Laboratory of Systems Pharmacology
Harvard Medical School
Wednesday 15th February
FW Jones Theatre, 3rd Floor, Medical Building, The University of Melbourne
Understanding effective combination cancer therapies: the impact of between-tumour and within-tumour heterogeneity
Combination cancer therapy is an important means to increase rates and durability of drug response, and combinations are commonly developed based on evidence of drug additivity or synergy in pre-clinical studies. However, I will show that the clinical efficacy of many combinations can be explained solely by their control of tumour heterogeneity without invoking additive or synergistic effects.
I will show that a majority of successful clinical trials of combinations can be accurately explained by a model of independent drug action, in which each individual patient benefits only from the drug to which his or her tumor is most sensitive with no contribution from the other drug. Thus many combinations are effective simply because of between-patient variability in response to single drugs. Undoubtedly some combinations are superior to independent action, most obviously curative regimens such as RCHOP which is effective in the treatment of diffuse large B-cell lymphoma. Isobologram analysis shows a lack of synergy in this combination. High-complexity DNA barcoding applied to one million subclones revealed that each single drug faces prolific pre-existing resistance but no subclone is cross-resistant to all drugs. Thus, the curative power of RCHOP derives from eradication of all within-tumour heterogeneity without meeting the conventional concept of synergy.
Together, these studies identify the management of between-tumour and within-tumour heterogeneity as key features of successful drug combinations, and provide novel and immediately actionable approaches to the development of combination therapies for cancer.
Adam Palmer is a CJ Martin Fellow with Prof. PK Sorger at Harvard Medical School’s Laboratory of Systems Pharmacology, where he applies experiments and computation to understand and to develop combination therapies in oncology. Previously Adam trained in biochemistry and physics at the University of Adelaide, and completed his Ph.D in Systems Biology at Harvard University with Prof. Roy Kishony, studying the evolution and mechanisms of antibiotic resistance.
Enquiries: Andrew Siebel (firstname.lastname@example.org)