PAtient-derived Lung cancer Models Study (PALMS)

PAtient-derived Lung cancer Models Study (PALMS)

Project Duration: 2005-Present

MOHCCN Consortium: Princess Margaret Cancer Consortium

Investigators: Geoffrey Liu, Ming-Sound Tsao

Partners:

  • Princess Margaret Cancer Centre

Aim/goals:

The PALMS cohort totals 677 patient tumors that have been obtained to establish models across primary and metastatic resections, endobronchial biopsies, and imaging-guided biopsies. The models established comprise mostly of patient-derived xenograft (PDX) models, but more recently, also patient- derived organoid (PDO) models. A number of these models, their matched patient samples and profiling, have been utilized to study a breadth of areas involving lung cancer genomics, transcriptomics, proteomics, molecular pathways, clinical classification, prognosis, drug and resistance mechanisms, and cfDNA. The MOHCCN funded subset focusses to identify novel putative oncogenic mechanisms in driver- negative lung adenocarcinomas with matched PDX models for biomarker therapeutics discovery with aims to:

  1. Use genome-wide analysis platforms (whole genome sequencing (WGS) and RNA-sequencing (RNAseq)) to comprehensively and systematically characterize the individual patient tumors used to establish patient-derived models in PALMS.
  2. Utilize Aim 1 data to elucidate the molecular mechanisms and critical pathways that underlie the biology of individual tumors. Bioinformatic and statistical algorithms are used to define clinico- molecular signatures/classifiers to distinguish patients whose associated patient-derived models developed when compared to patients whose models did not engraft/develop, as engraftment is a known indicator of biological aggressiveness and associated with poorer survival.
  3. Use Aim 1-2 data to test novel therapeutic strategies to improve biomarker-directed therapy outcomes, and model therapy resistance. Aims 1-2 will be applied in parallel to models to identify predictive and resistance biomarkers.

Summary:

In non-small cell lung cancer (NSCLC), mainly in adenocarcinomas the most common tumor genomic drivers are mutant KRAS (25%), mutant EGFR (20%) and rearranged ALK (4%). Effective targeted therapies are available for patients with EGFR or ALK altered tumors. A therapeutic option targeting KRAS G12C has recently become available in 2021, that account for approximately 13% of mutations in NSCLC. The remaining majority of adenocarcinomas are KRAS/EGFR/ALK driver-negative where the treatment is limited to systemic chemotherapy that has been associated with poor patient outcome.

There is an unmet need for more effective therapies in driver-negative tumors. The most comprehensive characterization of the genome (WGS/RNAseq) will be completed (as part of the MOHCCN study) on a set of driver-negative adenocarcinomas. Identification of novel putative driver mechanisms from these tumors then could be studied on the paired patient-derived tumor xenograft (PDX) models. These PDXs are state of the art tumor models that reflect the molecular, phenotypes and drug response complexities of their patient tumors, and could accelerate the biomarker and drug discovery processes.

PALMS has been highly successful through past Ontario Research Fund (ORF-RE), Premier Summit Award, multiple CIHR and CCSRI awards, and philanthropic funding to support model development and subsequent genomic and functional analyses of patient and their patient-derived models.

Representative publications include: (i) Organoid cultures as NSCLC preclinical models (Clin Cancer Res; PMID: 31694835); (ii) Integrative PDX pharmacogenomics analysis (Cancer Res; 31142512); (iii) Somatic alteration burden involving non-cancer genes predicts prognosis in early-stage NSCLC (Cancers (Basel); 31330989); (iv) Molecular heterogeneity of NSCLC PDXs closely reflect their primary tumors (Int J Cancer; 27750381); (v) CHCHD2 is co-amplified with EGFR in NSCLC and regulates mitochondrial function and cell migration (Mol Cancer Res; 25784717); (vi) Synergy of WEE1 and mTOR inhibition in mutant KRAS-driven NSCLC (Clin Cancer Res; 28821559); (vii) PDXs of human lung adeno and squamous cell carcinoma express distinct proteomic signatures (J Proteome Res; 20815376); (viii) Cetuximab inhibits T790M-mediated resistance to EGFR tyrosine kinase inhibitor in a lung adeno PDX (Clin Lung Cancer; 26926157); (ix) Clinical utility of PDXs to determine biomarkers of prognosis and map resistance pathways in EGFR-mutant lung adenocarcinoma (J Clin Oncol; 26124487); (x) BRAF V600E mutation and MET amplification as resistance pathways of the second-generation ALK inhibitor in lung cancer (Lung Cancer; 32521388); (xi) EGFR-mutated lung adenocarcinomas from patients who progressed on EGFR- inhibitors show high engraftment rates in PDXs (Lung Cancer, 32447118); and (xii) Early detection of multiple resistance mechanisms by ctDNA profiling in a patient with EGFR-mutant lung adenocarcinoma treated with osimertinib (Clin Lung Cancer; 32389504).