BRAF fusion, occurring in four tumors (4/60, 6.7%), all of which were "pan-negative" (lacking other common mutations) (4/18, 22.2%). The BRAF fusion PDX models showed variable growth rates and responses to MAPK inhibitors in vivo. Overexpression of BRAF fusions identified in our study, as well as other BRAF fusions previously identified in melanomas, resulted in a high degree of variability in 2D proliferation and 3D invasion between the different fusions. While exogenously expressed BRAF fusions all responded to MAPK inhibition in vitro, we observed potential differences in signaling and feedback mechanisms. In summary, BRAF fusions are actionable therapeutic targets, however there are significant differences in phenotypes, treatment responses, and signaling which may be clinically relevant.
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http://dx.doi.org/10.1038/s41388-018-0514-7DOI Listing
February 2019

A phase II clinical trial of the Aurora and angiogenic kinase inhibitor ENMD-2076 for previously treated, advanced, or metastatic triple-negative breast cancer.

Breast Cancer Res 2018 08 2;20(1):82. Epub 2018 Aug 2.

Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.

Background: Triple-negative breast cancer (TNBC) remains an aggressive breast cancer subtype with limited treatment options. ENMD-2076 is a small-molecule inhibitor of Aurora and angiogenic kinases with proapoptotic and antiproliferative activity in preclinical models of TNBC.

Methods: This dual-institution, single-arm, two-stage, phase II clinical trial enrolled patients with locally advanced or metastatic TNBC previously treated with one to three prior lines of chemotherapy in the advanced setting. Patients were treated with ENMD-2076 250 mg orally once daily with continuous dosing in 4-week cycles until disease progression or unacceptable toxicity occurred. The primary endpoint was 6-month clinical benefit rate (CBR), and secondary endpoints included progression-free survival, pharmacokinetic profile, safety, and biologic correlates in archival and fresh serial tumor biopsies in a subset of patients.

Results: Forty-one patients were enrolled. The 6-month CBR was 16.7% (95% CI, 6-32.8%) and included two partial responses. The 4-month CBR was 27.8% (95% CI, 14-45.2%), and the average duration of benefit was 6.5 cycles. Common adverse events included hypertension, fatigue, diarrhea, and nausea. Treatment with ENMD-2076 resulted in a decrease in cellular proliferation and microvessel density and an increase in p53 and p73 expression, consistent with preclinical observations.

Conclusions: Single-agent ENMD-2076 treatment resulted in partial response or clinical benefit lasting more than 6 months in 16.7% of patients with pretreated, advanced, or metastatic TNBC. These results support the development of predictive biomarkers using archival and fresh tumor tissue, as well as consideration of mechanism-based combination strategies.

Trial Registration: ClinicalTrials.gov, NCT01639248 . Registered on July 12, 2012.
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http://dx.doi.org/10.1186/s13058-018-1014-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090978PMC
August 2018

Dual compartmental targeting of cell cycle and angiogenic kinases in colorectal cancer models.

Anticancer Drugs 2018 10;29(9):827-838

Division of Medical Oncology, School of Medicine.

Cancer is a disease caused by several factors characterized by uncontrolled cell division, growth, and survival. ENMD-2076, is a novel orally active small molecule multikinase inhibitor targeting angiogenesis, proliferation, and the cell cycle. It is selectively active against the mitotic kinases aurora A and B, and kinases responsible for angiogenesis including VEGFR2/KDR and FGFR1 and 2. ENMD-2076 has been shown to inhibit tumor growth and prevent angiogenesis in vitro and in vivo in preclinical cancer models. Moreover, in a phase I trial, ENMD-2076 was well tolerated, exhibited a linear pharmacokinetic profile, and showed a promising antitumor activity in a number of solid tumors. In this study, we show that ENMD-2076 has antiproliferative effects, causes cell cycle arrest, and has activity in preclinical models of colorectal cancer (CRC), including patient-derived xenograft (PDX) models. Forty-seven human CRC cell lines were exposed in vitro to ENMD-2076 and analyzed for effects on cell cycle, apoptosis, and downstream effector proteins. The drug was then tested against 20 human CRC PDX models to further evaluate in-vivo antitumor activity. We show that ENMD-2076 exhibits a broad range of activity against a large panel of CRC cell lines with varying molecular characteristics. Mechanistically, ENMD-2076 exposure resulted in a G2/M cell cycle arrest, an increase in aneuploidy, and cell death in responsive cell lines. In addition, ENMD-2076 treatment resulted in a promising antitumor activity in CRC PDX models. These results support the continued development of ENMD-2076 in CRC including further exploration of rational combinations.
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http://dx.doi.org/10.1097/CAD.0000000000000673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143222PMC
October 2018