RNA-based therapies: A cog in the wheel of lung cancer defense

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Abstract

Lung cancer (LC) is a heterogeneous disease consisting mainly of two subtypes, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), and remains the leading cause of death worldwide. Despite recent advances in therapies, the overall 5-year survival rate of LC remains less than 20%. The efficacy of current therapeutic approaches is compromised by inherent or acquired drug-resistance and severe off-target effects. Therefore, the identification and development of innovative and effective therapeutic approaches are critically desired for LC. The development of RNA-mediated gene inhibition technologies was a turning point in the field of RNA biology. The critical regulatory role of different RNAs in multiple cancer pathways makes them a rich source of targets and innovative tools for developing anticancer therapies. The identification of antisense sequences, short interfering RNAs (siRNAs), microRNAs (miRNAs or miRs), anti-miRs, and mRNA-based platforms holds great promise in preclinical and early clinical evaluation against LC. In the last decade, RNA-based therapies have substantially expanded and tested in clinical trials for multiple malignancies, including LC. This article describes the current understanding of various aspects of RNA-based therapeutics, including modern platforms, modifications, and combinations with chemo-/immunotherapies that have translational potential for LC therapies.

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Cancer statistics, 2020

Rebecca Siegel, Kimberly D Miller, Ahmedin Jemal (2020)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2016) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2017) were collected by the National Center for Health Statistics. In 2020, 1,806,590 new cancer cases and 606,520 cancer deaths are projected to occur in the United States. The cancer death rate rose until 1991, then fell continuously through 2017, resulting in an overall decline of 29% that translates into an estimated 2.9 million fewer cancer deaths than would have occurred if peak rates had persisted. This progress is driven by long-term declines in death rates for the 4 leading cancers (lung, colorectal, breast, prostate); however, over the past decade (2008-2017), reductions slowed for female breast and colorectal cancers, and halted for prostate cancer. In contrast, declines accelerated for lung cancer, from 3% annually during 2008 through 2013 to 5% during 2013 through 2017 in men and from 2% to almost 4% in women, spurring the largest ever single-year drop in overall cancer mortality of 2.2% from 2016 to 2017. Yet lung cancer still caused more deaths in 2017 than breast, prostate, colorectal, and brain cancers combined. Recent mortality declines were also dramatic for melanoma of the skin in the wake of US Food and Drug Administration approval of new therapies for metastatic disease, escalating to 7% annually during 2013 through 2017 from 1% during 2006 through 2010 in men and women aged 50 to 64 years and from 2% to 3% in those aged 20 to 49 years; annual declines of 5% to 6% in individuals aged 65 years and older are particularly striking because rates in this age group were increasing prior to 2013. It is also notable that long-term rapid increases in liver cancer mortality have attenuated in women and stabilized in men. In summary, slowing momentum for some cancers amenable to early detection is juxtaposed with notable gains for other common cancers.

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Cancer statistics, 2019

Rebecca Siegel, Kimberly D Miller, Ahmedin Jemal (2019)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data, available through 2015, were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data, available through 2016, were collected by the National Center for Health Statistics. In 2019, 1,762,450 new cancer cases and 606,880 cancer deaths are projected to occur in the United States. Over the past decade of data, the cancer incidence rate (2006-2015) was stable in women and declined by approximately 2% per year in men, whereas the cancer death rate (2007-2016) declined annually by 1.4% and 1.8%, respectively. The overall cancer death rate dropped continuously from 1991 to 2016 by a total of 27%, translating into approximately 2,629,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the racial gap in cancer mortality is slowly narrowing, socioeconomic inequalities are widening, with the most notable gaps for the most preventable cancers. For example, compared with the most affluent counties, mortality rates in the poorest counties were 2-fold higher for cervical cancer and 40% higher for male lung and liver cancers during 2012-2016. Some states are home to both the wealthiest and the poorest counties, suggesting the opportunity for more equitable dissemination of effective cancer prevention, early detection, and treatment strategies. A broader application of existing cancer control knowledge with an emphasis on disadvantaged groups would undoubtedly accelerate progress against cancer.

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An mRNA Vaccine against SARS-CoV-2 — Preliminary Report

Lisa A Jackson, Evan J Anderson, Nadine G Rouphael … (2020)

Abstract Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The candidate vaccine mRNA-1273 encodes the stabilized prefusion SARS-CoV-2 spike protein. Methods We conducted a phase 1, dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 μg, 100 μg, or 250 μg. There were 15 participants in each dose group. Results After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti–S-2P antibody geometric mean titer [GMT], 40,227 in the 25-μg group, 109,209 in the 100-μg group, and 213,526 in the 250-μg group). After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719, and 1,192,154, respectively). After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events. Conclusions The mRNA-1273 vaccine induced anti–SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 ClinicalTrials.gov number, NCT04283461).

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Author and article information

Contributors

Mohd Wasim Nasser:

ORCID: http://orcid.org/0000-0003-2070-4972

wasim.nasser@unmc.edu

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol Cancer

Title: Molecular Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-4598

Publication date (Electronic): 19 March 2021

Publication date PMC-release: 19 March 2021

Publication date Collection: 2021

Volume: 20

Electronic Location Identifier: 54

Affiliations

[1 ]GRID grid.266813.8, ISNI 0000 0001 0666 4105, Department of Biochemistry and Molecular Biology, , University of Nebraska Medical Center, ; Omaha, NE-68198 USA

[2 ]GRID grid.266813.8, ISNI 0000 0001 0666 4105, Fred & Pamela Buffett Cancer Center, , University of Nebraska Medical Center, ; Omaha, NE-68198 USA

[3 ]GRID grid.478099.b, ISNI 0000 0004 0420 0296, Division of Oncology-Hematology, Department of Internal Medicine, , VA-Nebraska Western Iowa Health Care System, ; Omaha, NE 68105 USA

[4 ]GRID grid.266813.8, ISNI 0000 0001 0666 4105, Division of Oncology-Hematology, Department of Internal Medicine, , University of Nebraska Medical Center, ; Omaha, NE 68198 USA

[5 ]GRID grid.410425.6, ISNI 0000 0004 0421 8357, Department of Medical Oncology and Therapeutics Research, , City of Hope Comprehensive Cancer Center and Beckman Research Institute, ; Duarte, CA 91010 USA

[6 ]GRID grid.266813.8, ISNI 0000 0001 0666 4105, Eppley Institute for Research in Cancer and Allied Diseases, , University of Nebraska Medical Center, ; Omaha, NE-68198 USA

Author information

Mohd Wasim Nasser http://orcid.org/0000-0003-2070-4972

Article

Publisher ID: 1338

DOI: 10.1186/s12943-021-01338-2

PMC ID: 7977189

PubMed ID: 33740988

SO-VID: 33e07a00-41ab-4a63-9871-51f3391eedc0

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 29 December 2020

Date accepted : 23 February 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;

Award ID: R01CA218545

Award ID: R01CA247471

Award ID: R01CA195586

Award ID: P01 CA217798

Award ID: P30CA033572

Award ID: U54CA209978

Award ID: R01CA247471

Award ID: R01CA218545

Award ID: R01CA241752

Award Recipient : Ravi Salgia Maneesh Jain Surinder Kumar Batra

Funded by: FundRef http://dx.doi.org/10.13039/100000738, U.S. Department of Veterans Affairs;

Award ID: I01 BX004676

Award Recipient : Apar Kishor Ganti

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: lung cancer,rna interference,antisense oligonucleotides,anti-mirs,mrna-vaccine

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: lung cancer, rna interference, antisense oligonucleotides, anti-mirs, mrna-vaccine

RNA-based therapies: A cog in the wheel of lung cancer defense

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Karger: Oncology

Most cited references 266

Cancer statistics, 2020

Cancer statistics, 2019

An mRNA Vaccine against SARS-CoV-2 — Preliminary Report

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