Project: Development of Checkpoint Kinase 1 Inhibitors and Novel Diagnostics for the Treatment of Acute Myeloid Leukemia in Humans

The objective of this proposal is to develop a new small molecule drug therapy for the treatment of Acute Myeloid Leukaemia (AML). This treatment will be effective by a mechanism of action related to DNA repair and for which no current medicines are currently being developed._x000D__x000D_AML, the most frequent acute leukaemia in adults, is a heterogeneous group of diseases characterised by uncontrolled proliferation of clonal neoplastic hematopoietic precursor cells and impaired production of normal hematapoiesis. An estimated 12330 new cases of AML will occur in the United States in 2010 and 8950 deaths (Leukemia & Lymphoma Society). Approximately 50-75% of adults with AML achieve remission with the current standard of care; however, only 20-30% of these patients enjoy long term disease survival. Therefore, there is a significant requirement to improve treatment options for patients with AML. _x000D__x000D_The potential of drug molecules that inhibit DNA repair in cancer therapy is now well recognised and continues to evolve (Nat Rev Cancer 2008, 8, 193-204). Checkpoint kinase 1 (CHK1) belongs to a family of proteins known as kinases and performs a crucial role in sensing and responding to DNA damage (Clin Cancer Res 2008,14(13), 4032-4037). It is now known that AML has an unusual up regulation of the CHK1 enzyme due to the elevated levels of DNA damage seen in this disease. It has been shown that inhibition of CHK1 in these circumstances can be an effective treatment for the eradication of AML cell lines in vitro (Cancer Research 2009, 89, 8652)._x000D__x000D_An additional part of this collaborative proposal is focused on the development of more sensitive cellular and in vivo screening tools which will be used to not only aid in the drug development pathway but will also be developed into a companion diagnostic for clinical use thereby increasing the chances of complete remission and subsequent long term patient survival. It is further envisaged that measurement of TK activity in ex vivo clinical samples will predict the sub-population of AML patients most likely to respond to a CHK1 based therapy._x000D__x000D_The market for such a product is COly in the pharmaceutical and biotechnology sectors where, in the past five years, there has been an increasing trend to in-license pre-clinical drug candidate molecules to bolster existing clinical pipelines. The current trend in the sector is generating organisations ideally suited to in license such products as they are consolidating the more expensive areas of the industry such as late stage clinical development, clinical trials, manufacturing and sales & marketing._x000D__x000D_In addition, the development of new diagnostics for AML and cancer in general is seen as a "must have" by the US Food and Drug Administration (FDA) and companies with both a first in class drug and companion diagnostic are going to be well positioned to take advantage of the current in-licensing trend._x000D__x000D_Sentinel Oncology and Biovica will collaborate together in this project to achieve the above objectives with the commercial aims to license a drug / diagnostic product to the pharmaceutical and biotech sectors and in addition will also be able to offer new in vitro research tools as a spin-off product from the whole process. These multiple product offerings are seen by both organisations as an excellent risk mitigation strategy in the current international financial climate._x000D_

Acronym	SOLBIO (Reference Number: 6133)
Duration	03/01/2011 - 28/12/2012
Project Topic	The objective of this proposal is to develop a novel therapy and companion diagnostic for the treatment of AML. Specifically, we will discover a novel CHK1 inhibitor and a diagnostic based on a novel Thymidine kinase cell proliferation screening technology.
Project Results (after finalisation)	Sentinel ltd identified and characterized substances of interest for use as therapy to Acute Myleoid Leukemia (AML) and other cancers ._x000D__x000D_In accordance with the plan, the DiviTum assay was modified by Biovica International AB so that it is useful for the detection of TK­activity levels in cell extracts . Only slight modifications of the assay were necessary . With the modified assay, extracts of cells treated with drug candidate substances, provided by Sentinel, we re analyzed. The results were used in the evaluation of the potential use of the substances._x000D__x000D_Further, and also according to the plan, a more substantially modified and improved version of the DiviTum assay was developed, with the aim of obtaining a test that can easily be implemented on an automatic analysis system . By changes in the components and the assay procedure it is now possible to run the complete assay in one day, rather than three. Other improvements are an increased sample volume (20 µl rather than 1O µl), which reduces the systemic pipetting variation, and an assay temperature of 37 degrees centigrade rather than 32. The new version of the DiviTum assay w iii be validated in the summer/fall of 2013 and it is scheduled for market introduction in the fall/winter of 2013._x000D_
Network	Eurostars
Call	Eurostars Cut-Off 5

Project partner

Number	Name	Role	Country
2	Biovica International AB	Partner	Sweden
2	Sentinel Oncology Limited	Coordinator	United Kingdom