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Ovary cancer eludes immunity? Chemical databases will show a natural way to hinge with

Due to the development of resistance to chemotherapy and recurring tumors, patients with ovarian cancer often have low survival rates. Even the immunotherapy, sometimes, is not deveoided of insuccesses; therefore, new therapeutic options such as targeted therapy that boosts antitumor immunity are needed to improve treatment efficacy and patient survival. In a research published a couple of days ago in the journal Cancer Immunology Research, scientists of the Wistar Institute led by Dr. Rugang Zhang, PhD, discovered that inhibiting the nuclear protein KDM5A boosts a person’s immune response to tumors. KDM5A, also referred to as JARID1A, is a transcriptional repressor belonging to the class of Jumonji-C demethylases (JmjC-KDMs). KDMs consist of 20 demethylases which can be classified into 6 subfamilies. Among them, KDM5 subfamily including four highly related histone enzymes KDM5A to KDM5D can remove di- and tri-methylation marks from histone and be involved, for example, in differentiation and oncogenesis of hematopoietic stem cells.

KDM5A is linked with multiple human cancer types, including tumors of the breast, lung, prostate, and stomach. KDM5A is an oncogene that is often amplified in epithelial ovarian cancer and is known to repress multiple genes that are involved in tumor suppression. Overexpression of KDM5A promotes the migration, angiogenesis, and drug resistance of tumors. As a cancer-promoting gene, KDM5A also are reported demethylase-dependently inhibits tumor suppressor genes such as p27 and p16, and thus impairs proliferation of cancer cells via inducing cell arrest and senescence. Previous studies have shown that KDM5A increased breast cancer cell proliferation, while its knockdown induced apoptotic cell death. Unfortunately, due to the high similarity of among KDM5A, KDM4s and other members of KDM5 family, only few KDM5A inhibitors have been identified to date with most of them lacking selectivity for KDM5A. But KDM5a is not present only in cancer cells: immune cells use KDMs to regulate their own stability and immune program.

In this study, the scientists reveal the mechanism underpinning how KDM5A regulates immune cell infiltration and attack of tumors – by inhibiting genes involved in the antigen processing and presentation pathway. This biological pathway recognizes tumor cells and activates the immune system to invade and ultimately kill them. In vitro, the team found that genes involved in the antigen presentation pathway were indeed upregulated when they knocked out KDM5A and saw the same results when they used a KDM5A specific inhibitor. THis substance, called CPI-455, was originally discovere in 2018 and scientist published the discovery in 2019. By screening the ZINC chemical database, they dfound several compounds with promising possible ability to interact with KDM5a. Surprisingly, the top compound was derived form a natural compound, umbelliferone, represented in plants used in the folk medicine to treat blood coagulation disorders, and it is naturally present in essential oils of foods like carrot, fennel and coriander.

Attached to this coumarin skeleton, there is a O-lactyl-glycil-glycil sidechain that is the active moiety of the substance, which works by serving as a screen between the methylated histone and the active site of KDM5A. For in vivo studies using mice and mouse ovarian cancer cells, the Wister scientists validated the in vitro results. KDM5A inhibition reduced tumor burden and improved survival of the tumor-bearing mouse model. In the in vivo experiments, also, they saw an increase in the presence of CD8+ lymphocytes which are the effector killing cells of the immune system. Additionally, more of these cells were activated, which means they were able to act against tumors in mice. Scientists deem that these data demonstrate how KDM5A specific inhibitors may provide a novel therapeutic strategy to boost immune responses against certain cancers.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Liu H et al. Cancer Immunol Res 2022 Jun 21:OF1-OF11.

Yang GJ et al. Eur J Med Chem. 2021 Dec; 226:113855.

Yang GJ et al. J Hematol Oncol. 2021 Feb 17; 14(1):30.

Yang GJ et al. Cancers (Basel) 2019 Jan 15; 11(1):92.

Liang J et al. Bioorg Med Chem Lett. 2016; 26:4036–41.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica e salute sui siti web salutesicilia.com, medicomunicare.it e in lingua inglese sul sito www.medicomunicare.com
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