Exploring Novel Biological Rationales for the Design of Next-Generation Combination Therapies

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 5193

Special Issue Editors


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Guest Editor
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
Interests: chemotherapy; immunotherapy; preclinical models; tumor microenvironment; combination therapies; type I interferons; dendritic cells; natural compounds; microbiota

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Guest Editor
Department of Translational Medicine and Surgery, Section of General Pathology, Università Cattolica del Sacro Cuore, Largo F. Vito, 1 – Rome, Italy
Interests: immunogenic anticancer therapies; cancer evolution; cancer stem cells; immune escape; preclinical mod-els; tumor microenvironment; type I interferons; combination anticancer therapies

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Guest Editor
Medical Oncology Unit, Department of Onco-Hematology and Radiotherapy, “Bianchi Melacrino Morelli” Grand Metropolitan Hospital, Viale Europa, 89124 Reggio Calabria, Italy
Interests: tumor-specific active immunotherapy; immuno-checkpoint inhibitors; tumor-specific CTLs; immunomodulation; combination anticancer therapies; real-world evidence in cancer therapy

Special Issue Information

Dear Colleagues,

Combination therapy, a therapeutic strategy originating from the combination of two or more therapeutic agents with different mechanisms of action, represents a cornerstone of cancer treatment. Combinations of surgery, radiation therapy, chemotherapy, and immunotherapies are increasingly applied in almost all cancer types with variable clinical benefit. Despite advancements in the field, drugs are mostly combined without a deep knowledge of their off-target effects, often resulting in limited treatment efficacy. Additionally, strong preclinical rationale for combination is frequently missing. The purpose of this Special Issue is to highlight rationale-based preclinical and clinical original research articles evaluating combinations of standard-of-care treatments and experimental approaches or compounds, including natural compounds, in all cancer types. Combinations of repurposed drugs with standard or experimental treatments are also encouraged.

Dr. Laura Bracci
Dr. Antonella Sistigu
Dr. Pierpaolo Correale
Guest Editors

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Keywords

  • chemotherapy
  • immunotherapy
  • radiotherapy
  • immunomodulation
  • drug repurposing
  • natural compounds
  • combination therapies
  • biomarkers
  • preclinical models
  • clinical trials

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Published Papers (2 papers)

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Research

15 pages, 3455 KiB  
Article
Palmitoyl Carnitine-Anchored Nanoliposomes for Neovasculature-Specific Delivery of Gemcitabine Elaidate to Treat Pancreatic Cancer
by Akanksha Patel, Aishwarya Saraswat, Harsh Patel, Zhe-Sheng Chen and Ketan Patel
Cancers 2023, 15(1), 182; https://doi.org/10.3390/cancers15010182 - 28 Dec 2022
Cited by 10 | Viewed by 2526
Abstract
Being the fourth most fatal malignancy worldwide, pancreatic cancer is on track to become the second leading cause of cancer-related deaths in the United States by 2030. Gemcitabine is a first-line chemotherapeutic agent for pancreatic ductal adenocarcinoma (PDAC). Gemcitabine Elaidate (Gem Elaidate) is [...] Read more.
Being the fourth most fatal malignancy worldwide, pancreatic cancer is on track to become the second leading cause of cancer-related deaths in the United States by 2030. Gemcitabine is a first-line chemotherapeutic agent for pancreatic ductal adenocarcinoma (PDAC). Gemcitabine Elaidate (Gem Elaidate) is a lipophilic derivative which allows hENT1-independent intracellular delivery of gemcitabine and better pharmacokinetics and entrapment in a nanocarrier. Cancer cells and neovasculature are negatively charged compared to healthy cells. Palmitoyl-DL-carnitine chloride (PC) is a Protein kinase C (PKC) inhibitor which also provides a cationic surface charge to nanoliposomes for targeting tumor neovasculature and augmented anticancer potency. The objectives of our study are: (a) to develop and characterize a PKC inhibitor-anchored Gem Elaidate-loaded PEGylated nanoliposome (PGPLs) and (b) to investigate the anticancer activity of Gem Elaidate and PGPLs in 2D and 3D models of pancreatic cancer. The optimized PGPLs resulted in a particle size of 80 ± 2.31 nm, a polydispersity index of 0.15 ± 0.05 and a ζ-potential of +31.6 ± 3.54 mV, with a 93.25% encapsulation efficiency of Gem Elaidate in PGPLs. Our results demonstrate higher cellular uptake, inhibition in migration, as well as angiogenesis potential and significant apoptosis induced by PGPLs in 3D multicellular tumor spheroids of pancreatic cancer cells. Hence, PGPLs could be an effective and novel nanoformulation for the neovasculature-specific delivery of Gemcitabine Elaidate to treat PDAC. Full article
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15 pages, 51827 KiB  
Article
Cellular and Molecular Effects of Eribulin in Preclinical Models of Hematologic Neoplasms
by Hugo Passos Vicari, Keli Lima, Leticia Veras Costa-Lotufo and João Agostinho Machado-Neto
Cancers 2022, 14(24), 6080; https://doi.org/10.3390/cancers14246080 - 10 Dec 2022
Cited by 3 | Viewed by 1958
Abstract
Despite the advances in understanding the biology of hematologic neoplasms which has resulted in the approval of new drugs, the therapeutic options are still scarce for relapsed/refractory patients. Eribulin is a unique microtubule inhibitor that is currently being used in the therapy for [...] Read more.
Despite the advances in understanding the biology of hematologic neoplasms which has resulted in the approval of new drugs, the therapeutic options are still scarce for relapsed/refractory patients. Eribulin is a unique microtubule inhibitor that is currently being used in the therapy for metastatic breast cancer and soft tissue tumors. Here, we uncover eribulin’s cellular and molecular effects in a molecularly heterogeneous panel of hematologic neoplasms. Eribulin reduced cell viability and clonogenicity and promoted apoptosis and cell cycle arrest. The minimal effects of eribulin observed in the normal leukocytes suggested selectivity for malignant blood cells. In the molecular scenario, eribulin induces DNA damage and apoptosis markers. The ABCB1, ABCC1, p-AKT, p-NFκB, and NFκB levels were associated with responsiveness to eribulin in blood cancer cells, and a resistance eribulin-related target score was constructed. Combining eribulin with elacridar (a P-glycoprotein inhibitor), but not with PDTC (an NFkB inhibitor), increases eribulin-induced apoptosis in leukemia cells. In conclusion, our data indicate that eribulin leads to mitotic catastrophe and cell death in blood cancer cells. The expression and activation of MDR1, PI3K/AKT, and the NFκB-related targets may be biomarkers of the eribulin response, and the combined treatment of eribulin and elacridar may overcome drug resistance in these diseases. Full article
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