09 November 2016
DanStem Seminar by Andrea Viale
Andrea Viale, The department of Genomic Medicine at the University of Texas MD, Anderson Cancer Center Title: Metabolic targeting of chemoresistance perturbs clonal complexity in pancreatic cancer
November 15, 2016, 14:00-15:00
CPR seminar room 6.02.09
Title: Metabolic targeting of chemoresistance perturbs clonal complexity in pancreatic cancer
A major barrier to achieving durable remission and definitive cure in oncology patients is the emergence of tumor resistance, a common outcome of different disease types independent from the therapeutic approach undertaken. Patients with pancreatic ductal adenocarcinoma (PDAC) continue to have a poor prognosis despite concerted efforts to advance new drugs to the clinic. One reason for this, in PDAC and other tumors, is that tumors are constantly adapting and evolving in response to external perturbations and, only recently, advances in cancer genetics have begun to shed light on the molecular mechanisms underlying this functional complexity. Indeed, tumors represent a complex, dynamic ecosystem wherein functionally distinct populations of cells coexist and progressively drift from a founder clone into branches of subpopulations with accumulating genetic and functional diversity. Understanding how tumors evolve in vivo in response to therapy and how treatment perturbs tumors at a clonal level is key to unveil mechanisms of resistance and to identify new vulnerabilities in order to prevent tumor relapse.
Recently we developed a new clonal tracking platform to study tumor evolution in response to treatments. Lentivirus-based systems have been extensively used as a tool to investigate clonal dynamics, but they have been limited by lack of sensitivity and the inability to track identical clones in different animals. Here, using a revised version of barcoding technology coupled with deep-sequencing, we track hundreds of thousands of clones at the single-cell level in vivo. We generated cohorts of patient-derived xenografts in which tumors are virtually identical and maintained by the same clones (clonal replica tumors), representing a unique tool to address fundamental questions about clonal dynamics in response to external perturbations, such as pharmacological treatment. More importantly, resistant tumor clones in vivo can be identified through bioinformatic analysis and subsequently isolated and deeply characterized to identify mechanisms of resistance. Using this novel approach we demonstrate that standard of care in pancreatic cancer, despite inducing tumor regression, has minimal effect on the clonal composition of tumors that eventually relapse. Transcriptomic and metabolic characterization of residual tumor cells in PDX models as well as in patients after chemoradiation shows that resistant cells that contribute to tumor relapse are metabolically rewired to upregulate mitochondrial respiration (OXPHOS). Combining a novel inhibitor of oxidative phosphorylation (IACS-10759) developed at the MD Anderson Institute for Applied Cancer Science with standard of care drugs drastically reduces tumor clonal complexity, underscoring the promise of inhibiting mitochondrial respiration as a new therapeutic strategy to prolong patient survival by eradicating resistant clones that survive chemoradiation.
In a more broad consideration of our technology, our clonal tracking-based platform represents an unprecedented tool for dissecting tumor functional heterogeneity as well as a useful means for exploring treatment responses at the single-cell-level. Such granular investigations into tumor functional heterogeneity and treatment response will help guide the development of new personalized treatments.