Metabolic interventions in chronic lymphocytic leukemia:Towards tumor elimination and immune rejuvenation

Chronic lymphocytic leukemia (CLL), the most common adult leukemia in the Western world, remains incurable despite significant treatment advances. Targeted therapies, such as venetoclax + ibrutinib, directed at killing malignant cells, face the emergence of resistance, due to microenvironmental protective stimuli and genetic mutations (e.g. TP53). T-cell based immunotherapies show poor responses due to the acquired T-cell dysfunction of CLL patients.This thesis explores the effects of metabolic interventions in relation to two key aspects of CLL biology. The first part of the thesis focuses on unravelling the interplay between metabolic reprogramming of CLL cells and drug resistance. First, we exploit glutamine (Gln) dependency of CLL cells as a metabolic vulnerability to counteract microenvironmental-induced venetoclax resistance. Furthermore, the thesis explores the impact of disrupting Gln metabolism on TP53 dysfunctional cells. The second part of the thesis focuses on the interplay between metabolic impairment and T-cell dysfunction. Our study highlights that CLL cells induce pseudohypoxia, impaired mitochondrial metabolism and the production of immunosuppressive adenosine by the surrounding T cells. Next, a critical re-evaluation of T-cell dysfunction in CLL challenges its definition as (pseudo-)exhaustion, revealing a prevalence of senescent T cells. Intriguingly, the removal of CLL cells restores metabolic function and reverses senescent features. In conclusion, this thesis underscores the feasibility of metabolic interventions in CLL as adjuvant strategies to eliminate malignant cells while rejuvenating the T cells, opening avenues for novel therapeutic approaches

Localized prostate cancer genotyping: Another step towards personalized therapy

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Inside the 2016 American Society of Clinical Oncology Genitourinary Cancers Symposium: Part 1 - Kidney cancer

The American Society of Clinical Oncology Genitourinary Cancers Symposium, Moscone West Building, San Francisco, CA, USA, 7-9 January 2016 The American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, held in San Francisco (CA, USA), from 7 to 9 January 2016, focused on 'patient-centric care: translating research to results'. Every year, this meeting is a must for anyone studying genitourinary tumors to keep abreast of the most recent innovations in this field, exchange views on behaviors customarily adopted in daily clinical practice, and discuss future topics of scientific research. This two-part report highlights the key themes presented at the 2016 ASCO Genitourinary Cancers Symposium, with part 1 reporting the main novelties of kidney cancer and part 2 discussing the most relevant issues which have emerged for bladder and prostate tumors

Texture image analysis in differentiating malignant from benign adrenal cortical tumors in children and adults

OBJECTIVE: To investigate the possible role of chromatin texture parameters, nuclear morphology, DNA ploidy and clinical functional status in discriminating benign from malignant adrenocortical tumors (ACT). PATIENTS AND METHODS: Forty-eight cases of clinically benign (n=40) and clinically malignant (n=8) ACT with a minimum of 5-years' follow-up were evaluated for chromatin texture parameters (run length, standard deviation, configurable run length, valley, slope, peak and other 21 Markovian features that describe the distribution of the chromatin in the nucleus), nuclear morphology (nuclear area, nuclear perimeter, nuclear maximum and minimum diameter, nuclear shape), and DNA ploidy. Nuclear parameters were evaluated in Feulgen-stained 5 mum paraffin-sections analyzed using a CAS 200 image analyzer. RESULTS: Since ACTs present different biological features in children and adults, patients were divided into two groups: children (15 years). In the group of children DNA ploidy presented a marginal significance (p=0.05) in discriminating ACTs. None of the parameters discriminated between malignant and benign ACT in the adult group. CONCLUSION: ACTs are uncommon and definitive predictive criteria for malignancy remain uncertain, particularly in children. Our data point to DNA content evaluated by image analysis as a new candidate tool for this challenging task. Texture image analysis did not help to differentiate malignant from benign adrenal cortical tumors in children and adults

PD-1 blockade therapy in renal cell carcinoma: current studies and future promises

RCC is considered an immunogenic tumor with a prominent dysfunctional immune cell infiltrate, unable to control tumor growth. Evasion of immune surveillance, a process defined immune-editing, leads to malignant progression. The striking improvement of knowledge in immunology has led to the identification of immune checkpoints (such as CTLA-4 and PD-1), whose blockage enhances the antitumor immunity. The interaction between PD-1, an inducible inhibitory receptor expressed on lymphocytes and DCs, and PD-L1 ligand, expressed by tumor cells, results in a down-regulation of the T-cell response. Therefore, the PD-1/PD-L1 axis inhibition by targeted-antibodies, increasing the T-cell proliferation and cytotoxicity, represents a promising mechanism to stimulate the anti-tumor activity of the immune system, improving the outcomes of cancer patients. Several PD-1 and PD-L1 inhibitors have been evaluated in different tumor types, showing promising results. The interesting correlation between lymphocytes PD-1 expression and RCC advanced stage, grade and prognosis, as well as the selective PD-L1 expression by RCC tumor cells and its potential association with worse clinical outcomes, have led to the development of new anti PD-1/PD-L1 agents, alone or in combination with anti-angiogenic drugs or other immunotherapeutic approaches, for the treatment of RCC. In this review we discuss the role of PD-1/PD-L1 in RCC, focusing on the biological rationale, current clinical studies and promising therapeutic perspectives to target the PD-1 pathway

Angiogenesis genotyping in the selection of first-line treatment with either sunitinib or pazopanib for advanced renal cell carcinoma

Recent data from the COMPARZ study seem to suggest a noninferiority of pazopanib confronted with sunitinib in PFS and OS. We previously reported how VEGF and VEGFR polymorphisms might have a predictive role in patients treated with first-line sunitinib. Aim of our study was to investigate whether tumour angiogenesis genotyping could influence clinical outcome in RCC patients treated with either sunitinib or pazopanib, in order to help clinicians select the appropriate treatment for each patient. Results: 19 patients were treated with pazopanib while 78 received sunitinib. VEGF A rs833061 resulted significant in PFS in sunitinib vs pazopanib patients (CC+CT > TT in sunitinib, TT > CC+CT in pazopanib; p CC in sunitinib, CC > GG+CG in pazopanib; p CC in sunitinib, CC > AA+AC in pazopanib; p < 0,0001). OS showed no statistically significant difference. Conclusions: In our analysis patients with opposite polymorphisms of rs833061, rs2010963, rs699947 of VEGF A seems to have a better PFS if treated with either sunitinib or pazopanib. Our data seem to suggest that biology could have a role choosing first line treatment for mRCC patients. Methods: A retrospective analysis on 97 histologic samples of mRCC patients was conducted for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs

An Immune Gene Expression Signature Associated With Development of Human Hepatocellular Carcinoma Identifies Mice That Respond to Chemopreventive Agents

Program (HEPCAR, reference no. 667273-2); US Department of Defense(CA150272P3); an Accelerator Award (CRUCK, AECC, AIRC) (HUNTER,reference no. C9380/A26813), NCI Cancer Center Support Grant, National Cancer Institute; Tisch Cancer Institute (P30-CA196521); Samuel Waxman Cancer Research Foundation; Spanish National Health Institute (SAF2016-76390); and the Generalitat de Catalunya/AGAUR (SGR-1358). Agrin Moeini is supported by Spanish National Health Institute. Sara Torrecilla and Judit Peix are funded by Centro de Investigación Biomedica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd-ISCIII). Carla Montironi is a recipient of Josep Font grant. Carmen Andreu-Oller is supported by "la Caixa" INPhINIT Fellowship Grant (LCF/BQ/IN17/11620024). Roser Pinyol is supported by HEPCAR and AECC. Daniela Sia is supported by the Gilead Sciences Research Scholar Program in Liver Disease. Scott L. Friedman is supported by the National Institutes of Health Research project grant (R01,DK5662) and US Department of Defense (CA150272P3). Mathias Heikenwälder was supported by an ERC Consolidator grant (HepatoMetaboPath), the SFBTR 209, 1335 and SFBTR179.Background & Aims: Cirrhosis and chronic inflammation precede development of hepatocellular carcinoma (HCC) in approximately 80% of cases. We investigated immune-related gene expression patterns in liver tissues surrounding early-stage HCCs and chemopreventive agents that might alter these patterns to prevent liver tumorigenesis. Methods: We analyzed gene expression profiles of nontumor liver tissues from 392 patients with early-stage HCC (training set, N = 167 and validation set, N = 225) and liver tissue from patients with cirrhosis without HCC (N = 216, controls) to identify changes in expression of genes that regulate the immune response that could contribute to hepatocarcinogenesis. We defined 172 genes as markers for this deregulated immune response, which we called the immune-mediated cancer field (ICF). We analyzed the expression data of liver tissues from 216 patients with cirrhosis without HCC and investigated the association between this gene expression signature and development of HCC and outcomes of patients (median follow-up, 10 years). Human liver tissues were also analyzed by histology. C57BL/6J mice were given a single injection of diethylnitrosamine (DEN) followed by weekly doses of carbon tetrachloride to induce liver fibrosis and tumorigenesis. Mice were then orally given the multiple tyrosine inhibitor nintedanib or vehicle (controls); liver tissues were collected and histology, transcriptome, and protein analyses were performed. We also analyzed transcriptomes of liver tissues collected from mice on a choline-deficient high-fat diet, which developed chronic liver inflammation and tumors, orally given aspirin and clopidogrel or the anti-inflammatory agent sulindac vs mice on a chow (control) diet. Results: We found the ICF gene expression pattern in 50% of liver tissues from patients with cirrhosis without HCC and in 60% of nontumor liver tissues from patients with early-stage HCC. The liver tissues with the ICF gene expression pattern had 3 different features: increased numbers of effector T cells; increased expression of genes that suppress the immune response and activation of transforming growth factor β signaling; or expression of genes that promote inflammation and activation of interferon gamma signaling. Patients with cirrhosis and liver tissues with the immunosuppressive profile (10% of cases) had a higher risk of HCC (hazard ratio, 2.41; 95% confidence interval, 1.21-4.80). Mice with chemically induced fibrosis or diet-induced steatohepatitis given nintedanib or aspirin and clopidogrel down-regulated the ICF gene expression pattern in liver and developed fewer and smaller tumors than mice given vehicle. Conclusions: We identified an immune-related gene expression pattern in liver tissues of patients with early-stage HCC, called the ICF, that is associated with risk of HCC development in patients with cirrhosis. Administration of nintedanib or aspirin and clopidogrel to mice with chronic liver inflammation caused loss of this gene expression pattern and development of fewer and smaller liver tumors. Agents that alter immune regulatory gene expression patterns associated with carcinogenesis might be tested as chemopreventive agents in patients with cirrhosis

Low-risk Prostate Cancer: Identification, Management, and Outcomes.

ContextThe incidence of low-risk prostate cancer (PCa) has increased as a consequence of prostate-specific antigen testing.ObjectiveIn this collaborative review article, we examine recent literature regarding low-risk PCa and the available prognostic and therapeutic options.Evidence acquisitionWe performed a literature review of the Medline, Embase, and Web of Science databases. The search strategy included the terms: prostate cancer, low risk, active surveillance, focal therapy, radical prostatectomy, watchful waiting, biomarker, magnetic resonance imaging, alone or in combination.Evidence synthesisProspective randomized trials have failed to show an impact of radical treatments on cancer-specific survival in low-risk PCa patients. Several series have reported the risk of adverse pathologic outcomes at radical prostatectomy. However, it is not clear if these patients are at higher risk of death from PCa. Long-term follow-up indicates the feasibility of active surveillance in low-risk PCa patients, although approximately 30% of men starting active surveillance undergo treatment within 5 yr. Considering focal therapies, robust data investigating its impact on long-term survival outcomes are still required and therefore should be considered experimental. Magnetic resonance imaging and tissue biomarkers may help to predict clinically significant PCa in men initially diagnosed with low-risk disease.ConclusionsThe incidence of low-risk PCa has increased in recent years. Only a small proportion of men with low-risk PCa progress to clinical symptoms, metastases, or death and prospective trials have not shown a benefit for immediate radical treatments. Tissue biomarkers, magnetic resonance imaging, and ongoing surveillance may help to identify those men with low-risk PCa who harbor more clinically significant disease.Patient summaryLow-risk prostate cancer is very common. Active surveillance has excellent long-term results, while randomized trials have failed to show a beneficial impact of immediate radical treatments on survival. Biomarkers and magnetic resonance imaging may help to identify which men may benefit from early treatment

Molecular portrait of high alpha-fetoprotein in hepatocellular carcinoma: implications for biomarker-driven clinical trials

The clinical utility of serum alpha-fetoprotein (AFP) in patients with hepatocellular carcinoma (HCC) is widely recognised. However, a clear understanding of the mechanisms of AFP overexpression and the molecular traits of patients with AFP-high tumours are not known. We assessed transcriptome data, whole-exome sequencing data and DNA methylome profiling of 520 HCC patients from two independent cohorts to identify distinct molecular traits of patients with AFP-high tumours (serum concentration?>?400?ng/ml), which represents an accepted prognostic cut-off and a predictor of response to ramucirumab. Those AFP-high tumours (18% of resected cases) were characterised by significantly lower AFP promoter methylation (p?<?0.001), significant enrichment of progenitor-cell features (CK19, EPCAM), higher incidence of BAP1 oncogene mutations (8.5% vs 1.6%) and lower mutational rates of CTNNB1 (14% vs 30%). Specifically, AFP-high tumours displayed significant activation of VEGF signalling (p?<?0.001), which might provide the rationale for the reported benefit of ramucirumab in this subgroup of patients

The most effective but largely ignored target for prostate cancer early detection and intervention

Over the past two decades, the global efforts for the early detection and intervention of prostate cancer seem to have made significant progresses in the basic researches, but the clinic outcomes have been disappointing: (1) prostate cancer is still the most common non-cutaneous cancer in Europe in men, (2) the age-standardized prostate cancer rate has increased in nearly all Asian and African countries, (3) the proportion of advanced cancers at the diagnosis has increased to 8.2% from 3.9% in the USA, (4) the worldwide use of PSA testing and digital rectal examination have failed to reduce the prostate cancer mortality, and (5) there is still no effective preventive method to significantly reduce the development, invasion, and metastasis of prostate cancer… Together, these facts strongly suggest that the global efforts during the past appear to be not in a correlated target with markedly inconsistent basic research and clinic outcomes. The most likely cause for the inconsistence appears due to the fact that basic scientific studies are traditionally conducted on the cell lines and animal models, where it is impossible to completely reflect or replicate the in vivo status. Thus, we would like to propose the human prostate basal cell layer (PBCL) as “the most effective target for the early detection and intervention of prostate cancer”. Our proposal is based on the morphologic, immunohistochemical and molecular evidence from our recent studies of normal and cancerous human prostate tissues with detailed clinic follow-up data. We believe that the human tissue-derived basic research data may provide a more realistic roadmap to guide the clinic practice and to avoid the potential misleading from in vitro and animal studies