Context Matters-Why We Need to Change From a One Size Fits all Approach to Made-to-Measure Therapies for Individual Patients With Pancreatic Cancer

Abstract

Pancreatic cancer is one of the deadliest cancers and remains a major unsolved health problem. While pancreatic ductal adenocarcinoma (PDAC) is associated with driver mutations in only four major genes (KRAS, TP53, SMAD4, and CDKN2A), every tumor differs in its molecular landscape, histology, and prognosis. It is crucial to understand and consider these differences to be able to tailor treatment regimens specific to the vulnerabilities of the individual tumor to enhance patient outcome. This review focuses on the heterogeneity of pancreatic tumor cells and how in addition to genetic alterations, the subsequent dysregulation of multiple signaling cascades at various levels, epigenetic and metabolic factors contribute to the oncogenesis of PDAC and compensate for each other in driving cancer progression if one is tackled by a therapeutic approach. This implicates that besides the need for new combinatorial therapies for PDAC, a personalized approach for treating this highly complex cancer is required. A strategy that combines both a target-based and phenotypic approach to identify an effective treatment, like Reverse Clinical Engineering^® using patient-derived organoids, is discussed as a promising way forward in the field of personalized medicine to tackle this deadly disease.

Keywords: 3D cell culture models; KRAS; combined targeted and phenotypic approach; pancreatic ductal adenocarcinoma (PDAC); patient-derived tumor organoids; personalized medicine; reverse clinical engineering; tumor heterogeneity.

FIGURE 1

Different approaches to drug discovery. (A): A target-based approach aims to identify a hit to a known target using a biochemical screen. (B): A phenotypic-based approach identifies hits based on their effect in a cell-based assay, e.g., their ability to induce apoptosis or growth arrest, without necessarily knowing the compound’s biochemical target and its role in disease biology. (C): A combined targeted phenotypic approach leverages both, a target-based and phenotypic approach. The effect of compounds is tested in a cellular environment and hits selected based on their effect on the cells’ phenotype. A powerful model system here are patient-derived organoids that recapitulate the genetic and molecular alterations of a patient’s tumor, and which are for example used in the approach of Reversed Clinical Engineering^®. Then, using target deconvolution strategies like the integration of genomic, transcriptomic, and proteomic data, mechanisms (induced by the “hits”) conferring to drug sensitivity and/or resistance and suitable compounds for treatment can be identified for each individual patient tumor.

FIGURE 2

PDAC heterogeneity requires a personalized approach for treatment. PDAC is a highly heterogenous cancer at the cellular level, often driven by KRAS mutations but with multiple layers of dysregulation affecting each other, that also need to be considered. Alterations occur at various levels including genomic, transcriptomic, epigenomic and metabolomic aberrations. The resulting clinically and molecularly heterogenous tumor is unlikely to be successfully treated with a “one drug fits all” approach but requires a personalized approach specifically targeting its individual dysregulations.