On April 2, 2017 Cyclacel Pharmaceuticals, Inc. (NASDAQ:CYCC) (NASDAQ:CYCCP) ("Cyclacel" or the "Company"), reported the presentation by independent investigators of preclinical data demonstrating therapeutic potential of CYC065, the Company’s second-generation, cyclin-dependent kinase (CDK) 2/9 inhibitor, as a targeted anti-cancer agent (Press release, Cyclacel, APR 2, 2017, View Source [SID1234518375]). The data show that CYC065 substantially inhibited growth, triggered apoptosis, and induced anaphase catastrophe in murine and human lung cancer cells with known high metastatic potential. This was in marked contrast to effects in immortalized pulmonary epithelial murine and human cells. CYC065 markedly inhibited migration and invasion of lung cancer cells and affected distinctive pathways involved in DNA damage response, apoptosis, cell cycle regulation and cell migration. The data were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2017, April 1 – 5, 2017, in Washington, D.C. Schedule your 30 min Free 1stOncology Demo! "This study adds to the growing evidence of the value of CDK inhibition as an approach to treating cancer," said Spiro Rombotis, President and Chief Executive Officer of Cyclacel. "CYC065 is in a Phase 1, first-in-human trial to evaluate safety, tolerability and pharmacokinetics in patients with solid tumors. The trial is at an expanded sixth dose escalation level with the objective of determining maximum tolerated dose and recommended dosing for Phase 2. Evidence of target engagement with prolonged Mcl-1 suppression in peripheral blood cells has been observed in patient samples from the study. We believe that CYC065 is one of the first medicines to demonstrate this in a human trial and look forward to pursuing this lead as part of our transcription regulation program."
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In the preclinical study, a group of researchers led by Professor Ethan Dmitrovsky, M.D., including Masanori Kawakami M.D., Ph.D., from The University of Texas MD Anderson Cancer Center, Houston, Texas, explored whether CYC065’s antineoplastic effects engaged anti-metastatic pathways. In vitro migration and invasion assays showed that CYC065 markedly inhibited migration and invasion of lung cancer cell lines, including KRAS mutant line. Reverse Phase Protein Arrays (RPPA) interrogated nearly 300 growth-regulatory proteins in murine and human lung cancer.
CYC065 treatment resulted in up-regulation of proteins involved in DNA damage and apoptosis, and down-regulation of ones involved in mTOR- and integrin pathways. Ingenuity pathway analysis (IPA) revealed up-regulation of pathways that engaged ATM signaling, G2/M DNA damage checkpoint regulation, or apoptosis signaling, down-regulation of pathways involved in mTOR signaling, cell cycle regulation, or integrin—mediated cell migration.
Data presented at AACR (Free AACR Whitepaper) show CYC065’s potential to cause anaphase catastrophe and to inhibit migration and invasion of lung cancer cells including the one with mutant KRAS. Anaphase catastrophe is a novel mechanism of action which offers an innovative approach to combat aneuploid cancer cells containing abnormal numbers of chromosomes. The data highlight CYC065’s potential to target key molecular features of cancers.
The study concluded that CYC065 elicits marked antineoplastic effects in lung cancers despite presence of KRAS mutations through anaphase catastrophe and also inhibited migration and invasion of lung cancer cells.
Abstract: 128
Title: The next generation CDK2/9 inhibitor CYC065 elicits marked antineoplastic effects in lung cancer by engaging anti-metastatic pathways
Date/time: Sunday, April 2, 2017 1:00 — 5:00 p.m. ET
Location: Section 5, Poster Board 24
Session Title:
Novel Agents
Authors: Masanori Kawakami1, Jason Roszik2,3, Lin Zheng1, Jonathan Kurie1, Lisa Maria Mustachio1, Xi Liu1, Ethan Dmitrovsky1 1. Department of Thoracic/Head and Neck Medical Oncology, 2. Genomic Medicine, 3.Cancer Biology; The University of Texas MD Anderson Cancer Center, Houston, Texas.
The abstract can be accessed through the AACR (Free AACR Whitepaper) website, www.aacr.org.
About CYC065
Cyclacel’s second generation CDK2/9 inhibitor, CYC065, is being evaluated in an ongoing, first-in-human, Phase 1 trial in patients with advanced solid tumors. In addition to determining safety and recommended dosing for Phase 2, the study aims to investigate CYC065’s effects on the Mcl-1 biomarker, which is implicated in the evolution of resistance in cancer. Evidence of target engagement with prolonged Mcl-1 suppression in peripheral blood cells was observed in patient samples from the study, as well as decreases in kinase substrate phosphorylation and increases in PARP cleavage, consistently with the Company’s preclinical data. CYC065 is mechanistically similar but has much higher dose potency, in vitro and in vivo, and improved metabolic stability than seliciclib, Cyclacel’s first generation CDK inhibitor. Similar to palbociclib, the first CDK inhibitor approved by FDA in 2015, CYC065 may be most useful as a therapy for patients with both liquid and solid tumors in combination with other anticancer agents, including Bcl-2 antagonists, such as venetoclax, or HER2 inhibitors, such as trastuzumab.