Advances in epigenetic therapeutics with focus on solid tumors

AbstractEpigenetic (“above genetics”) modifications can alter the gene expression without altering the DNA sequence. Aberrant epigenetic regulations in cancer include DNA methylation, histone methylation, histone acetylation, non-coding RNA, and mRNA methylation. Epigenetic-targeted agents have demonstrated clinical activities in hematological malignancies and therapeutic potential in solid tumors. In this review, we describe mechanisms of various epigenetic modifications, discuss the Food and Drug Administration-approved epigenetic agents, and focus on the current clinical investigations of novel epigenetic monotherapies and combination therapies in solid tumors.

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Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-019-0095-0 ◽

2019 ◽

Vol 4 (1) ◽

Cited By ~ 71

Author(s):

Yuan Cheng ◽

Cai He ◽

Manni Wang ◽

Xuelei Ma ◽

Fei Mo ◽

...

Keyword(s):

Dna Methylation ◽

Clinical Trials ◽

Targeted Therapy ◽

Cancer Therapy ◽

Histone Methylation ◽

Hematological Malignancies ◽

Therapeutic Potential ◽

Dna Modifications ◽

Epigenetic Regulators ◽

Regulate Gene

AbstractEpigenetic alternations concern heritable yet reversible changes in histone or DNA modifications that regulate gene activity beyond the underlying sequence. Epigenetic dysregulation is often linked to human disease, notably cancer. With the development of various drugs targeting epigenetic regulators, epigenetic-targeted therapy has been applied in the treatment of hematological malignancies and has exhibited viable therapeutic potential for solid tumors in preclinical and clinical trials. In this review, we summarize the aberrant functions of enzymes in DNA methylation, histone acetylation and histone methylation during tumor progression and highlight the development of inhibitors of or drugs targeted at epigenetic enzymes.

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CAR-NK Cells in the Treatment of Solid Tumors

International Journal of Molecular Sciences ◽

10.3390/ijms22115899 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5899

Author(s):

Ewa Wrona ◽

Maciej Borowiec ◽

Piotr Potemski

Keyword(s):

Nk Cells ◽

Solid Tumors ◽

Hematological Malignancies ◽

Toxicity Profile ◽

Multiple Sources ◽

Eligibility Criteria ◽

Hematological Neoplasms ◽

Current State ◽

Car T ◽

The Cost

CAR-T (chimeric antigen receptor T) cells have emerged as a milestone in the treatment of patients with refractory B-cell neoplasms. However, despite having unprecedented efficacy against hematological malignancies, the treatment is far from flawless. Its greatest drawbacks arise from a challenging and expensive production process, strict patient eligibility criteria and serious toxicity profile. One possible solution, supported by robust research, is the replacement of T lymphocytes with NK cells for CAR expression. NK cells seem to be an attractive vehicle for CAR expression as they can be derived from multiple sources and safely infused regardless of donor–patient matching, which greatly reduces the cost of the treatment. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have activity against non-hematological neoplasms. Here, we present a thorough overview of the current state of knowledge regarding the use of CAR-NK cells in treating various solid tumors.

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Repurposing existing drugs for new uses: a cohort study of the frequency of FDA-granted new indication exclusivities since 1997

Journal of Pharmaceutical Policy and Practice ◽

10.1186/s40545-020-00282-8 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Babak Sahragardjoonegani ◽

Reed F. Beall ◽

Aaron S. Kesselheim ◽

Aidan Hollis

Keyword(s):

Therapeutic Potential ◽

Drug Repurposing ◽

Status Quo ◽

New Drugs ◽

Generic Entry ◽

Small Molecule Drugs ◽

Clinical Investigations ◽

Fda Approval ◽

Limited Duration ◽

Observation Period

Abstract Background Drug repurposing (i.e., finding novel uses for existing drugs) is essential for maximizing medicines’ therapeutic utility, but obtaining regulatory approval for new indications is costly. Policymakers have therefore created temporary indication-specific market exclusivities to incentivize drug innovators to run new clinical investigations. The effectiveness of these exclusivities is poorly understood. Objective To determine whether generic entry impacts the probability of new indication additions. Methods For a cohort of all new small-molecule drugs approved by the FDA between July 1997 and May 2020, we tracked new indications added for the subset of drugs that experienced generic entry during the observation period and then analyzed how the probability of a new indication changed with the number of years since/to generic entry. Results Of the 197 new drugs that subsequently experienced generic entry, only 64 (32%) had at least one new indication added. The probability of a new indication addition peaked above 4% between 7 and 8 years prior to generic entry and then to dropped to near zero 15 years after FDA approval. We show that the limited duration of exclusivity reduces the number of secondary indications significantly. Conclusion Status quo for most drug innovators is creating novel one-indication products. Despite indication-specific exclusivities, the imminence of generic entry still has a detectable impact on reducing the chances of new indication additions. There is much room for improvement when it comes to incentivizing clinical investigations for new uses and unlocking existing medicines’ full therapeutic potential.

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PD-L1 lncRNA splice isoform promotes lung adenocarcinoma progression via enhancing c-Myc activity

Genome Biology ◽

10.1186/s13059-021-02331-0 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Shuang Qu ◽

Zichen Jiao ◽

Geng Lu ◽

Bing Yao ◽

Ting Wang ◽

...

Keyword(s):

Alternative Splicing ◽

Lung Adenocarcinoma ◽

Solid Tumors ◽

Immune Checkpoint ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

Non Coding Rna ◽

Adenocarcinoma Cells ◽

Lung Adenocarcinoma Cells ◽

Long Non Coding Rna

Abstract Background Although using a blockade of programmed death-ligand 1 (PD-L1) to enhance T cell immune responses shows great promise in tumor immunotherapy, the immune-checkpoint inhibition strategy is limited for patients with solid tumors. The mechanism and efficacy of such immune-checkpoint inhibition strategies in solid tumors remains unclear. Results Employing qRT-PCR, Sanger sequencing, and RNA BaseScope analysis, we show that human lung adenocarcinoma (LUAD) all produce a long non-coding RNA isoform of PD-L1 (PD-L1-lnc) by alternative splicing, regardless if the tumor is positive or negative for the protein PD-L1. Similar to PD-L1 mRNA, PD-L1-lnc in various lung adenocarcinoma cells is significantly upregulated by IFNγ. Both in vitro and in vivo studies demonstrate that PD-L1-lnc increases proliferation and invasion but decreases apoptosis of lung adenocarcinoma cells. Mechanistically, PD-L1-lnc promotes lung adenocarcinoma progression through directly binding to c-Myc and enhancing c-Myc transcriptional activity. Conclusions In summary, the PD-L1 gene can generate a long non-coding RNA through alternative splicing to promote lung adenocarcinoma progression by enhancing c-Myc activity. Our results argue in favor of investigating PD-L1-lnc depletion in combination with PD-L1 blockade in lung cancer therapy.

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CAR T cell therapy in solid tumors: a short review

memo - Magazine of European Medical Oncology ◽

10.1007/s12254-021-00703-7 ◽

2021 ◽

Author(s):

Öykü Umut ◽

Adrian Gottschlich ◽

Stefan Endres ◽

Sebastian Kobold

Keyword(s):

T Cell ◽

Cell Therapy ◽

Solid Tumors ◽

Hematological Malignancies ◽

Short Review ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Solid Malignancies ◽

Car T

SummaryChimeric antigen receptor (CAR) T cell therapy has been established in the treatment of hematological malignancies. However, in solid tumors its efficacy remains limited. The aim of this article is to give an overview of the field of cell therapy itself, to introduce the underlying concepts of CAR T cell-based treatment approaches and to address its limitations in advancing the treatment for solid malignancies.

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