Cancer Cell Article Demonstrates First Definitive Evidence For Targeting of Pol I As New Approach To Cancer Therapy
San Diego/PRNewswire via COMTEX/ -- Cylene Pharmaceuticals today announced that research collaborators at the Peter MacCallum Cancer Centre (Peter Mac) in Melbourne, Australia have established, for the first time, that RNA Polymerase I (Pol I) activity is essential for cancer cell survival and that its inhibition selectively activates p53 to kill tumors. Published today in Cancer Cell, the findings show that Cylene's Pol I inhibitor, CX-5461, selectively destroys cancer by activating p53 in malignant but not in normal cells.
The researchers repeated these studies with in vivo models of blood cancers and demonstrated that the drug removed malignant cells from the bloodstream, while allowing normal healthy blood cells to grow, thus differentiating CX-5461 from genotoxic treatments. Targeting cancer's dependence upon Pol I to trigger cancer-specific activation of p53 signifies an entirely new approach to cancer therapy.
"The Pol I program represents the total package. Dr. Ross Hannan, Associate Professor and Group Leader at Peter Mac's Growth Regulation Laboratory, performed elegant studies to validate Pol I as a cancer target, Cylene created CX-5461 as the first selective small molecule inhibitor of Pol I, and together we showed that this approach potently kills malignant cells through activation of p53," stated William G. Rice, PhD, President and CEO of Cylene Pharmaceuticals. "Building on our mechanistic understanding of CX-5461, we have identified specific genetic markers to select patient populations with the most sensitive solid tumor or hematological cancers."
"The combination of cancer's reliance on Pol I, the impressive preclinical activity of CX-5461, the development of clear predictive and prognostic biomarkers and the novelty of the therapeutic strategy is compelling," continued Dr. Rice. "As such, a First-in-Human clinical trial with CX-5461 is planned in collaboration with our colleagues at Peter Mac later this year."
The Cancer Cell publication highlighted a number of potential competitive advantages of CX-5461. An unanticipated finding was that malignant cells are considerably more dependent upon maintenance of high levels of Pol I activity than previously believed, and even modest inhibition of Pol I triggers cancer cell death. These results suggest that selective activation of a surveillance pathway to activate p53, using Pol I inhibitors such as CX-5641, is likely to be therapeutically useful in the treatment of a wide range of tumors. In addition, as a cancer-specific inducer of p53, CX-5461 was shown to be 300 times more potent than currently studied non-genotoxic p53 activators with alternate mechanisms.
About Pol I and CX-5461CX-5461 is a first-in-class, selective small molecule inhibitor of RNA polymerase I (Pol I) that triggers a stress surveillance pathway to activate p53 in cancer cells. The tumor suppressor protein p53, known as "the guardian of the genome," orchestrates cellular responses to diverse stress factors. Activation of this protein can lead to cell cycle arrest or cell death and it is pivotal in determining whether cancer cells proliferate or die. CX-5461 inhibits upregulated Pol I transcription in cancer cells, causing the release of ribosomal proteins (RP) from the nucleolus. These RP then bind to Mdm2, liberating p53 from the Mdm2-p53 complex to induce apoptosis in cancer cells. Non-genotoxic activation of p53 has long been an attractive approach to treating cancers, but it has not yet been successfully exploited in the clinic. CX-5461 has therapeutic potential in both solid tumor and hematological malignancies, yet hematologic cancers, the vast majority of which have wild-type p53 status, are exquisitely sensitive to CX-5461 and represent the clearest path to clinical proof of concept.
About Cylene PharmaceuticalsCylene Pharmaceuticals is a clinical stage private company developing small molecule drugs against newly validated targets in essential cancer pathways. Cylene's leadership in exploiting CK2 pathways enables rational drug combinations for improved treatment outcomes against many cancer indications. The Company's Pol I program provides a non-genotoxic mechanism for activating p53 to kill cancer cells. Cylene's unique approaches deliver innovative cancer agents that can enable pharmaceutical companies to expand their portfolios and extend the efficacy, lifecycle and reach of current cancer therapeutics. For more information on Cylene and its programs, please visit www.cylenepharma.com .
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SOURCE Cylene Pharmaceuticals, Inc.
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