Research

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7 pages, 634 KiB

Open AccessArticle

Using a 31-Gene Expression Profile Test to Stratify Patients with Stage I–II Cutaneous Melanoma According to Recurrence Risk: Update to a Prospective, Multicenter Study

by Sebastian Podlipnik, Aram Boada, Jose L. López-Estebaranz, Manuel M. Martín-González, Pedro Redondo, Brian Martin, Ann P. Quick, Christine N. Bailey, Sarah J. Kurley, Robert W. Cook and Susana Puig

Cancers 2022, 14(4), 1060; https://doi.org/10.3390/cancers14041060 - 19 Feb 2022

Cited by 5 | Viewed by 1524

Abstract

Background: Fifteen to forty percent of patients with localized cutaneous melanoma (CM) (stages I–II) will experience disease relapse. The 31-gene expression profile (31-GEP) uses gene expression data from the primary tumor in conjunction with clinicopathologic features to refine patient prognosis. The study’s objective [...] Read more.

Background: Fifteen to forty percent of patients with localized cutaneous melanoma (CM) (stages I–II) will experience disease relapse. The 31-gene expression profile (31-GEP) uses gene expression data from the primary tumor in conjunction with clinicopathologic features to refine patient prognosis. The study’s objective was to evaluate 31-GEP risk stratification for disease-free survival (DFS) in a previously published cohort with longer follow-up. Methods: Patients with stage IB–II CM (n = 86) were prospectively tested with the 31-GEP. Follow-up time increased from 2.2 to 3.9 years. Patient outcomes were compared using Kaplan-Meier and Cox regression analysis. Results: A Class 2B result was a significant predictor of 3-year DFS (hazard ratio (HR) 8.4, p = 0.008) in univariate analysis. The 31-GEP significantly stratified patients by risk of relapse (p = 0.005). A Class 2B result was associated with a lower 3-year DFS (75.0%) than a Class 1A result (100%). The 31-GEP had a high sensitivity (77.8%) and negative predictive value (95.0%). Conclusions: The 31-GEP is a significant predictor of disease relapse in patients with stage IB–II melanoma and accurately stratified patients by risk of relapse. Full article

(This article belongs to the Special Issue Advances in Prognosis and Theranostics of Cancer)

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18 pages, 2837 KiB

Open AccessArticle

ITIH5-Derived Polypeptides Covering the VIT Domain Suppress the Growth of Human Cancer Cells In Vitro

by Michael Rose, Sebastian Huth, Marc Wiesehöfer, Josef Ehling, Corinna Henkel, Julia Steitz, Twan Lammers, Jennifer Kistermann, Oliver Klaas, Maximilian Koch, Sandra Rushrush, Ruth Knüchel and Edgar Dahl

Cancers 2022, 14(3), 488; https://doi.org/10.3390/cancers14030488 - 19 Jan 2022

Cited by 4 | Viewed by 2188

Abstract

Oncogenic drivers such as mutated EGFR are the preferred targets in modern drug development. However, restoring the lost function of tumor suppressor proteins could also be a valid approach to combatting cancer. ITIH5 has been revealed as a potent metastasis suppressor in both [...] Read more.

Oncogenic drivers such as mutated EGFR are the preferred targets in modern drug development. However, restoring the lost function of tumor suppressor proteins could also be a valid approach to combatting cancer. ITIH5 has been revealed as a potent metastasis suppressor in both breast and pancreatic cancer. Here, we show that ITIH5 overexpression in MDA-MB-231 breast cancer cells can also locally suppress tumor growth by 85%, when transplanted into the mammary fat pad of nude mice. For a potential drug development approach, we further aimed to define downsized ITIH5 polypeptides that still are capable of mediating growth inhibitory effects. By cloning truncated and His-tagged ITIH5 fragments, we synthesized two recombinant N-terminal polypeptides (ITIH5^681aa and ITIH5^161aa), both covering the ITI heavy chain specific “vault protein inter-alpha-trypsin” (VIT) domain. Truncated ITIH5 variants caused dose-dependent cell growth inhibition by up to 50% when applied to various cancer cell lines (e.g., MDA-MB-231, SCaBER, A549) reflecting breast, bladder and lung cancer in vitro. Thus, our data suggest the substantial role of the ITIH5-specific VIT domain in ITIH5-mediated suppression of tumor cell proliferation. As extracellularly administered ITIH5 peptides mimic the growth-inhibitory effects of the full-length ITIH5 tumor suppressor protein, they may constitute the basis for developing anticancer drugs in the future. Full article

(This article belongs to the Special Issue Advances in Prognosis and Theranostics of Cancer)

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26 pages, 8266 KiB

Open AccessArticle

Biosynthesized Silver Nanoparticles for Cancer Therapy and In Vivo Bioimaging

by Shagufta Haque, Caroline Celine Norbert, Rajarshi Acharyya, Sudip Mukherjee, Muralidharan Kathirvel and Chitta Ranjan Patra

Cancers 2021, 13(23), 6114; https://doi.org/10.3390/cancers13236114 - 04 Dec 2021

Cited by 30 | Viewed by 3435

Abstract

In the current communication, a simple, environmentally compatible, non-toxic green chemistry process is used for the development of silver nanoparticles (AgZE) by the reaction between silver nitrate (AgNO₃) and the ethanolic leaf extract of Zinnia elegans (ZE). The optimization of AgZE [...] Read more.

In the current communication, a simple, environmentally compatible, non-toxic green chemistry process is used for the development of silver nanoparticles (AgZE) by the reaction between silver nitrate (AgNO₃) and the ethanolic leaf extract of Zinnia elegans (ZE). The optimization of AgZE is carried out using a series of experiments. Various physico-chemical techniques are utilized to characterize the nanomaterials. The cell viability assay of AgZE in normal cells (CHO, HEK-293T, EA.hy926, and H9c2) shows their biocompatible nature, which is supported by hemolytic assay using mouse RBC. Interestingly, the nanoparticles exhibited cytotoxicity towards different cancer cell lines (U-87, MCF-7, HeLa, PANC-1 and B16F10). The detailed anticancer activity of AgZE on human glioblastoma cell line (U-87) is exhibited through various in vitro assays. In vivo the AgZE illustrates anticancer activity by inhibiting blood vessel formation through CAM assay. Furthermore, the AgZE nanoparticles when intraperitoneally injected in C57BL6/J mice (with and without tumor) exhibit fluorescence properties in the NIR region (excitation: 710 nm, emission: 820 nm) evidenced by bioimaging studies. The AgZE biodistribution through ICPOES analysis illustrates the presence of silver in different vital organs. Considering all the results, AgZE could be useful as a potential cancer therapeutic agent, as well as an NIR based non-invasive imaging tool in near future. Full article

(This article belongs to the Special Issue Advances in Prognosis and Theranostics of Cancer)

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11 pages, 1038 KiB

Open AccessArticle

Selective Internal Radiation Therapy in Breast Cancer Liver Metastases: Outcome Assessment Applying a Prognostic Score

by Imke Schatka, Monique Tschernig, Julian M. M. Rogasch, Stephanie Bluemel, Josefine Graef, Christian Furth, Jalid Sehouli, Jens-Uwe Blohmer, Bernhard Gebauer, Uli Fehrenbach and Holger Amthauer

Cancers 2021, 13(15), 3777; https://doi.org/10.3390/cancers13153777 - 27 Jul 2021

Cited by 4 | Viewed by 1670

Abstract

Selective internal radiation therapy (SIRT) is a therapy option in patients with breast cancer liver metastasis (BCLM). This analysis aimed at identifying a prognostic score regarding overall survival (OS) after SIRT using routine pretherapeutic parameters. Retrospective analysis of 38 patients (age, 59 (39–84) [...] Read more.

Selective internal radiation therapy (SIRT) is a therapy option in patients with breast cancer liver metastasis (BCLM). This analysis aimed at identifying a prognostic score regarding overall survival (OS) after SIRT using routine pretherapeutic parameters. Retrospective analysis of 38 patients (age, 59 (39–84) years) with BCLM and 42 SIRT procedures. Cox regression for OS included clinical factors (age, ECOG and prior treatments), laboratory parameters, hepatic tumor load and dose reduction due to hepatopulmonary shunt. Elevated baseline ALT and/or AST was present if CTCAE grade ≥ 2 was fulfilled (>3 times the upper limit of normal). Median OS after SIRT was 6.4 months. In univariable Cox, ECOG ≥ 1 (hazard ratio (HR), 3.8), presence of elevated baseline ALT/AST (HR, 3.8), prior liver surgery (HR, 10.2), and dose reduction of 40% (HR, 8.1) predicted shorter OS (each p < 0.05). Multivariable Cox confirmed ECOG ≥ 1 (HR, 2.34; p = 0.012) and elevated baseline ALT/AST (HR, 4.16; p < 0.001). Combining both factors, median OS decreased from 19.2 months (0 risk factors; n = 14 procedures) to 5.9 months (1 factor; n = 20) or 2.2 months (2 factors; n = 8; p < 0.001). The proposed score may facilitate pretherapeutic identification of patients with unfavorable OS after SIRT. This may help to balance potential life prolongation with the hazards of invasive treatment and hospitalization. Full article

(This article belongs to the Special Issue Advances in Prognosis and Theranostics of Cancer)

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12 pages, 1276 KiB

Open AccessArticle

Gene Expression Profiling of Olfactory Neuroblastoma Helps Identify Prognostic Pathways and Define Potentially Therapeutic Targets

by Chiara Romani, Eliana Bignotti, Davide Mattavelli, Anna Bozzola, Luigi Lorini, Michele Tomasoni, Laura Ardighieri, Vittorio Rampinelli, Alberto Paderno, Simonetta Battocchio, Cristina Gurizzan, Paolo Castelnuovo, Mario Turri-Zanoni, Carla Facco, Fausto Sessa, Alberto Schreiber, Marco Ferrari, Antonella Ravaggi, Alberto Deganello, Piero Nicolai, Michela Buglione, Davide Tomasini, Roberto Maroldi, Cesare Piazza, Stefano Calza and Paolo Bossi Show full author list Hide full author list

Cancers 2021, 13(11), 2527; https://doi.org/10.3390/cancers13112527 - 21 May 2021

Cited by 17 | Viewed by 2522

Abstract

Olfactory neuroblastoma (ONB) is a rare sinonasal neoplasm with a peculiar behavior, for which limited prognostic factors are available. Herein, we investigate the transcriptional pathways altered in ONB and correlate them with pathological features and clinical outcomes. We analyze 32 ONB patients treated [...] Read more.

Olfactory neuroblastoma (ONB) is a rare sinonasal neoplasm with a peculiar behavior, for which limited prognostic factors are available. Herein, we investigate the transcriptional pathways altered in ONB and correlate them with pathological features and clinical outcomes. We analyze 32 ONB patients treated with curative intent at two independent institutions from 2001 to 2019 for whom there is available pathologic and clinical data. We perform gene expression profiling on primary ONB samples and carry out functional enrichment analysis to investigate the key pathways associated with disease-free survival (DFS). The median age is 53.5 years; all patients undergo surgery and a pure endoscopic approach is adopted in the majority of cases (81.2%). Most patients have advanced disease (stages III–IV, 81.2%) and 84.4% undergo adjuvant (chemo)radiotherapy. The median follow-up is 35 months; 11 (26.8%) patients relapse. Clinical characteristics (gender, stage and Hyams’ grade) are not associated with the outcomes. In contrast, TGF-beta binding, EMT, IFN-alpha response, angiogenesis, IL2-STAT5 and IL6-JAK-STAT3 signaling pathways are enriched in patients experiencing recurrence, and significantly associated with shorter DFS. Clustering of transcriptional profiles according to pathological features indicates two distinct molecular groups, defined by either cytokeratin-positive or -negative immunostaining. Definition of the characterizing ONB transcriptomic pathways may pave the way towards tailored treatment approaches. Full article

(This article belongs to the Special Issue Advances in Prognosis and Theranostics of Cancer)

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Review

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17 pages, 1433 KiB

Open AccessReview

A Nanoparticle’s Journey to the Tumor: Strategies to Overcome First-Pass Metabolism and Their Limitations

by Joshua J. Milligan and Soumen Saha

Cancers 2022, 14(7), 1741; https://doi.org/10.3390/cancers14071741 - 29 Mar 2022

Cited by 27 | Viewed by 4176

Abstract

Nanomedicines represent the cutting edge of today’s cancer therapeutics. Seminal research decades ago has begun to pay dividends in the clinic, allowing for the delivery of cancer drugs with enhanced systemic circulation while also minimizing off-target toxicity. Despite the advantages of delivering cancer [...] Read more.

Nanomedicines represent the cutting edge of today’s cancer therapeutics. Seminal research decades ago has begun to pay dividends in the clinic, allowing for the delivery of cancer drugs with enhanced systemic circulation while also minimizing off-target toxicity. Despite the advantages of delivering cancer drugs using nanoparticles, micelles, or other nanostructures, only a small fraction of the injected dose reaches the tumor, creating a narrow therapeutic window for an otherwise potent drug. First-pass metabolism of nanoparticles by the reticuloendothelial system (RES) has been identified as a major culprit for the depletion of nanoparticles in circulation before they reach the tumor site. To overcome this, new strategies, materials, and functionalization with stealth polymers have been developed to improve nanoparticle circulation and uptake at the tumor site. This review summarizes the strategies undertaken to evade RES uptake of nanomedicines and improve the passive and active targeting of nanoparticle drugs to solid tumors. We also outline the limitations of current strategies and the future directions we believe will be explored to yield significant benefits to patients and make nanomedicine a promising treatment modality for cancer. Full article

(This article belongs to the Special Issue Advances in Prognosis and Theranostics of Cancer)

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22 pages, 2213 KiB

Open AccessReview

Targeted Drug Delivery and Theranostic Strategies in Malignant Lymphomas

by Tomas Etrych, Alena Braunova, David Zogala, Lukas Lambert, Nicol Renesova and Pavel Klener

Cancers 2022, 14(3), 626; https://doi.org/10.3390/cancers14030626 - 26 Jan 2022

Cited by 11 | Viewed by 6374

Abstract

Malignant lymphomas represent the most common type of hematologic malignancies. The first clinically approved TDD modalities in lymphoma patients were anti-CD20 radioimmunoconjugates (RIT) ¹³¹I-tositumomab and ⁹⁰Y-ibritumomab-tiuxetan. The later clinical success of the first approved antibody–drug conjugate (ADC) for the treatment of [...] Read more.

Malignant lymphomas represent the most common type of hematologic malignancies. The first clinically approved TDD modalities in lymphoma patients were anti-CD20 radioimmunoconjugates (RIT) ¹³¹I-tositumomab and ⁹⁰Y-ibritumomab-tiuxetan. The later clinical success of the first approved antibody–drug conjugate (ADC) for the treatment of lymphomas, anti-CD30 brentuximab vedotin, paved the path for the preclinical development and clinical testing of several other ADCs, including polatuzumab vedotin and loncastuximab tesirine. Other modalities of TDD are based on new formulations of “old” cytostatic agents and their passive trapping in the lymphoma tissue by means of the enhanced permeability and retention (EPR) effect. Currently, the diagnostic and restaging procedures in aggressive lymphomas are based on nuclear imaging, namely PET. A theranostic approach that combines diagnostic or restaging lymphoma imaging with targeted treatment represents an appealing innovative strategy in personalized medicine. The future of theranostics will require not only the capability to provide suitable disease-specific molecular probes but also expertise on big data processing and evaluation. Here, we review the concept of targeted drug delivery in malignant lymphomas from RIT and ADC to a wide array of passively and actively targeted nano-sized investigational agents. We also discuss the future of molecular imaging with special focus on monoclonal antibody-based and monoclonal antibody-derived theranostic strategies. Full article

(This article belongs to the Special Issue Advances in Prognosis and Theranostics of Cancer)

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21 pages, 2406 KiB

Open AccessReview

STARD3: A Prospective Target for Cancer Therapy

by Kanwal Asif, Lorenzo Memeo, Stefano Palazzolo, Yahima Frión-Herrera, Salvatore Parisi, Isabella Caligiuri, Vincenzo Canzonieri, Carlotta Granchi, Tiziano Tuccinardi and Flavio Rizzolio

Cancers 2021, 13(18), 4693; https://doi.org/10.3390/cancers13184693 - 18 Sep 2021

Cited by 9 | Viewed by 3624

Abstract

Cancer is one of the major causes of death in developed countries and current therapies are based on surgery, chemotherapeutic agents, and radiation. To overcome side effects induced by chemo- and radiotherapy, in recent decades, targeted therapies have been proposed in second and [...] Read more.

Cancer is one of the major causes of death in developed countries and current therapies are based on surgery, chemotherapeutic agents, and radiation. To overcome side effects induced by chemo- and radiotherapy, in recent decades, targeted therapies have been proposed in second and even first lines. Targeted drugs act on the essential pathways involved in tumor induction, progression, and metastasis, basically all the hallmark of cancers. Among emerging pathways, the cholesterol metabolic pathway is a strong candidate for this purpose. Cancer cells have an accelerated metabolic rate and require a continuous supply of cholesterol for cell division and membrane renewal. Steroidogenic acute regulatory related lipid transfer (START) proteins are a family of proteins involved in the transfer of lipids and some of them are important in non-vesicular cholesterol transportation within the cell. The alteration of their expression levels is implicated in several diseases, including cancers. In this review, we report the latest discoveries on StAR-related lipid transfer protein domain 3 (STARD3), a member of the START family, which has a potential role in cancer, focusing on the structural and biochemical characteristics and mechanisms that regulate its activity. The role of the STARD3 protein as a molecular target for the development of cancer therapies is also discussed. As STARD3 is a key protein in the cholesterol movement in cancer cells, it is of interest to identify inhibitors able to block its activity. Full article

(This article belongs to the Special Issue Advances in Prognosis and Theranostics of Cancer)

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