Preclinical Development of Therapeutics in Murine Models of Lung Cancer

Division Of Basic Sciences - Nci

Investigators

Abstract

Lung cancer represents the most frequent form of malignancy comprising more than one-quarter of all cancer clinical cased worldwide, while concomitantly representing one of few cancer types with steadily increasing occurrence. Non-small cell lung carcinomas (NSCLC) are proven to be challenging tumor type for clinical management with frequent re-occurrence of drug resistant cancer after initial surgery/therapy and prominent metastatic potential. In addition, through CAOR collaborative outreach program to support intramural CCR investigators, we have adopted or established in-house several GEM and PDX models for the small cell lung cancer (SCLC) malignancy and employed them in several clinically impactful projects under the guidance of CCR clinical investigators. We have successfully completed an intramural collaboration aimed at efficacy testing of several photosensitizing agents in RTK-driven lung cancer models. Delivering on the mission of supporting CCR intramural research aimed at mitigating clinical impacts from lung carcinogenesis, CAPR supported the lung cancer research of CCR clinical investigator Dr. Udayan Guha by establishing a collection of PDX models using patient samples from CCR clinical trial network in lung cancer patients. CAPR has completed several correlative co-clinical experiments to interrogate molecular basis of resistant disease and identify valid avenues to prevent and treat oligo-resistant recurrent lung malignancies. In collaboration with Dr. Guha's clinical program, CAPR lung cancer modelling experts launched a broad scale effort aimed at establishing and biobanking a PDX collection of lung cancer samples isolated from clinical patients relapsed on the third generation EGFR inhibitors (specifically, osimertinib). As the key objective for subsequent application of this collection, the tumor samples have been evaluated for expression of TTF-1, CK-7, and pMET biomarkers and two efficacy studies conducted with combination of osimertinib and a cMET inhibitor. Overall, six large scale preclinical efficacy experiments have been conducted to date to investigate combinatorial potency of cMet inhibitor and osimertinib, as well as to correlate the disease response in different PDX models with MET gene amplification status (MET amplification studies were concomitantly conducted on the same patient samples in Dr. Guha's lab) and resistance mechanists suggested that can be interrogated at the diagnostic stage to justify a choice of 3rd generation EGFRi combined with cMET inhibition. Another project, in which CAPR joined efforts with Dr. Azam Ghafoor's clinical laboratory, a Rb/p53/Myc-dependent models (known as RP and RPM models) for small cell lung cancer have been established and pAdCre-based viral induction conditions for these models optimized. Preliminary work has been completed in these interesting and capacious models to examine the effect of epigenetic modulation in PD-L1 immune checkpoint inhibitor locus expression and the functional potency of the antigen presentation machinery in these SCLC models. Two GEM models - one RP and one RPM - have been comprehensively characterized by MRI imaging modality and histopathologic markers specific for the infiltrating immune system to prepare a basis for subsequent tolerability and efficacy experimentations using combined checkpoint inhibition and targeted therapeutics. In collaboration with CCR clinical investigator Dr. Anish Tomas, CAPR preclinical lung modelling program established and characterized several PDX models for SCLC based on clinical biopsies collected in patients with platinum-sensitive vs. platinum-resistant tumors. These models have been assessed for expression pf SCLC-specific biomarkers that are predictive of clinical responses to ataxia telangiectasia and Rad related (ATR) and topoisomerase-1 combined inhibition, as well as other therapeutic combinations targeting replicative stress and cancer-selective transcription that are proposed to be an effective treatment option in relapsed SCLC patients who progressed after first-line therapeutic intervention. Together with in-depth evaluation of cell population subtypes in established PDX models to explore correlation between plasticity of SCLC cancer cell ensembles and response to therapeutic intervention, these data are being currently analyzed with a foresight of designing a series of most meaningful and informative preclinical efficacy studies using these models.