GENETAG TECHNOLOGY, INC — Department of Health and Human Services SBIR Phase I: 102

Description

DESCRIPTION provided by applicant Cancer is one of the leading causes of death worldwide and lung carcinoma is the leading cause of cancer related death Lung cancer is classified histologically as either small cell lung carcinoma SCLC of lung cancers or non small cell lung carcinoma NSCLC of lung cancers Genetic alterations driving NSCLC are known in only of cases and are mainly attributable to mutually exclusive mutations in the KRAS EGFR ALK HER BRAF PI KCA MET AKT or MAP K genes Clinical trials have shown that targeted therapy using tyrosine kinase inhibitors TKIs against mutant EGFR or ALK proteins is superior to traditional chemotherapy which non selectively kills rapidly dividing cells These findings highlight the value of designing effective inhibitors of other drivers of NSCLC the discovery of other driver mutations and the development of companion diagnostics Chromosomal rearrangements in the ROS ALK and RET gene account for of NSCLC cases equating to new annual cases of NSCLC worldwide Constitutive activation of the ROS tyrosine kinase domain is inhibitable by the FDA approved ALK inhibitor crizotinib which has shown efficacy in clinical trials with patients with ROS rearranged NSCLC As a consequence of targeted therapy however secondary drug resistance mutations in ROS and ALK have arisen in patients no longer responding to therapy Some but not all secondary mutations in ROS or ALK can be overcome with alternative TKIs such as cabozantinib foretinib or ceritinib Thus knowing the status of ROS ALK or RET mutations can inform both first and second line therapy GeneTAG Technology Inc specializes in developing DNA Detection Switch DDS probe systems for real time PCR that use labeled probes and competitive quencher labeled antiprobes Our novel probe systems offer unparalleled single based discrimination iDDS probes error checking amplification ZIPR probes or cost effective multi target screening with generic components Universal probes The Specific Aims of this Phase I application are to develop a two stage screening assay for ROS ALK and RET gene fusions and to develop iDDS probe endpoint detection assays against drug resistance mutations in ROS and ALK Performing endpoint analysis of amplified targets increases the diagnostic yield obtainable from small samples such as fine needle aspirates Experiments will be performed with synthetic DNA ultramers cDNA from cells overexpressing the fusion templates and deidentified blinded FFPE tissue sections from NSCLC patients from collaborators at Emory Hospital and Akesogen Successful completion of this proposal will justify subsequent Phase II validation studies in preparation for filing for FDA approval Currently no FDA approved diagnostics assays are available to detect ROS or RET rearrangements or drug resistance mutations in ROS or ALK Thus the proposed studies address an important unmet need in patient care PUBLIC HEALTH RELEVANCE Cancer is a leading cause of mortality worldwide and lung cancer is the most common cause of cancer related death with non small cell lung cancer NSCLC accounting for of lung cancers Insights into the oncogenic mechanisms of NSCLC have provided an opportunity for inhibiting the functions of specific mutant genes driving the cancer The primary objectives of this Phase I application are to develop tests to selectively detect ROS ALK and RET gene fusions as well as secondary drug resistance mutations occurring in ROS and ALK These assays will be based on novel probe systems we have developed that are highly suited for detecting such gene fusions and secondary mutations The planned screening assay will detect different ROS ALK and RET fusion products that are lung cancer specific These gene fusions are observed in up to of NSCLC cases Data generated from this study will serve as the foundation for Phase II assay validation studies and a follow on application with the FDA for approval of a mutant ROS ALK and RET diagnostic assay The availability of such an FDA approved test to physicians will facilitate therapy that is tailored to patients harboring these specific rearrangements and will expedite drug management and drug discovery based on using this test