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Investigational Drug Treatments for Triple-Negative Breast Cancer

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Investigational Drug Treatments for Triple-Negative Breast Cancer Journal of Personalized Medicine Review Investigational Drug Treatments for Triple-Negative Breast Cancer Christos Damaskos 1,2,*,†, Nikolaos Garmpis 2,3,† , Anna Garmpi 4,†, Konstantinos Nikolettos 2, Panagiotis Sarantis 5 , Vasiliki E. Georgakopoulou 6 , Afroditi Nonni 7, Dimitrios Schizas 8 , Efstathios A. Antoniou 2,3, Michalis V. Karamouzis 5 , Nikos Nikolettos 9, Konstantinos Kontzoglou 2,3, Alexandros Patsouras 2, Errika Voutyritsa 2, Athanasios Syllaios 8, Evangelos Koustas 5, Nikolaos Trakas 10 and Dimitrios Dimitroulis 3 1 Renal Transplantation Unit, Laiko General Hospital, 11527 Athens, Greece 2 N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; [email protected] (N.G.); [email protected] (K.N.); [email protected] (E.A.A.); [email protected] (K.K.); [email protected] (A.P.); [email protected] (E.V.) 3 Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; [email protected] 4 First Department of Propedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; [email protected] 5 Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; [email protected] (P.S.); [email protected] (M.V.K.); [email protected] (E.K.) 6 Department of Pulmonology, Laiko General Hospital, 11527 Athens, Greece; [email protected] 7 Citation: Damaskos, C.; Garmpis, N.; First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; [email protected] Garmpi, A.; Nikolettos, K.; Sarantis, 8 First Department of Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University P.; Georgakopoulou, V.E.; Nonni, A.; of Athens, 11527 Athens, Greece; [email protected] (D.S.); [email protected] (A.S.) Schizas, D.; Antoniou, E.A.; 9 Obstetric-Gynecologic Clinic, Medical School, Democritus University of Thrace, Karamouzis, M.V.; et al. 68100 Alexandroupolis, Greece; [email protected] Investigational Drug Treatments for 10 Department of Biochemistry, Sismanogleio Hospital, 15126 Athens, Greece; [email protected] Triple-Negative Breast Cancer. J. Pers. * Correspondence: [email protected]; Tel.: +30-6948467790 Med. 2021, 11, 652. https:// † These Authors contributed equally to this study. doi.org/10.3390/jpm11070652 Abstract: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) and Academic Editor: Ramesh Narayanan accounts for 10–20% of cases. Due to the lack of expression of several receptors, hormone ther- apy is largely ineffective for treatment purposes. Nevertheless, TNBC often responds very well to Received: 23 May 2021 chemotherapy, which constitutes the most often recommended treatment. New beneficial targeted Accepted: 8 July 2021 therapies are important to be investigated in order to achieve enhanced outcomes in patients with Published: 10 July 2021 TNBC. This review will focus on recent therapeutic innovations for TNBC, focusing on various in- hibitors such as phosphoinositide 3-kinase (PI3K) pathway inhibitors, poly-ADP-ribosyl polymerase Publisher’s Note: MDPI stays neutral (PARP) inhibitors, aurora kinase inhibitors, histone deacetylase inhibitors (HDACIs), and immune with regard to jurisdictional claims in checkpoint inhibitors. published maps and institutional affil- iations. Keywords: novel therapeutic strategies; immunotherapy; targeted therapies; PI3kb/mTOR inhibitors; PARP inhibitors; histone deacetylase inhibitors Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. 1. Introduction This article is an open access article distributed under the terms and Breast cancer (BC) is considered the second most commonly occurring pathology conditions of the Creative Commons in the world [1]. BC is more frequently diagnosed in less developed and industrialized Attribution (CC BY) license (https:// countries, it also constitutes the second notable cause of mortality in Europe and the United creativecommons.org/licenses/by/ States after lung cancer [1,2]. Additionally, according to the American Cancer Society, about 4.0/). 12% of women in the USA are prone to develop BC during their lifetime [3–6]. J. Pers. Med. 2021, 11, 652. https://doi.org/10.3390/jpm11070652 https://www.mdpi.com/journal/jpm J.J. Pers. Pers. Med. Med. 20212021, ,1111, ,x 652 FOR PEER REVIEW 22 of of 26 27 TripleTriple-negative-negative breast breast cancer cancer (TNBC) (TNBC) is is a a less less common common type type of of BC. BC. About About 1 10–20%0–20% of of BCBCss are are TNBC. TNBC. TNBC TNBC consists consists of of cancer cancer cells, cells, which which either either do do not not express express estrogen estrogen and and progesteroneprogesterone receptors receptors or or produce produce the the protein protein named named HER2 HER2 (Figure (Figure 1). These1). These cancers cancers tend totend be more to be common more common in women in women younger younger than the than age the of 40, age who of 40, are who usually are usuallyAfricanAfrican Amer- icanAmerican [7]. [7]. A B ER PR BC cell TNBC cell HER2 Figure 1. The lack of expression of receptors in triple-negative breast cancer. (A): Most breast cancer Figure 1. The lack of expression of receptors in triple-negative breast cancer. (A): Most breast cancer cellscells express express estrogen estrogen receptor, receptor, progesterone progesterone receptor receptor and and human human epidermal epidermal growth growth factor factor receptor receptor 2.2. (B (B):): Triple Triple-negative-negative breast breast cancer cancer lacks lacks the the expression expression of of these these receptors. receptors. BC: BC: Breast Breast cancer; cancer; ER: ER: EstrogenEstrogen receptor; receptor; PR: PR: Progesterone Progesterone receptor; receptor; HER2: HER2: Human Human epidermal epidermal growth growth factor factor receptor receptor 2; 2; TNBC:TNBC: Triple Triple-negative-negative breast breast cancer. cancer. RiskRisk factors factors for for TNBC, areare notnot clear.clear. Human Human genes genes BRCA1 BRCA1 and and BRCA2 BRCA2 produce produce tumor tu- morsuppressor suppressor proteins. proteins. These These proteins proteins participate participate in damaged in damaged DNA repairing DNA repairing and, therefore, and, therefore,play a crucial play role a crucial in ensuring role in the ensuring stability the of stability each cell’s of geneticeach cell’s material. genetic Since material. these Since genes thareese mutated, genes are DNA mutated, damage DNA may damage not be repaired may not properly. be repaired As aproperly. result, cells As area result, more likelycells areto developmore likely additional to develop genetic additional alterations, genetic which alterations, may lead which to cancer. may Suchlead to gene cancer. mutations Such geneare the mutations inherited are mutations the inherited in BRCA1 mutations and BRCA2in BRCA1 genes, and which BRCA2 are genes, reported which to increase are re- potherted risk to of increase female the TNBC risk [ 8of,9 ].female TNBC [8,9]. TreatmentTreatment for for TNBC TNBC depends depends on on different different factors, factors, such such as as the the stage stage and and the the grade grade of of thethe cancer. cancer. It It is is usually usually a a combination combination of of surgery, surgery, radiotherapy radiotherapy and and chemotherapy. chemotherapy. Unlike Unlike most other types of BC, TNBC does not express estrogen, progesterone and HER2 receptors. most other types of BC, TNBC does not express estrogen, progesterone and HER2 recep- Therefore, hormone therapy is largely ineffective for treatment purposes. Nevertheless, tors. Therefore, hormone therapy is largely ineffective for treatment purposes. Neverthe- TNBC often responds very well to chemotherapy [10–12]. However, chemotherapy can less, TNBC often responds very well to chemotherapy [10–12]. However, chemotherapy cause various serious adverse effects such as cardiotoxicity, myelosuppression, alopecia can cause various serious adverse effects such as cardiotoxicity, myelosuppression, alo- and gastrointestinal problems [13]. Neutropenia and neutropenic fiber can be fatal for the pecia and gastrointestinal problems [13]. Neutropenia and neutropenic fiber can be fatal patients [14]. Except for toxicity, drug resistance to chemotherapy is another major problem. for the patients [14]. Except for toxicity, drug resistance to chemotherapy is another major MicroRna-based therapies have been also examined in animal models with BC, but more problem. MicroRna-based therapies have been also examined in animal models with BC, research needs to be done [15]. Thus, it is of paramount importance to create new drugs, but more research needs to be done [15]. Thus, it is of paramount importance to create personalized to the type of cancer and the needs of the patient, in order to increase efficacy new drugs, personalized to the type of cancer and the needs of the patient, in order to and reduce toxicity. increase efficacy and reduce toxicity. Major effort has been devoted by researchers in order to classify TNBC. Technology hasMajor facilitated effort researchers has been devoted to analyze by researchers numerous datain order to compareto classify different
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