PathMAP NSCLC: A functional companion diagnostic test to predict optimal therapy for patients with non-small cell lung cancer.

DESCRIPTION provided by applicant Lung cancer LC is the leading cause of cancer death in the US with an estimated deaths in Non small cell LC is the predominant category of the disease NSCLC Molecular characterization of tumors has shifted the paradigm of one drug fits all Currently molecularly targeted agents MTAs and companion diagnostics CDx are being developed to target oncogenic drivers in signaling pathways and select patients most likely to respond respectively This personalized approach was successful in increasing response rates RR to erlotinib by enriching for patients with EGFR activating mutations RR versus in unselected patients Unfortunately within a year for most patients emergence of resistance mechanisms results in disease progression with little insight into appropriate follow up therapy In addition many patients have no clinicaly actionable biomarkers and are considered poor candidates for MTAs However many of these individuals can benefit from MTAs Five year survival rates are only in patients with distant metastatic disease when the disease is typically diagnosed Therefore there is an urgent medical need for improved predictive tests Here we propose to develop PathMAP r NSCLC an innovative CDx test to predict the optimal therapeutic approach for patients with advanced NSCLC This will be achieved by comparing the pharmacodynamic responses of signal transduction pathways upon exposure to four MTAs erlotinib crizotinib trametinib and sorafenib which target aberrantly activated proteins in these pathways PathMAP NSCLC will be commerciality enabled using the SnapPath r Cancer Diagnostics System the first and only user friendly clinic ready method which automates and standardizes the interrogation of a patientandapos s live tumor cells Phase I Segment Specific Aim Optimize dispersion of NSCLC biopsies on the SnapPath instrument to prepare live cells for ex vivo modulation biopsies will be used to determine optimal SnapPath processing conditions Flow rates and total cycles will be varied to enable equal distribution to multiple testing chambers without perturbing signaling and cell death Specific Aim Evoke Functional Signaling Profiles in NSCLC clinical samples against erlotinib biopsies will be profiled using the SnapPath Process Milestones for transitioning to Phase II Effectively disperse and distribute clinical NSCLC biopsies on the SnapPath instrument Successfully generate functional profiles in andgt of the clinical samples Phase II Segment Specific Aim Optimize ex vivo conditions and response profile to predict sensitivity to MTAs NSCLC cell lines will be categorized into sensitive or resistant groups and functionally profiled to create the PathMAP NSCLC model Specific Aim Test predictive ex vivo cut off values using TumorGrafts and clinical NSCLC samples The PathMAP NSCLC model will be used to predict MTA efficacy in TumorGraft models and human clinical samples from patients with metastatic NSCLC These results are intended to be a proof of principle in humans PUBLIC HEALTH RELEVANCE Lung cancer is the leading cause of cancer related deaths worldwide and of all lung cancers are classified as NSCLC The overall goal of our proposal is to develop a companion diagnostic test to help clinicians predict the optimal therapeutic approach for patients with metastatic NSCLC The test will use an individualandapos s functional response to four highly prominent molecularly targeted agents MTAs