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Targeting Subgroup-specific Cancer Epitopes for Effective Treatment of Pediatric Medulloblastoma
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Sidharth Mahapatra, Naveenkumar Perumall
Aurora kinase A and B maintain genomic stability through their involvement in chromosome separation during mitosis [95]. Overexpression has been shown to lead to oncogenesis in multiple types of cancers, aside from medulloblastoma [96]. Aurora kinase A (AURKA) inhibition was shown to induce apoptosis in DAOY cells and to lead to a time-dependent G2/M phase arrest [97]. Moreover, AURKA inhibition reduced the IC„ of etoposide and cisplatin concurrently enhancing their cytotoxic effects in vitro [97]. Aurora kinase B (Aurora B) co-expression has been shown specifically in the high MYC-expressing group 3 tumors. Inhibition of Aurora B in MYC overexpressing cells not only reduced tumor cell proliferation but also sensitized them to apoptosis [98]. In MB xenograft models, Aurora B inhibition impaired cerebellar tumor growth and augmented survival [98].
Atypical Teratoid / Rhabdoid Tumors – AT/RT
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Michael C. Frühwald, Jaclyn A. Biegel, Susan N. Chi
Aurora kinase A (AURKA) is a member of a family of cell cycle-associated serine/threonine kinases and regulates centrosome maturation and mitosis.109 AURKA as a downstream target of SMARCB1 is overexpressed in rhabdoid tumors. Re-expression of SMARCB1 decreases the expression of AURKA by repression of promoter activity. Targeting AURKA in rhabdoid cell lines in vitro by siRNA or small molecular inhibitors induces cell death.110 As rhabdoid tumor xenografts demonstrated responses to a selective AURKA inhibitor, alisertib (MLN8237),111 and as preclinical data demonstrated that AURKA inhibition enhanced radiation sensitivity of rhabdoid cell lines, the compound has been evaluated in clinical trials. Alisertib is currently undergoing phase I and II clinical trial investigations for different tumor indications in adults and children, including AT/RT, resulting in noteworthy responses.
Hepatic tumors
Published in Prem Puri, Newborn Surgery, 2017
Benjamin A. Farber, William J. Hammond, Michael P. La Quaglia
Fibrolamellar HCC (FLHCC) is a rare primary liver tumor that typically presents in children and young adult patients with no background history of liver disease or hepatitis, and sporadic cases have been reported in infants.162 The tumor was first described in 195645 as a variant of conventional HCC, but is now recognized as a unique pathologic entity. Patients typically do not have viral hepatitis or cirrhosis, and do not exhibit elevations in serum AFP. Recent advances in the tumor biology of FLHCC show a 400-kb deletion in one copy of chromosome 19 in tumor samples producing a chimeric transcript between the first exon of the heat shock protein, DNAJB1, with all but the first exon of the catalytic subunit of protein kinase A, PRKACA.163 This chimera is a functional kinase, and few other changes are seen in the genomic DNA.164 Total surgical resection is paramount in treatment of FLHCC, and outcomes have been reported to be more favorable for FLHCC than conventional HCC. Lymph node metastases are common, and presence of extrahepatic disease is a consistent, independent predictor of overall and recurrence-free survival.165 Recent transcriptomic evaluation of FLHCC shows key oncologically relevant pathways to have elevated transcription levels, including EGF/ErbB and Wnt signaling pathways, which may lead to new avenues of treatment. Ongoing clinical trials are evaluating the use of an oral aurora kinase A inhibitor, the transcript of which was found to be elevated in FLHCC tumor samples (ClinicalTrials.gov identifier: NCT02234986).166
Aurora kinase inhibitors: a patent review (2014-2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Aurora kinase family includes three subtypes: named as Aurora A, B and C. They all possess a highly conserved C-terminal domain and an N-terminal domain but have differences in functionality [4]. In the cell cycle, Aurora A is responsible for mitotic entry, centrosome maturation, and separation, spindle assembly and spindle damage repair [5]. Aurora A is activated by ajuba at the beginning of the S phase and at G2/M transition its activity arrives at a peak to stimulate duplicated centrosomes to separate and initiate the mitotic entry [4]. Aurora A kinase activity depends on the phosphorylation status of a threonine residue (T288) located on the ‘activation loop’ of the enzyme. In prometaphase, Aurora A is targeted to microtubules by phosphorylating TPX2 to contribute to spindle assembly and bipolar spindle microtubule conformation [6]. In addition, Aurora A also has a variety of non-mitotic functions, such as DNA damage response (DDR) [7] and activation of epithelial–mesenchymal transition (EMT) reprograming [8]. Inhibition of Aurora A would result in uneven distribution of chromosomes to daughter cells and abnormal spindle structure, followed by aneuploidy [9].
Novel tyrosine-kinase inhibitors for the treatment of chronic myeloid leukemia: safety and efficacy
Published in Expert Review of Hematology, 2018
Fulvio Massaro, Gioia Colafigli, Matteo Molica, Massimo Breccia
Aurora kinase family has a main role in mitotic spindle formation and centrosome maturation. Danusertib, a pan-Aurora kinase inhibitor, has demonstrated activity also against ABL1 (IC50 = 25 nM) including T315I and other mutations. Particularly, this drug inhibits proliferation of CD34+ cells both from BP-CML patients with (IC50 = 25 nM) or without (IC50 = 9 nM) T315I mutation [18]. A phase I, dose escalation trial was conducted among 37 patients, 22 in advanced phase CML (7 in AP, 15 in BP) and 15 with Ph+ ALL. T315I mutation was detected in 54% of patients. Almost 90% of patients had developed resistance to one or more TKIs, 32% had received an alloSCT. Between evaluable patients, 20% of cases (4/20) achieved a result: a complete hematologic response (CHR) and a CCyR were reported in CML patients. Toxicity profile was characterized by grade 3–4 AEs such as febrile neutropenia (17.2%), diarrhea (14%), mucosal inflammation and stomatitis (7% each), hypotension, hyponatremia, AST increased, mental status changes (3.4%) and vomiting (3%) [19]. Despite an interesting profile of efficacy, the most limiting feature of danusertib is represented by its intravenous schedule of administration, consistent of 7 days of continuous treatment in a 14-day cycle.
Pre-clinical models of small cell lung cancer and the validation of therapeutic targets
Published in Expert Opinion on Therapeutic Targets, 2020
Jane S. Y. Sui, Petra Martin, Steven G. Gray
Of the several recurrent genetic aberrations identified in SCLC, the MYC family genes (MYC, MYCL, and MYCN) have emerged as oncogenic drivers that may constitute novel therapeutically tractable targets [104]. Using the pre-clinical models discussed above various studies have identified that alterations to the MYC family may render SCLC sensitive to either Aurora Kinase inhibitors [104,105], or to BET inhibitors [106–110] (Figure 1, Table 3). Subgroup analysis of c-MYC by IHC in archival tumor biopsies from a Phase II trial (NCT02038647) of the Aurora Kinase inhibitor Alisertib ± paclitaxel in SCLC suggests that tumors with high c-MYC expression may indeed be susceptible to this compound [111], but caution is indicated as the number of samples in this subgroup analysis was restricted to n = 33 and further studies are therefore warranted) (Table 3). In a more recent development, a Crispr-based approach in SCLC cell lines and xenografts has identified that loss of pRb in SCLC renders them hyperdependent on Aurora B kinase, and as such amenable to Aurora B kinase-specific inhibitors [112]. In the same issue, Buchanan and colleagues identified a synthetic lethal interaction with RB1 and Aurora Kinase A [113]. Identifying which patients will respond to Aurora Kinase inhibitors is therefore becoming increasingly important. In this regard, a proteomic-based approach of SCLC identified two major subgroups characterized as either high TTF-1/low cMYC, or low TTF-1/high cMYC. This low TTF-1/high cMYC subgroup was confirmed as being predictive of responsiveness to Aurora Kinase inhibitors [114] (Table 3).