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Cancers
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New Precision Medicine Approaches in Haematological Malignancies: Novel Targets and...
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New Precision Medicine Approaches in Haematological Malignancies: Novel Targets and Advanced Therapies

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Methods and Technologies Development".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 10241

Special Issue Editors

Dr. Ilaria Stefania Pagani

E-Mail Website
Guest Editor
Cancer Program, Precision Medicine Theme, South Australian Health & Medical Research Institute, Adelaide 5000, Australia
Interests: metabolism; cancer relapse; precision medicine; microbiome; immunology; drug discovery; leukaemia
Special Issues, Collections and Topics in MDPI journals
Dr. Hannah Wardill

E-Mail Website
Guest Editor
Cancer Program, Precision Medicine Theme, South Australian Health & Medical Research Institute, Adelaide 5000, Australia
Interests: supportive cancer care; survivorship; precision medicine; risk prediction; personalised cancer care; host-microbe interactions
Special Issues, Collections and Topics in MDPI journals
Dr. Teresa Sadras

E-Mail Website
Guest Editor
Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
Interests: B cell development; acute lymphoblastic leukemia; cytokine receptors; cell signaling; cancer genomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is our pleasure to announce a call for submissions to this Special Issue of Cancers, entitled "New Precision Medicine Approaches in Haematological Malignancies: Novel Targets and Advanced Therapies".

Blood cancer is one is the biggest causes of cancer death worldwide. Patients have increased chances of surviving if the disease is diagnosed earlier and people have access to better personalised therapies. Additionally, toxicities and long-term adverse effects, including organ damage, are often associated to current blood cancer therapies, and impair life quality. In the last decade, novel genetic, epigenetic, metabolic, and immunological vulnerabilities have been identified, and in some cases have led to the development of new targeted therapies. However, despite rapid initial responses, disease often recurs with an often fatal outcome. We welcome original research articles and reviews that cover any relevant topics in this area. Possible topics include, but are not limited to, the following:

  • Role of the immune system in blood cancer progression and relapse, and advances in immunotherapies.
  • Mechanisms of resistance and targeted therapies.
  • Genomic and epigenetic mechanisms influencing clinical outcome, including mutations, gene fusions, copy number variations, and other chromosomal rearrangements.
  • Exploiting metabolic vulnerabilities for personalised therapies, including mutations in key metabolic enzymes.
  • Side effects and toxicities of the current blood cancer therapies, and strategies for reducing them.
  • Omics approaches, including single-cell technologies, for identifying new biomarkers.
  • RAS pathway mutations in blood cancers and new targeted therapies.
  • Tumour microenvironment, cell dormancy, and relapse.

We look forward to receiving your contributions.

Dr. Ilaria Stefania Pagani
Dr. Hannah Wardill
Dr. Teresa Sadras
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • blood cancer
  • cancer relapse
  • resistance
  • targeted therapies
  • immune therapies
  • metabolism
  • cancer mutations

Published Papers (5 papers)

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Research

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13 pages, 2842 KiB  
Article
Insights into Facilitated Subcutaneous Immunoglobulin Use in Patients with Secondary Immunodeficiency Diseases: A FIGARO Subgroup Analysis
by Maria Dimou, Matthaios Speletas, Cinzia Milito, Aleksandra Pyzik, Dörte Huscher, Marta Kamieniak, David Pittrow and Michael Borte
Cancers 2023, 15(18), 4524; https://doi.org/10.3390/cancers15184524 - 12 Sep 2023
Viewed by 1073
Abstract
The Facilitated Immunoglobulin Administration Registry And Outcomes (FIGARO) Study was a European, multicenter, prospective, observational study conducted across Europe designed to provide insights on the clinical use and tolerability of facilitated subcutaneous immunoglobulin (fSCIG). Data herein are reported for the cohort of patients [...] Read more.
The Facilitated Immunoglobulin Administration Registry And Outcomes (FIGARO) Study was a European, multicenter, prospective, observational study conducted across Europe designed to provide insights on the clinical use and tolerability of facilitated subcutaneous immunoglobulin (fSCIG). Data herein are reported for the cohort of patients with secondary immunodeficiency (SID), with a subgroup analysis by age. The SID cohort included 31 patients: 1 pediatric, 15 adult, and 15 older adult patients. Over the 36-month observation period, the median monthly dose of fSCIG (30 g) and median monthly infusion volume per patient (300 mL) remained constant in both adult-age cohorts. Serum trough levels tended to increase over time. Most patients required only one infusion site and could receive the full dose every 3–4 weeks. There was a trend toward self-administration at home. In the adult group, infusion site inflammation and headache were reported at the inclusion visit (n = 1 each), with no adverse drug reactions reported at any of the follow-up visits. No acute severe bacterial infections were reported during the study follow-up. These results demonstrate the feasibility and tolerability of fSCIG use in patients with SID and the flexibility of administration settings including self-administration at home in patients aged ≥65 years. Full article
(This article belongs to the Special Issue New Precision Medicine Approaches in Haematological Malignancies: Novel Targets and Advanced Therapies)
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15 pages, 2246 KiB  
Article
Precision Medicine Approach Based on Molecular Alterations for Patients with Relapsed or Refractory Multiple Myeloma: Results from the MM-EP1 Study
by Fabio Andreozzi, Matteo Dragani, Cyril Quivoron, Fabien Le Bras, Tarek Assi, Alina Danu, Karim Belhadj, Julien Lazarovici, Sophie Cotteret, Olivier A. Bernard, Vincent Ribrag and Jean-Marie Michot
Cancers 2023, 15(5), 1508; https://doi.org/10.3390/cancers15051508 - 28 Feb 2023
Cited by 1 | Viewed by 1929
Abstract
Background: Despite that cytogenetic and molecular analysis of tumor cells can rapidly identify recurring molecular abnormalities, no personalized therapy is currently available in the setting of relapsed/refractory multiple myeloma (r/r MM). Methods: MM-EP1 is a retrospective study aimed at comparing a personalized molecular-oriented [...] Read more.
Background: Despite that cytogenetic and molecular analysis of tumor cells can rapidly identify recurring molecular abnormalities, no personalized therapy is currently available in the setting of relapsed/refractory multiple myeloma (r/r MM). Methods: MM-EP1 is a retrospective study aimed at comparing a personalized molecular-oriented (MO) versus a non-molecular-oriented (no-MO) approach in r/r MM. Actionable molecular targets and their associated therapies were the BRAF V600E mutation and BRAF inhibitors; t(11;14)(q13;q32) and BCL2 inhibitors; and t(4;14)(p16;q32) with FGFR3 fusion/rearrangements and FGFR3 inhibitors. Results: One hundred three highly pretreated r/r MM patients with a median age of 67 years (range 44–85) were included. Seventeen (17%) patients were treated using an MO approach with BRAF inhibitors (vemurafenib or dabrafenib, n = 6), BCL2 inhibitor (venetoclax, n = 9), or FGFR3 inhibitor (erdafitinib, n = 2). Eighty-six (86%) patients received non-MO therapies. Overall response rate was 65% in MO patients versus 58% in the non-MO group (p = 0.053). Median PFS and OS were 9 and 6 months (HR = 0.96; CI95 = 0.51–1.78; p = 0.88) and 26 and 28 months (HR = 0.98; CI95 = 0.46–2.12; p = 0.98), respectively, in MO and no-MO patients. Conclusion: Despite the low number of patients treated with an MO approach, this study highlights the strengths and weakness of a molecular-targeted approach for the treatment of multiple myeloma. Widespread biomolecular techniques and improvement of precision medicine treatment algorithms could improve selection for precision medicine in myeloma. Full article
(This article belongs to the Special Issue New Precision Medicine Approaches in Haematological Malignancies: Novel Targets and Advanced Therapies)
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21 pages, 6877 KiB  
Article
Repurposing the Bis-Biguanide Alexidine in Combination with Tyrosine Kinase Inhibitors to Eliminate Leukemic Stem/Progenitor Cells in Chronic Myeloid Leukemia
by Fabien Muselli, Lucas Mourgues, Nathalie Rochet, Marielle Nebout, Agnès Guerci, Els Verhoeyen, Adrien Krug, Laurence Legros, Jean-François Peyron and Didier Mary
Cancers 2023, 15(3), 995; https://doi.org/10.3390/cancers15030995 - 03 Feb 2023
Cited by 1 | Viewed by 1813
Abstract
Background & aims: In CML, Leukemic Stem Cells (LSCs) that are insensitive to Tyrosine Kinase Inhibitors are responsible for leukemia maintenance and relapses upon TKI treatment arrest. We previously showed that downregulation of the BMI1 polycomb protein that is crucial for stem/progenitor cells [...] Read more.
Background & aims: In CML, Leukemic Stem Cells (LSCs) that are insensitive to Tyrosine Kinase Inhibitors are responsible for leukemia maintenance and relapses upon TKI treatment arrest. We previously showed that downregulation of the BMI1 polycomb protein that is crucial for stem/progenitor cells self-renewal induced a CCNG2/dependent proliferation arrest leading to elimination of Chronic Myeloid Leukemia (CML) cells. Unfortunately, as of today, pharmacological inhibition of BMI1 has not made its way to the clinic. Methods: We used the Connectivity Map bioinformatic database to identify pharmacological molecules that could mimick BMI1 silencing, to induce CML cell death. We selected the bis-biguanide Alexidin (ALX) that produced a transcriptomic profile positively correlating with the one obtained after BMI silencing in K562 CML cells. We then evaluated the efficiency of ALX in combination with TKI on CML cells. Results: Here we report that cell growth and clonogenic activity of K562 and LAMA-84 CML cell lines were strongly inhibited by ALX. ALX didn’t modify BCR::ABL1 phosphorylation and didn’t affect BMI1 expression but was able to increase CCNG2 expression leading to autophagic processes that preceed cell death. Besides, ALX could enhance the apoptotic response induced by any Tyrosine Kinase Inhibitors (TKI) of the three generations. We also noted a strong synergism between ALX and TKIs to increase expression of caspase-9 and caspase-3 and induce PARP cleavage, Bad expression and significantly decreased Bcl-xL family member expression. We also observed that the blockage of the mitochondrial respiratory chain by ALX can be associated with inhibition of glycolysis by 2-DG to achieve an enhanced inhibition of K562 proliferation and clonogenicity. ALX specifically affected the differentiation of BCR::ABL1-transduced healthy CD34+ cells but not of mock-infected healthy CD34+ control cells. Importantly, ALX strongly synergized with TKIs to inhibit clonogenicity of primary CML CD34+ cells from diagnosed patients. Long Term Culture of Initiating Cell (LTC-IC) and dilution of the fluorescent marker CFSE allowed us to observe that ALX and Imatinib (IM) partially reduced the number of LSCs by themselves but that the ALX/IM combination drastically reduced this cell compartment. Using an in vivo model of NSG mice intravenously injected with K562-Luciferase transduced CML cells, we showed that ALX combined with IM improved mice survival. Conclusions: Collectively, our results validate the use of ALX bis-biguanide to potentiate the action of conventional TKI treatment as a potential new therapeutic solution to eradicate CML LSCs Full article
(This article belongs to the Special Issue New Precision Medicine Approaches in Haematological Malignancies: Novel Targets and Advanced Therapies)
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Review

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15 pages, 1761 KiB  
Review
Immunotherapy in Acute Leukemias: Past Success Paves the Way for Future Progress
by Adel Chergui and John L. Reagan
Cancers 2023, 15(16), 4137; https://doi.org/10.3390/cancers15164137 - 17 Aug 2023
Cited by 2 | Viewed by 1425
Abstract
Immunotherapy as a cancer treatment modality has undergone recent widespread proliferation across all cancer types, especially amongst patients with solid tumors. However, the longest tenured immunotherapy approach to cancer is allogeneic stem cell transplantation (allo-SCT) for two hematologic malignancies: acute myeloid and acute [...] Read more.
Immunotherapy as a cancer treatment modality has undergone recent widespread proliferation across all cancer types, especially amongst patients with solid tumors. However, the longest tenured immunotherapy approach to cancer is allogeneic stem cell transplantation (allo-SCT) for two hematologic malignancies: acute myeloid and acute lymphoid leukemia (AML and ALL, respectively). While allo-SCT remains a standard of care for eligible patients, recent advances/applications of monoclonal antibodies, immune checkpoint inhibitors, bispecific T-cell engagers (BiTEs), and CAR T-cell therapy are changing the treatment landscape for these acute leukemias by either direct to tumor immune targeting or through decreased toxicities that expand patient eligibility. Pre-clinical data and clinical trials have shown promising results for novel immunotherapies in acute leukemia, and multiple ongoing trials are investigating these novel approaches. While there have been promising results with these approaches, particularly in the relapsed/refractory setting, there remain challenges in optimizing the use of these therapies, such as managing cytokine release syndrome and other immune-related toxicities. Immunotherapy is a rapidly evolving field in the treatment of acute leukemia and has the potential to significantly impact the management of both AML and ALL. This review highlights the history of immunotherapy in the treatment of acute leukemias, the evolution of immunotherapy into more targeted approaches, the potential benefits and limitations of different immune targeting approaches, and ongoing research and development in the field. Full article
(This article belongs to the Special Issue New Precision Medicine Approaches in Haematological Malignancies: Novel Targets and Advanced Therapies)
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18 pages, 1620 KiB  
Review
Mechanisms of Resistance and Implications for Treatment Strategies in Chronic Myeloid Leukaemia
by Govinda Poudel, Molly G. Tolland, Timothy P. Hughes and Ilaria S. Pagani
Cancers 2022, 14(14), 3300; https://doi.org/10.3390/cancers14143300 - 06 Jul 2022
Cited by 17 | Viewed by 3339
Abstract
Tyrosine kinase inhibitors (TKIs) have revolutionised the management of chronic myeloid leukaemia (CML), with the disease now having a five-year survival rate over 80%. The primary focus in the treatment of CML has been on improving the specificity and potency of TKIs to [...] Read more.
Tyrosine kinase inhibitors (TKIs) have revolutionised the management of chronic myeloid leukaemia (CML), with the disease now having a five-year survival rate over 80%. The primary focus in the treatment of CML has been on improving the specificity and potency of TKIs to inhibit the activation of the BCR::ABL1 kinase and/or overcoming resistance driven by mutations in the BCR::ABL1 oncogene. However, this approach may be limited in a significant proportion of patients who develop TKI resistance despite the effective inhibition of BCR::ABL1. These patients may require novel therapeutic strategies that target both BCR::ABL1-dependent and BCR::ABL1-independent mechanisms of resistance. The combination treatment strategies that target alternative survival signalling, which may contribute towards BCR::ABL1-independent resistance, could be a successful strategy for eradicating residual leukaemic cells and consequently increasing the response rate in CML patients. Full article
(This article belongs to the Special Issue New Precision Medicine Approaches in Haematological Malignancies: Novel Targets and Advanced Therapies)
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