Seminar | Momeneh Foroutan & Simone Alexander

Mechanisms of Resistance to FOLFOX in Metastatic Colorectal Cancer Patients

DR MOMENEH FOROUTAN 
Research Fellow in Computational Cancer Biology, Tumour Heterogeneity in Metastatic Cancer
UMCCR and Department of Clinical Pathology

FOLFOX is one of the first-line chemotherapy regimens for the treatment of metastatic colorectal cancer (mCRC); however, many patients fail to respond and experience progression of disease. The molecular profiles of metastatic tumours and their association with drug sensitivity/resistance of metastatic tumour cells is largely unknown.

To better understand the molecular mechanisms underlying treatment resistance in CRC liver metastasis tumours, we Tumour Heterogeneity in Metastatic Cancer group generated patient-derived organoids and treated them by FOLFOX. The group profiled the organoids for their genomic (whole-genome or exome sequencing) and transcriptomic (RNA-seq) data under Vehicle or FOLFOX treated conditions.

Dr Faroutan will describe the molecular consistency between tumour and organoids, and compare the genomics and transcriptomics profiles of the sensitive and resistant groups at the level of genes, gene-sets and pathways. This work unravels potential molecular mechanisms underlying resistance to FOLFOX and introduces genes and pathways that could be targeted using available drugs to overcome resistance.

Preventing Cancer’s Coup D’état: New Tactics to Combat Therapy Résistance

SIMONE ALEXANDER
Master's student, Tumour Heterogeneity in Metastatic Cancer
UMCCR Department of Clinical Pathology

When small subsets of drug-resistant cancer cells escape the effect of drugs and chemotherapy, they can persist at the tumour site and eventually grow out to form relapsed disease. By marking a population of cancer cells with a number of unique and identifiable “barcodes” we can identify these drug resistant cell subpopulations and devise new strategies to combat their nefarious ways.

In a first-of-its-kind experiment, the Tumour Heterogeneity in Metastatic Cancer group performed a multi-kinase drug screen of over 430 compounds using genetically-barcoded liver-metastasis-derived colorectal cancer cells. Having observed different patterns of selection between different drugs, the group then investigated the potential for combining therapies with opposing selection patterns, to explore the potential utility of barcoding techniques during the rational design of combination therapies.

Finally, the group has developed a “Dual Barcoding” method of cell tracking, which is the duplexed application of both genetic and optical barcodes. Dual Barcoding allows us to elegantly combine the high-resolution cell tracing of the genetic barcodes, with the real-time imaging and cell sorting potential of the optical barcodes. In a proof-of-principle experiment, they were able to assess the technique’s utility in the investigation of Intratumoral heterogeneity and drug resistance.