On November 23, 2015 Cyclacel Pharmaceuticals, Inc. (Nasdaq:CYCC) (Nasdaq:CYCCP) ("Cyclacel" or the "Company"), reported the presentation of preclinical data demonstrating that CYC065, a highly-selective, second-generation cyclin dependent kinase (CDK) 2/9 inhibitor prolongs survival in MYCN-addicted neuroblastoma models (Press release, Cyclacel, NOV 23, 2015, View Source [SID:1234508320]). The in vitro and in vivo preclinical data will be presented at the 4th Neuroblastoma Symposium, November 26-27, 2015 in Newcastle Upon Tyne, United Kingdom.
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"MYC activates a major genetic pathway in cancer that is very difficult to target directly," said Spiro Rombotis, Cyclacel’s President and Chief Executive Officer. "CYC065 treatment of MYC-addicted neuroblastoma via CDK2/cyclin E inhibition offers a novel approach to target this critical cancer mechanism. Tumor regression or improved survival is seldom seen in animal models of cancers addicted to MYC proteins, such as MYCN. We are encouraged by the CYC065 data as they add to the growing evidence of the value of CDK inhibition as an innovative approach to treat cancer. Previous data demonstrated that CDK2/9 inhibitors target key molecular features of cancers with poor prognosis, such as cyclin E amplification/overexpression, MLL rearrangements and MYC-amplification/overexpression. We have recently initiated a first-in-human, Phase 1 trial of CYC065 in patients with advanced solid tumors."
The study evaluated the ability of two Cyclacel CDK2/9 inhibitors, CYC065 and CCT68127, to inhibit cell proliferation and induce apoptosis of neuroblastoma cells in vitro and in vivo. In vivo efficacy was evaluated in subcutaneous xenograft models of both MYCN-amplified and non-amplified neuroblastoma cells and the Th-MYCN genetically-engineered mouse model of neuroblastoma. The study showed that neuroblastoma cell lines with MYCN amplification and high MYCN expression levels were sensitive to both CDK2/9 inhibitors. CYC065 and CCT68127 depleted MYCN protein in a time- and dose-dependent manner, blocked neuroblastoma cell proliferation and induced apoptosis. Both CYC065 and CCT68127 resulted in significantly reduced tumor burdens and prolonged survival in MYCN-addicted neuroblastoma models in vivo.
Presentation details:
Presentation title: Orally available small molecule CDK inhibitors CYC065 and CCT68127 prolong survival in MYCN-addicted neuroblastoma models.
Authors: Poon E, Jamin Y, Hakkert A, Hallsworth A, Thway K, Barker K, Sbirkov Y, Pickard L, Urban Z, Almeida G, Tardif N, Webber H, Box G, Valenti M, De Haven Brandon A, Poudel P, Sadanandam A, Eccles S, Robinson SP, Zheleva D, Petrie K, Chesler L.
Location: 4th Neuroblastoma Society Symposium 2015, 26 — 27 November, Newcastle, UK
About MYCN
The MYCN gene encodes a transcription factor that is expressed in fetal brain and neural crest and is critical for normal development of brain and nerve. MYCN is over-expressed in a number of different types of cancer, most notably neuroblastoma, but also including rhabdomyosarcoma, medulloblastoma, astrocytoma, Wilms’ tumor, and small cell lung cancer. Amplification of the MYCN oncogene is the most common genomic alteration in aggressive neuroblastomas and is associated with poor clinical outcome. No drugs that directly target MYCN are available prompting the investigation of indirect approaches such as exploitation of a synthetic lethal relationship between MYCN amplification/overexpression and inhibition of CDK2.
About Neuroblastoma
According to the American Cancer Society, neuroblastoma is the most common cancer in infants less than one year old and it accounts for about six percent of all pediatric cancers or about 700 cases per year. The disease kills one in every seven children diagnosed with it. There are no approved treatments. The presented study demonstrated that CYC065 and CCT68127 target MYCN, and have potent in vitro and in vivo anti-tumor activities, suggesting therapeutic potential in neuroblastoma with amplification of MYCN oncogene.